C H APTE R

15
The ReninAngiotensin System
1

Thu H. Le , Steven D. Crowley , Susan B. Gurley and

1

Thomas M. Coffman

2,3

Division of Nephrology, Department of Medicine, University of Virginia, Charlottesville, VA, USA

2
Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical
Centers, Durham, North Carolina, USA
3

Cardiovascular and Metabolic Disorders Research Program, Duke-NUS, Singapore

receptors, are similarly
effective for treating these
1214
THE
dis-orders.
The purpose
Highly conserved through phylogeny, the reninof this chapter is to provide
COMPON
angiotensin system (RAS) is an essential an overview of the major
ENTS OF
regulator of blood pressure and fluid balance.physiological features of
THE
This biological system is a multi-enzymatic the RAS, focusing on its
cascade in which angiotensinogen, its majorrole in the kidney.
RENINAN
substrate, is processed in a two-step reaction by
GIOTENS
renin- and angiotensin-converting enzyme (ACE),
result-ing in the sequential generation of
IN
angiotensin I and angiotensin II. Along with its
SYSTEM
importance in maintaining normal circulatory
Renin
homeostasis, abnormal activation of the RAS can
contribute to the development of hyperten-sion
The aspartyl protease
and target organ damage.
renin was first isolated
The importance of the RAS in clinical
from the kidney by
medicine is highlighted by two sets of
Tigerstedt more than a
observations. First are associa-tions between
century ago. Renin is
polymorphisms of genes encoding RAS
synthesized as a precursor
16
components and cardiovascular disease.
protein,
pro-renin,
Second, and perhaps more compelling, is the
containing an additional 43
impressive efficacy of pharmacological agents
amino acids at the Nthat inhibit the synthesis or activity of angiotensin
terminus that block the
15
II. For example, angiotensin con-verting enzyme
enzymes active site.
(ACE) inhibitors are very effective and wellActive renin is generated
7
tolerated anti-hypertensive agents. Along with
by removal of this Ntheir ability to lower blood pressure, these agents
terminal peptide fragment,
also effectively prevent or ameliorate morbidity
presumably by proteases in
and mortality associated with cardiovascular
the juxtaglomerular cells of
the kidney. Whether intact
diseases. In this regard, large clinical trials have
pro-renin has a distinct
demonstrated that ACE inhibi-tors improve
physiological role remains
survival in patients with congestive heart
8,9
to be determined; however,
failure, and in patients with risk factors for
10
there is accumulat-ing
coronary artery disease. They also slow the
evidence
suggesting
progression of a vari-ety of kidney diseases,
11
specific
contributions
of
including diabetic nephropathy.
Angiotensin
the
pro-renin
molecule
in
receptor blockers (ARBs), which block AT1

1619

some normal and disease states.

secretion
are
tightly
Active renin specifically cleaves the 10 aminoregulated
at
the
acids from the N-terminus of angiotensinogen to juxtaglomerular apparatus
form angio-tensin I. A substantial excess of by
two
dis-tinct
angiotensinogen is pres-ent in serum, and ACE ismechanisms:
a
renal
20
ubiquitous in the endothelium and plasma. baroreceptor21,22
and
Accordingly, in the bloodstream, the amount of sodium chloride delivery to
renin is the rate-limiting step determining the the macula densa.2325
level of angiotensin II, and thus the activity of the Through these sensing
sys-tem. The primary source of renin in the mechanisms, levels of
circulation is the kidney, where its expression and renin in plasma can be

incrementally titrated in
response to changes in
blood pressure and salt
balance. These regulatory
principles provide a basis
for
many
of
the
physiological characteristics of the RAS, and
regulation of renin release
in the kid-ney will be
discussed in detail below.

Seldin and Giebischs The Kidney, Fifth Edition.

DOI: http://dx.doi.org/10.1016/B978-0-12-381462-3.00015-X

428

15. THE RENINANGIOTENSIN SYSTEM

32

Japanese men. PRR

In addition to its proteasemay also play a role in
activity, renin may also binddevelop-ment.
specifically to other proteinsDeletion of PRR in
19,2628
or putative receptors.
mice results in early
This binding may induceembry-onic lethality.33
physiologi-cally
significantIn a family with X27
intracellular signaling. It haslinked
mental
been suggested that theretardation
and
mannose-6-phosphate receptorepilepsy,
linkage
(M6P-R), also known asanalysis identified an
insulin-like growth factor IIexonic splice enhancer
receptor, binds renin and pro-in the PRR gene as the
renin, leading to internal-only mutation, and
26
ization and degradation. this resulted in the
Nguyen et al. reported clon-loss of the capacity of
ing a receptor from humanrenin to phosphorylate
34
kidney expression library thatERK1/2.
binds renin and pro-renin The
pro-renin
specifically and with highreceptor appears to
affinity, termed the (pro)reninhave other func-tions
receptor (PRR). Binding ofindependent of the
PRR causes a conformationalreninangiotensin
change of renin that leads tosystem. For example,
increased
renin
catalyticit is found as part of a
activity. Similarly, binding ofcomplex required for
PRR to pro-renin causes athe normal function of
confor-mational
change,V-ATPase in several
resulting in an ezymaticallycell
lineages,
active pro-renin without the
including
cardiac
requirement for cleavage of
35
myocytes. The prothe pro-segment. Furthermore,
renin receptor acts as
binding of renin to this
an adaptor between
receptor induces a rapid and
the Wnt receptor and
sustained
activation
of
V-ATPase in a Wnt/ERK1/ERK2,
without
catenin
signaling
affecting concentrations of
complex required for
27
calcium or cAMP. It has
normal
CNS
been suggested that it may
36
development. Thus,
mediate
angiotensin
IIdele-tion of the proindependent effects of renin,
and might also indicate arenin receptor gene
29
a
lethal
functional role of pro-renin. causes
phenotype
at
a
very
Although the physiological
early
embryonic
stage,
significance of PRR remains
con-trasts
unclear, recent studies suggestwhich
significantly
with the
PRR may have a role in blood
phenotype
of
renin
pressure
regulation.
37
knock-outs,
Transgenic rats overexpresindicating important
functions
of
the
sing human PRR selectively in
receptor
that
are
vascular smooth muscle cells
display
elevated
bloodindependent of its
30,31
pressure and heart rate.
actions in the RAS.
In addition, human PRR geneTwo groups have
polymorphism
has
beenrecently
described
shown to be associated withstudies of mouse lines
ambulatory blood pressure in
in which the pro-renin

receptor was deleted

specifi-cally
from
podocytes. In both
cases, there was a
similar,
dramatic
phenotype
characterized
by
disrup-tion of the
glomerular filtration
barrier, with marked
proteinuria
and
abnormal
podocyte
structure, perhaps

due
to
dysregulatedthereby eventually to
38,39
blood
autophagy.
Thus, whileincreased
pressure.
However,
this molecule appears to play a
critical role in the kidney,because amino acid
much remains to be learned 235 is in a nonabout its functions in nor-malconserved portion of
kidney
physiology
andthe angiotensinogen
disease, including the extent toprotein and variation
which these functions areof this amino acid
influenced by renin or pro-does not affect protein
renin binding.
stability, a mechanism
to
explain
the
physiological
consequences of the
Angiotensinogen
mutation was not
clear. An appar-ent
Angiotensinogen,
the
explanation
came
substrate for renin, is the
later,
when
the
source of all angiotensin
M235T variant was
peptides. Angiotensinogen in
found to be in linkage
the circulation is derived
disequilibrium
with
primarily from synthesis in the
another variant in the
liver. In humans, plasma 0
5 untranslated region
concentrations
of
41
of the AGT gene.
angiotensinogen are typically
This second variant, a
40
near the Km for renin, so
single
nucleotide
that changes in plasma
substitution in the
concentration may influence
promoter of the AGT
the rate of angiotensin I
gene, was associated
generation at any given level
with
increased
of
renin.
In
human
transcriptional activity
hypertensive
siblings,
41
of the gene. Higher
2
Jeunemaitre et al. showed
levels of AGT mRNA
that a specific variant of the
were found in patients
human angiotensinogen gene,
carrying the variant
M235T, was linked to
41
allele.
The causal
hyperten-sion, and was also
capac-ity
of
associated with a modestly
alterations in plasma
elevated
plasma
angiotensinogen level
angiotensinogen
to
affect
blood
concentration, about 120% of
pressure
was
normal. They proposed that
demonstrated
in
this variant of the AGT gene
studies
of
mice
leads to an increase in plasma
engineered to carry
angiotensinogen levels and

from 0 to 4 copies of
42
the AGT gene. In
these animals, there
was a positive correlation between
the
number of AGT gene
copies, plasma levels
of angiotensinogen,
and blood pressure.

In addition to its
synthesis by the liver,
angiotensi-nogen
is
also produced by
other tissues including
the brain, the immune
system,
and
the
43
kidney.
In
the
kidney, synthesis of
angiotensinogen
in
proximal tubules has
been
well44
documented,
and
proximal
tubule
synthesis may be
regulated in part by
the
end-product,
45
angiotensin
II.
Along
with
angiotensinogen, the
kidney expresses all
of
the
other
components of the
RAS. Accordingly, it
has been suggested
that regulation and
functioning
of
autonomous tissue
reninangiotensin
systems in the kidney,
as well as

I. EPITHELIAL
TRANSPORT AND
AND
REGULATION
NONEPITHELIAL

THE COMPONENTS OF THE RENINANGIOTENSIN SYSTEM

cardiovascular,
other organs, may contribute to the and
renal
physiological func-tions of the system, diseases.52,55
46
especially in disease states.
This In addition to
I,
hypothesis has been used to explainangiotensin
additional com-plexity of the system,other biologically
peptides
whereby the apparent activity of theactive
are
substrates
for
RAS is not reflected by measured
ACE.
Perhaps
the
plasma levels of it major components.
For example, in the broad popu-lationmost important of
is
of patients with hypertension, diabetes, these
and
car-diovascular
disease,bradykinin.56
pharmacological antagonists of theACE
degrades
RAS lower blood pressure and prevent bradykinin into
end-organ damage, even in the absence an
inactive
of overt elevation of plasma renin peptide,
levels. However, the precise nature andrepresenting
a
physiological contributions of thesesig-nificant
tissue systems has been difficult to biological
define experimentally.
pathway
for
bradykinin
metabolism
in
57
vivo ; in older
literature, ACE
Angiotensin Converting
was referred to as
Enzyme
kininase II. Since
has
Angiotensin converting enzymebradykinin
(ACE) is a carboxy-peptidase thatvasodilator and
generates the vasoactive peptidenatri-uretic
56
angiotensin II by cleaving two aminoproperties,
it
acids from the c-terminus of the has
been
47
inactive precursor angiotensin I. suggested
that
There are two distinct forms of ACE, one mechanism
somatic and testic-ular, both generatedof blood pressure
with
by alternative splicing of a single reduction
4850
gene.
Somatic ACE is expressed asACE inhibition is
an ectoenzyme on the surface ofblockade of this
endothelial cells throughout the body,kininase activity.
and is particularly abundant in lung,This was clearly
intestine, choroid plexus, placenta, anddemonstrated by
and
on brush border membranes in theBrown
kidney. A soluble form of ACE thatassociates, who
circulates in plasma is formed by showed that the
enzymatic cleavage of tissue-boundanti-hypertensive
51
ACE at its transmembrane domain. efficacy of ACE
is
As with other components of the RAS,inhibitors
attenuated
by
molecular variants of ACE have been
pro-posed as candidate genes insimultaneous
hypertension, cardiovascu-lar, andadminis-tration of
a
bradykinin
52
kidney diseases.
Insertion (I) and
receptor
deletion (D) polymorphisms of the
58
antagonist.
human ACE gene are common,
and have been associated with altered Using
53,54
levels of ACE in plasma.
In somegenome-based
cohorts, but not others, these
ACE gene variants have been linked to strategies,
differing suscephomologs of ACE
tibilities
to
hypertension,have
been

5961

identified.
One of these,
ACE2, exhibits

429

more than 40% identity at the proteinACE2 in renal

level with the catalytic domain ofdiseases, such as
59,60
ACE.
Similar to ACE, ACE2 is
diabetic and nonexpressed on the surface of certaindiabetic kidney
endothelial cell populations. However,disease,6770 and
compared to the ubiquitous distribution
67,71,
of ACE, the expression pattern ofhypertension
72
in
both
ACE2 is
experimental
more limited, with most abundant
expression in kid-ney followed by heartmodels and
59,60
and testis.
Their substrate
human cohorts.
specificities
also
differ;
ACE2 A
third
hydrolyzes angiotensin II with high member of the
efficiency, but has much lower activityACE gene family,
59,62
against angiotensin I.
Hydrolysis ofcollectrin,
was
angiotensin II by ACE2 generatesidentified as a
that
is
another peptide with putative biologicalgene
62upregulated in the
actions:
angiotensin
1-7.
Accumulating evi-dence indicates thatsub-total
this peptide causes vasodilation,nephrectomy
natriuresis, and may promote reducedmodel of chronic
73
63
blood pres-sures
via the Maskidney disease.
Collectrin
is
64
receptor. It has been further sug-highly
gested that ACE2 may be a major homologous
to
pathway for synthesis of angiotensin 1- the
65
7. Thus, the functions of ACE2 maytransmembrane
be determined by its distinct actions to portion of ACE2,
metabolize angiotensin II and tobut lacks the
generate angioten-sin 1-7.
carboxypeptidase
61
domain.
Its
Although the precise physiologicalphysiological
role of ACE2 is not clear, it wasfunctions
are
originally identified and cloned from a
74,75
emerging
and
cDNA library prepared from ventricular
59appear to regulate
tissue of a patient with heart failure. amino
acid
Initial studies in ACE2transport by the
deficient mice have suggested
a role for
364,365
ACE2 in cardiac function
and inkidney.
blood pressure regula66
tion. More recent work by many
groups has demon-strated roles for
I. EPITHELIAL
AND

Angiotensin
Receptors
The biological
actions
of
angiotensin II are
mediated by cell
surface receptors
that belong to the
large family of 7
transmembrane
7,76
receptors.
The
angiotensin
receptors can be
divided into two
pharmacological
classes, type 1
(AT1) and type 2
(AT2), based on
their
different
affinities
for
various
nonpeptide
antagonists
(Figure
15.1).
Studies
using
these antagonists
sug-gested
that
most
of
the
classically
recognized
functions of the
RAS
are
mediated by AT1
76
receptors. Gene
targeting studies
have confirmed
these
77
conclusions.
AT1 receptors
from a number of
species have been
7880
cloned
and
two
subtypes,
designated AT1A
and

NONEPITHELI TRANSPORT AND

AL
REGULATION

430

15. THE RENINANGIOTENSIN SYSTEM

This pathway may

contribute to chronic
92
kidney injury.
The murine AT1
receptors are products
of separate genes and
share
substantial
sequence 83,93,94
homology.
AT1A receptors
predominate in most
organs, except

the adrenal gland and

regions of the CNS,
where
AT1B
expression may be
more
93,95,96
prominent.
A
single
report has suggested
that AT1B receptors
FIGURE 15.1 Angiotensinogen is
might also exist in
cleaved by renin to form angio-tensin I,
97
which is then cleaved by angiotensin- man, but this has not
converting enzyme (ACE) to formbeen confirmed in the
angiontesin II, the major effector unpublished work of
independent
molecule of the RAS. The biological several
and
the
effects of angiotensin II are mediated by groups,
the
G-protein-coupled
seven-consensus view is that
transmembrane cell surface receptorsthere is no human
AT1 and AT2. Angiotensin II is counter-part
to the
hydrolyzed by angiotensin-convertingmurine AT
receptor.
1B
enzyme 2 (ACE2), a homologue of
Thus,
the
AT1A
ACE. This hydrolysis results in the
genera-tion of the angiotensin 17receptor is considered
closest murine
peptide, the actions of which arethe
mediated by the Mas receptor. After: Le,homolog to the single
TH and Coffman TM. Targeting human AT1 receptor.
genes in the renin-angiotensin
The
binding
system.
Current
Opinion
in
signatures of the AT1A
Nephrology and Hypertension 2008,
and AT1B recep-tors
17:57-63. Lippincott Williams &
are
virtually
Wilkins.
98
identical, and it was
difficult
to
discriminate their in vivo
functions
pharmacologically.
Experiments
using
gene
targeting
AT1B, have been identified inprovided insights have
into
8183
84
rat
and mouse. In thethe discrete functions
classical view, AT1 receptorsof the two AT1
signal through Gq-linked
signaling pathways involving
phospholipase C, IP3, and
increases
in
intracellular
85
calcium. However, the AT1
receptor has also been linked
86
to JAK/STAT activation, as
well as -arrestin-dependent
pathways linked to ERK
8789
activation.
In addition,
recent stud-ies have shown
that the AT1 receptor has the
capacity to transactivate the
EGF receptor, which may be
90,91
inde-pendent of ligand.

99,100

receptor genes.
Although the AT1B
receptor has a unique
role to mediate thirst
responses
in
the
101
CNS,

AT1A receptors have

the predominant role in
determin-ing the level
of blood pressure,102104
and in mediating

vasoconstrictor
99,102
responses.
The
phenotype
of
markedly
reduced
blood pressures and
profound
sodium sensitivity in
mice lacking the AT1A
102,105
recep-tor
underscores
its
importance in blood
pressure
control.
Pharmacological
and genetic studies
have confirmed that
virtually all of the
classically recognized
functions of the RAS
are mediated by AT1
receptors.
Until
recently, little was
known about the
physiological role of
AT2
receptors.
AT2
receptors are found in
abundance
during
fetal
106,107
development,
but their expression
generally
falls
after
birth.
However, persistent
AT2
receptor
expression can be
detected in several
adult tissues including
the kidney, adrenal
gland and the brain,
and absolute levels of
AT2
receptor
expression may be
modu-lated
by
angiotensin II and
certain 108
growth
factors.
AT2
receptors appear to
signal by coupling to
Gi2
and
Gi3
109
proteins.
Using
site-directed
mutagenesis, the intermediate portion of the
third intracellular loop
of the AT2
receptor was found to
be
necessary
for
normal
receptor
110,111
signaling.
Moreover, it has been
suggested that
activation of AT2
receptors stimulates
bradykinin, nitric

oxide, and guanosine

0 0
changes
cyclic 3 ,5 -monophosphatebehavioral
112,113
(cGMP),
and thesewere also
in
AT2pathways may mediate actions observed
deficient mice. They
decreased
of the receptor to promotehad
spontaneous
and
rearing
natriuresis and blood pres-suremovements
115,116
and
lowering. Finally, there is alsoactivity,
drinking
evidence to support HETEs asimpaired
to water
second messengers for AT2response 116
receptors in the kidney,deprivation.
leading
to
ERK1/2Transgenic mice that
114
overexpress the AT2
phosphorylation.
gene under
Targeted disruption of thereceptor
control of a cardiacmouse Agtr2 gene did notspecific
promoter
cause a dramatically abnormalhave
decreased
phenotype. These anisensitivity to AT1mals
clearly
manifestmediated pressor and
increased sensitivity to thechronotropic
pressor actions of angiotensinactions.117 Moreover,
115,116
II.
One of the AT2the pressor actions of
angiotensin II are
deficient
lines manifested increasedsignificantly
baseline blood pressure andattenuated in these
115
heart rate.
Interestingly,trans-genic mice. This

attenuation
was
completely reversed
following
pretreatment with a
specific AT2 receptor
antagonist.
Taken
together, these data
suggest that a primary function of the
AT2 receptor may be
to
negatively
modulate the actions
of the AT1 receptor.
Along similar lines,
the recently described
non-peptide agonist,
com-pound 21, has
been used to uncover
additional functions of
the AT2 receptor,
which appear quite
diverse. Studies with
this agonist regarding
blood pressure have
been

I. EPITHELIAL
TRANSPORT AND
AND
REGULATION
NONEPITHELIAL

THE COMPONENTS OF THE RENINANGIOTENSIN SYSTEM

the principal cell

variable, but it appears to have minimal of the collecting
effect on blood pressure in normal tubule epithelium
situations; the potential to affect blood
pressure in disease states may beinduces
transcription of
118
different.
the -subunit, the

multimeric
coupling of the
-, -, and Aldosterone
subunits of the
Aldosterone is a steroid hormoneEnaC, and the
synthesized in the zona glomerulosatranslocation of
(ZG) of the adrenal gland. The twothe
ENaC
dominant regulators of aldosteronecomplex to the
luminal surface of
synthesis and release are angiotensin IIthe tubule.125,126
119Aldosteroneand the level of serum potassium.
induced
The RAS-dependent component ofexpression of the
aldosterone regula-tion is triggered byENaC-subunit,
in
particular,
binding of angiotensin II to AT1follows a diurnal
119
pattern
receptors in the ZG.
Stimulation ofvaria-tion
that depends on
circadian
aldosterone release by angiotensin II the
contributes to enhanced sodium reab-transcrip-tion 127
sorption
and
anti-natriuresis.factor Period1.
Aldosterone
Independently of angioten-sin II,
stimulates
ENaC
hyperkalemia can control the release of
transcription
and
aldosterone through a process that
largely
involves the membrane depolari-zationactivity
through
the
120,121
of ZG cells.
In addition,
upregulation of
adrenocorticotropic hormone (ACTH)serum-and
can stimulate aldosterone via its Gglucocorticoid121
protein coupled receptor.
Elevationsregulated kinase 1
in ACTH influ-ence aldosterone(sgk1).128130 At
production only during short-termthe transcriptional
stress, as this response is attenuated level,
Sgk1
with persistent expo-sure to ACTH. In phosphorylates
contrast, angiotensin II and potassium ALL1-fused gene
can both exert a chronic, sustained
from
stimulation of aldoste-rone generation
chromosome
9
122
by the zona glomerulosa.
(Af9), which in
The classically recognized effects of turn blocks the
aldosterone to influence sodiumrepressor effects
handling in the distal nephron areof the histone H3
mediated by aldosterone binding to the Lys79
mineralocorti-coid receptor (MR). The
MR is a 107 kD protein that acts as amethyltransferase
of
transcription factor to regulate genedisruptor
expres-sion in target tissues. Thetelomeric
molecular mechanisms used by the MR silencing
to drive epithelial sodium channel
(ENaC) function in the collecting
123
tubule have been reviewed recently.
Cortisol actually exhibits a higher
affinity for the mineralocorticoid
receptor than aldosterone, but locally
expressed
11-hydroxysteroid
dehydroge-nase type 2 protects the
MR by converting cortisol to cortisone,
124
which does not activate the MR. The
bind-ing of aldosterone to the MR in

431

alternative splice
variant a (Dot1a)
on ENaC 131
gene
transcription.
At
the
posttranslational
level,
Sgk1
phosphorylates
Nedd4-2, causing
ENaC proteins to
remain in the
apical membrane
of the principal
132,133
cell.
Once
inserted into the
luminal
membrane of
the principal cell,
ENaC
permits
cellular uptake of
intraluminal
sodium,
generating
an
electronegative
potential in the
distal
tubular
lumen
which
favors secretion
of
potassium
from the principal
cell
into
the
urinary filtrate via
the renal outer
medullary potassium
channel
(ROMK). Sgk1
may
also
phosphorylate
ROMK, similarly
increasing
its
apical
density,
further
facilitating
the
kaliuresis induced
134
by aldosterone.
In
addition,
aldosterone
appears
to
directly increase
ROMK
135
expression.
Finally,
aldosterone
modulates
sodium transport
in
the
distal
nephron
independently
of
ENaC by enhancing expression and activity of
the
thiazide-sensitive Na-Cl co-transporter (NCC).
Sgk-1 mediates
this effect by
phosphorylating
serine/ threonine
kinase with-nolysine 4 (WNK4),

thereby diminishing the inhibitoryconnecting tubule

136
effects of WNK4 on NCC activity. may be able to
Through these pathways, the MR reg-compensate for a
ulates sodium and potassium transport lack of ENaC
within the mineralocorticoid-responsiveactivity in the
distal
nephron.
segments of the distal nephron.
Alternatively, the
in
Recent human phenotyping studiesdiscrepancy
phenotypes
and animal studies using gene-targeting
the
strategies
have
confirmed
thebetween
global
and
contribution of the MR to tubular
function and salt balance. For example,conditional
in humans with a mutation lead-ing to aknockout mice
constitutively active MR, early onset may be due to
137
functions
hyperten-sion develops,
whereasdiscrete
of aldosterone to
heterozygosity for an inactivatingmodulate solute
in the
mutation of the MR leads to salt-transport
proximal
141,142
wasting,
hypotension,
metabolictubule
138
acidosis, and hyperkalemia.
Miceand/or medullary
genetically deficient for the MRthick ascending
similarly develop severe salt-wastinglimb.143
139
that leads to neonatal death, whereasMutations
that
mice with genetic deletion of the MRactivate the ENaC
restricted to the principal cell waste salt may
cause
and lose body weight only when hypertension,1441
140
exposed to a low-sodium diet, 46 whereas global
suggesting that at baseline the lateinactivation of the
distal convoluted tubule and early
subunits of the

ENaC in mice
causes sodiumwasting,
potassium
retention,
and
early mortality,
and in humans
pseudohypoaldosteronis
m type 1 with
severe
salt147
wasting.
In
contrast,
inactivation of the
-ENaC
gene
only
in
the
collecting
duct
does not impair
sodium
and
potassium
148
balance,
again
indicating that the
regula-tion
by
aldosterone
of
ENaC in the latter
regions of

I. EPITHELIAL AL TRANSPORT
AND
AND
NONEPITHELI REGULATION

432

15. THE RENINANGIOTENSIN SYSTEM

pres-sure and changes

the distal convoluted tubulein
renal
sodium
and/or the connecting tubuleexcretion is wellmay also contribute to sodiumdocumented.160 For
149
and fluid homeostasis.
example, an elevation
in perfusion pressure
In
addition
to
itsin the renal artery
physiologic effects on renalresults in a rapid
solute handling, aldosteroneincrease in sodium
has the capacity to mediateand water excretion
direct cellular injury in theby the kidney, so150
pressure
kidney.
In this regard,called
160
natriuresis.
Based
pathologic
functions
of
on
such
observations,
aldosterone in non-tubular
and
corenal compartments becomeGuyton
workers
suggested
increasingly relevant. For
that whenever arte-rial
example, aldosterone impairspressure is elevated,
vascular
reactivity
byactivation of this
diminishing expression ofpressure-natriuresis
glucose-6-phosphate in themechanism will cause
151
endothelium
and mediatessufficient excretion of
direct vascular injury via asodium and water to
systemic
placental
growth
factor-return
152
pressures
to
nordependent pathway.
In
161
mal.
They
further
mesangial cells, aldosterone
activates sgk-1, NF-kB, andhypothesized that the
capacity
MAP kinases, leading tosubstantial
for
sodium
excretion
cellular
proliferation,
by
the
kidney
generation of oxidative stress,
provides
a
and connective tissue growthcompensatory system
153155
factor
expression.
of virtually infinite
Emerging evidence suggestgain
to
oppose
aldosterone may also promoteprocesses, including
oxidative stress and apoptosisincreases in peripheral
directly
withinvas-cular resistance,
156,157
podocytes.
Consistentwhich would tend to
blood
with these pathologic effectsincrease
pressure. It follows
of aldosterone in several cell
that defects in renal
lineages of the kidneyexcretory
func-tion
glomerulus, human studieswould therefore be a
have now demonstrated a rolepre-requisite
for
for aldo-sterone blockade insustaining a chronic
ameliorating the progressionincrease in intraof
proteinuric
kidneyarterial pressure.
158
disease.
The
RAS
has
potent
actions
to
modulate
pressurenatriuresis
relationships in the
Integrated Actions of kidney162,163
and
the RAS in the Kidney these
actions shape the
of
The important role of thecharacteristics
kidney in regulation of bloodRAS-dependent blood
pressure has been longpressure regulation in
159
physiology
recognized,
and
thenormal
and
in
disease
states.
relationship
between
For
example,
as
alterations in systemic blood
depicted in Figure

15.2, chronic infusion

of
angiotensin
II
causes a shift of the
pressure
natriuresis
curve to the right,
suggesting that when
the RAS is activated,
higher pressures are

required to excrete antrolled

by
renal
164perfusion pressure and
equivalent sodium load
the
luminal
(Figure 15.2). Conversely,by
delivery
of
sodium
administration of ACE inhibitors or ARBs shifts the curvechloride to the macula
to the left, meaning thatdensa in the distal
natriuresis is facilitated atnephron. The major
of
these
lower levels of blood pres-features
regulatory
processes
sure (Figure 15.2). The basic
features of endogenous controlare described in the
of the RAS are consistent with sections that follow.
these homeo-static functions.
As shown in Figure 15.2, the
system is activated at lowSources of
levels
of
salt
intake,Renin
stimulating renal sodium
reabsorption and conservation The major source
of body fluid volumes and of renin in the
blood pressure. In contrast,circulation is the
kidney.
Following
with high sodium intake, the bilateral nephrectomy,
system
is
suppressed,plasma levels of renin
facilitating natriuresis.
and angiotensin II fall
165
precipitously. In the
kidney, the location of
renin-expressing cells
varies
from
REGULATIO development through
N OF RENIN adulthood, and in
response
to
homeostatic
As discussed above, the
challenges.
During
concentration of renin inembryonic developplasma is the rate-limiting stepment,
reninin
the
production
ofexpressing cells are
angiotensin II. Accordingly,found in the undifferthe activity of the RAS in the entiated metanephric
circulation
is
largelymesenchyme.166
In
determined by the factors thatthe fetal kidney, these
regulate renin. The kidney iscells are present in the
intrarenal
the major source of renin,large
arteries,
glomeruli,
where its generation and
166
In
secretion are primarily con-and interstitium.

the adult kidney, renin

expression
is
primarily restricted to
granular cells which
are modified smooth
muscle cells within
the
juxtaglomerular
apparatus (JGA). The
JGA
is located in the region
where the afferent
arteriole enters the
167,168
glomerulus.
As
shown in Figure 15.3,
the JGA is a highly
organized
structure
composed of three
distinct
anatomical
parts: granular cells,
the mac-ula densa,
and
the
extraglomerular
169
mesangial
cells.
The macula densa is a
specialized
tubular
area that marks the
transition from the
ascending loop of
Henle to the distal
tubule lying in direct
contact
with
the
vascular pole of the
glomerulus
from
169
which it originated.
By light microscopy,
the unique characteristics of the macula
densa epithelial cells
can be dis-cerned by
their
narrow,
columnar shape and
apparent

I. EPITHELIAL
TRANSPORT AND
AND
REGULATION
NONEPITHELIAL
REGULATION OF RENIN

4
(foldnormal)

excretionorintake

3
2

1
NaCl

aldosterone (fold normal)

Renin, angiotensin and

1
0

1
2
3
NaCl intake (fold normal)

arteriole
Sympathetic
nerve
endings
Afferent

FIGURE

15.2

433
Chronic

infusion of angiotensin II
ACEI causes a shift of the pressure
or natriuresis curve to the right.
ARB Conversely, administration of
ACE inhibitors or ARBs shifts
the curve to the left. After:
Guyton, AC et al. In:
Hypertension,
Pathophysiology, Diagnosis
and Management. Laragh,
60
JH and Brenner, BM (Eds).
Raven
Press, (mmHg)
NY (Publ). pp
Mean blood
pressure
1311-1326, 1995.

ecretion of renin is carried

out at the JGA. There are
three major pathways reguGlomerus
Flating the secretion of renin
I by granular cells at the JGA:
the baroreceptor, the macula densa mechanism, and
direct stimula-tion by the
sympathetic
nervous
system.
The
renal
baroreceptor monitors renal
per-fusion pressure and
signals an increase in renin

Although
a JG cells are
c clearly the
c primary
u source
of
m
renin
in
the
u
l adult kidney,
studies
by
I.
EPITHELIA

when
renalthereby stimulating release of
perfusion
renin. Increased activity of renal
pressure falls.sympathetic
In the macula
densa
mechanism, nerves directly
stimulates
macula densavia activation
of
adrenergic
cells sense theSympathetic innervation also
decrease
inboth the baroreceptor and
chloride ionsmacula densa mechanisms.
in the filtrateAfter: Francois H and
in the distalCoffman TM. Prostanoids
tubule,

Gome differentiated,
z andbut can be
associ recruited
ates during periods
sugge of homeostatic
st thatpertubations
renin- such
as
expre dehydra-tion
ssing and
cells hypotension.
are For example,
not in
termi angiotensinonally gen-deficient
L
NONEPITHEL
AND IAL

mice, arteriole
renin and
is
intrarenal
expre arteries.170
ssed Similarly,
extensin
mice
ively subjected
along to a lowthe sodium
entire diet
length combined
of thewith
affere captopril
nt

TRA ORT AND

NSP REGULAT

ION

and blood
pressure:
which way
is up? J
Clin Invest.
2004;release
renin
114(6):757759.
American
Society for
Clinical
Investigatio
n.

treatment,
reninexpressing
cells can
be found
throughout
the length
of
the
afferent
arteriole, in
the
glomerular
and

434

15. THE RENINANGIOTENSIN SYSTEM

whether
this
extraglomerular messangium,alternative
pathway
and
in
the
glomerularfor RAS activation
170
capsule. Studies by Lalouelplays any major role
physiology
or
and associates suggest thatin
renin is also present in thedisease pathogenesis.
connecting tubule, at least in
the mouse kidney. Moreover,
their studies indicate that reninBaroreceptor
expression in the connectingRegulation of
tubule may be regulated byRenin Release
171
sodium intake. Although its
physiological role is unclear, it The baroreceptor
has been suggested that renintheory was developed
to
explain
expressed in the distal
observations that renin
nephron may contribute tosecretion is directly
regulation of angiotensinstimulated by reduced
peptide concentrations in therenal perfusion. This
tubular lumen.
theory
was
first
developed
in
the
Expression of renin outsidecontext
of
the kidney has also beenexperimental
documented.
Levi
andobservations
that
associates
have
recentlygranularity of the JG
shown that mast cells expresscells was inversely
renin mRNA and con-taincorrelated with the
large quantities of reninmagnitude of renal
protein, apparently within theperfusion pressure.175
172
secretory granules.
MastSince then, numerous
cell-derived
renin
canstudies have shown
efficiently
convertthat renin
angiotensinogen
tosecretion is inversely
to
renal
angiotensin I after mast cellrelated
172
degranulation.
Moreover,perfusion pres-sure or
release of renin by cardiac pulse
21,176179
mast cells can be triggered byamplitude.
ische-mia,
producingThis relationship is
preserved
in
pathophysiologic
denervated
consequences such as release
180,181
and in
of
norepinephrine
andkidneys
isolated
generation
of
cardiac
173
arrhythmias.
Takenperfused kidneys with
non-functioning
together, this work has sug-a
densa
gested that resident mast cellsmacula
182184
in the heart and perhaps othermechanism.
organs, upon appropriateThus, the baroreceptor
stimulation, are capa-ble ofis an inde-pendent
generating ample quantities ofmechanism
for
renin to activate the RAScontrolling
renin,
locally, and thereby affect
residing within the
organ function. Furthermore,
it
appears
the
factorskidney and clearly
from
controlling renin release fromseparate
mast cells will be quiteregulation by the
different from those thatsympathetic nervous
regulate JG cells, and aresystem.179
In
likely to involve signalsrenovascular
associated with inflammationhypertension,
the
174
and injury.
Nonetheless, itbaroreceptor is the
remains to be determinedprimary mecha-nism

for stimulating renin

release.
In
the
presence of a critical
stenosis of the renal
artery, renal perfusion
pressure
drops,
stimulating renin and
generating
185
hypertension.

While the independenthyperreninemia after

nature of the baroreceptorunilateral renal artery
mechanism and its localizationstenosis.195
This
to the kidney has been clearly
suggests
an
absolute
established, identification of
its precise nature has beenrequire-ment for PGI2
elusive. Various models havein triggering renin
been proposed to explain therelease after baroremechanism
for
pressureceptor activation. A
sensing and consequent signalnumber of questions
transduction, including direct
stretch of the JG cells due to remain concerning the
transmural pressure across themechanism and cell
22,186
afferent
arteriole
orlineages control-ling
of
key
indirect pathways involvingsynthesis
secondary
release
ofmediators such as
187
prostacyclin, and the
autocoids.
Some of these candidatecellular targets for
soluble factors include nitricthese
mediators
188190
oxide
andaffecting
renin
191,192
prostanoids,
which are
196
release.
stimulatory or endothelins, which are
193
inhibitory.
Gene- Over the past 40
much
targeting in the mouse hasyears,
been utilized to
deliberation has been
examine the role of some ofrendered regarding the
these mediators in theexistence and location
baroreceptor response. In oneof a baroreceptor for
study, genetic deletion ofrenin release. The
mechanism by which
endothelial
nitric
oxide
renal
perfusion
synthase (eNOS) had no effectpressure
regulates
on renin release in response torenin
secre-tion
change in renal perfusionremains
poorly
pressure,
suggesting thatunderstood. However,
eNOS-derived nitric oxide isthis
mecha-nism
to
be
not a mediator of theappears
dependent
on
barorecep-torrenin
194
coupling.
On the otherextracellular calcium
hand, the absence of the IP concentration. Kurtz
and
colleagues
receptor, the single known
demonstrated
that
receptor
for
PGI2when the extracellular
(prostacyclin),
conferredlevel of calcium is
substantial
resistance
tolowered,
the
hypertension
andinhibitory effect of
renal
perfusion

I. EPITHELIAL AND
NONEPITHELIAL
TRANSPORT AND
REGULATION

pressure on renin
release
is
197
abolished.
A
potential mediator in
this process may
involve
connexin
proteins that form gap
junctions between JG
cells and adjacent
endothelial
cells.
Disruption
of
connexin40 (Cx40) in
the mouse, either
through gene deletion
or point mutation,
results
in hyperreninemia and
hypertension, and loss
of pres-sure control of
198,366renin
release
368
; similar to the
effect observed with
the
lowering
of
extracellular cal-cium
197
concentration.
Other
connexin
proteins have been
demonstrated to also
play a role in renin
release. Connexin45,
another gap junction
protein, can replace
the
function
of
connexin40,
since
genetic substitution of
the coding region of
connexin40
by
connexin45 resulted in
the attenuation of
hypertension and near
normalization of the
pressure control of
200
renin
secre-tion.
Replacement
of
connexin43
by
connexin32 in

REGULATION OF RENIN

In addition to
the mouse resulted in decreased renin the well-studied
levels that did not change in responseNKCC2
to a high-salt diet and protec-tion from transporter,
the
hypertension induced by a 2-kidney- Na1/H1
201
1clip model. A consensus remains toexchanger
be established regarding whetherisoform
2
connexin proteins (and which one (s)),(NHE2)
are indeed the elusive baroreceptor, but expressed on the
the evi-dence suggests that connexinsapical surface of
play an essential role in the regulation the macula densa
of renin release in response to changealso plays a role
in perfusion pressure. Future studies are in renin release,
required to determine whether these perhaps through
connexins interact in coordi-nation withits effect on macother mediators mentioned above in theula densa cell
baroreceptor response.
volume. A recent
study by PetiPeterdi
and
Macula Densa Mechanism for Renin colleagues
Regulation
demonstrated that
The second major pathway forNHE2-deficient
have
physiological regula-tion of renin is the mice
so-called macula densa mechanism,significant
whereby cells at the macula densamechanisms
sense a reduction in chloride ions in the responsible
for
filtrate of the distal tubule, triggering increased renin
25
renin release. In this circumstance,levels which are
release of renin and the consequent macula-densa
generation of angiotensin II arespe-cific,208 since
believed to serve as a mechanism for
enhancing renal sodium reabsorption inthese mice have
states of fluid volume depletion. The been
anatomical association of the maculacharacterized to
normal
densa with the JG cells stimulated the have
first speculation by Goormaghtigh ofblood pressure.209
202
its physiological function.
As
mentioned above, the macula densa is Several
made up of specialized epithelial cellscandidate
at the terminal portion of the thick signaling
pathways linking
ascending limb. Their basolateraldistal
tubule
membrane is in contact with glomerularsolute
mesangial cells which, in turn, areconcentration to
contiguous with gran-ular cells in thecontrol of renin
24
JGA. The role of the macula densa in have
been
renin
regulation
was
initiallyproposed. These
169
hypothesized by Vander in 1967, andinclude
there is now general consensus that this adenosine, nitric
and
mechanism provides a control of reninoxide,
210
prostanoids.
secretion that is
The
most
directly determined by sodium chloridecompelling
203,204
delivery to the distal nephron.
current evi-dence
Moreover, several studies indicate
suggests that MD
that chloride flux through the Na-K-2Clstimulation
of
transporter (NKCC2) regulates therenin involves
signaling pathways linked to renin
205,206
secretion.
Increased chloride
delivery to the
MD inhibits, whereas reduced chloride
delivery
stimu-lates,
renin
23,197,207
release.

activation of
cyclo-oxygenase
211
(COX)-2
constitutively
expressed at high
levels in the
macula
densa,
generat-ing
the
prostanoid
212,213
PGE2.
PGE2
then
activates an
EP receptor on
granular cells in
the
JGA
to
stimulate
renin
214
release.
The
EP4 receptor is
likely the major
EP receptor that
mediates
the
actions of PGE2
in this process.
Facemire et al.
demonstrated that
EP4
recep-tordeficient
mice
display a B70%
reduction in renal
renin expression
and plasma renin
concentration
com-pared
to
wild-type
mice
after
treatment
with
furose215
mide.
In
contrast, deletion
of EP2 receptors
in the mice has no
effect on renin
stimulation
by
furosemide.
Interestingly, this
study
also
suggested that the
source of PGE2
in this pathway is
not dependent on
micro-somal PGE
synthases 1 and 2
(mPGES1,
mPGES2). The
capacity
for
prostaglandins to
directly stimulate
renin
secretion
has been long
216,217
recognized.
Moreover,

435

studies using specific inhibitors and

sodium chloride
COX-2 deficient
transport at the
mice have clearly demonstrated the macula densa is
importance of COX-2 in the macula
223
218,219
unaffected.
densa pathway.
In addition,
the activity of various components of
this system has been demonstrated in Macula densa
cells express high
the isolated perfused macula
220
221levels of neuronal
densa segments and JG cell lines. nitric
oxide
195
However, at least one study
hassynthase
224,225
failed to confirm a non-redun(nNOS).
dant role for individual EP receptors forThe role of NO in
PGE2 in furo-semide-stimulated reninregulation
of
release in vivo.
renin was first
Initial evidence suggesting a role for
tested
using
adenosine in MD signaling came from
nonselective
studies using the selective A1AR
inhibitors of nitric
antagonist
8-cyclopentyl-1,3oxide synthesis,
dipropylxanthine. The major effect of
which attenuated
the inhibitor was to attenuate the
renin
release
actions of increasing luminal NaCl
stimulated
by
concentrations
to
inhibit
renin
reduced
luminal
222
release.
Later studies using A1AR-sodium chloride
226
deficient mice confirmed that the role
concentrations.
of adenosine is primarily restricted to,227
The specific
the arm mediating inhibition of renin
roles
of
the
release. In A1AR-deficient mice, renininhibitory actions of enhanced sodium individual NOS
have
chloride delivery to the macula densaisoforms
examined
are blocked, whereas stimulation ofbeen
renin secretion caused by reducedusing mice with

targeted deletion
of
nNOS
or
eNOS. In these
studies, activation
of the macula
densa
pathway
was achieved by
administration of
NKCC2 blocking
loop diuretics in
vivo
and
in
isolated perfused
mouse kid-neys.
Deficiency
of
either nNOS or
eNOS alone did
not significantly
affect
macula
densa-dependent
228
renin secretion,
while nonspecific
NOS
blockade
attenu-ated renin
stimulation
by
loop
diuretics.
This suggests that
nitric oxide plays
a
permissive,
rather than a

I. EPITHELIAL AL TRANSPORT
AND
AND
NONEPITHELI REGULATION

436

15. THE RENINANGIOTENSIN SYSTEM

experiments
primary, role in the macula controlling for these
densa control of reninfactors, a clear rela228
tionship
between
release.
increasing
renal
sympathetic
nerve
activity and renin
secretion
is
Short Loop
237,238
maintained.
Feedback:
However, as discussed
Regulation of Renin
above,
renal
by Angiotensin II
denervation does not
abolish the capacity
of
181,239
Angiotensin
II
alsothe baroreceptor
contributes to the regulatoryor
densa
pathways for renin and maymacula
control its own synthesis
mechanisms
to
182184
by activating AT1 receptors,stimulate renin.
highly expressed at the JGA,Accordingly,
it
thereby suppressing renin
229,230
appears
likely
that
release.
Evidence
supporting the existence ofsympathetic tone has a
this
so-called
short-loopmodulatory,
rather
feedback mechanism includesthan primary, role in
studies in the isolated perfused
kidney, where infusion ofregula-tion of renin.
angiotensin II sup-pressesRecently,
a
179
renin
release. randomized controlled
Administration of ACE inhibi-clini-cal
trial
tors and angiotensin receptor
demonstrated
that
blockers
increases
renin
renal
sympathetic
mRNA expression and causes
231
denervation is more
JGA hypertrophy.
Similarly, mice lacking AT1Aeffective than medical
receptors also develop marked
103,230manage-ment alone in
JGA
hypertrophy.
2/2
patients with resistant
However, in Agtr1a
103
chimeric mice,
and inhypertension.240 The
kidney cross-transplantationoriginal report did not
232
experiments,
JGAmention
any
hypertrophy correlated with
measurement
of
renin,
blood pressure, but not with
the absence of AT1 receptorsbut it will be of
at the JGA, indicating asignificant interest to
significant
role
fordeter-mine the effect
baroreceptor mechanisms in
this response. Nonetheless, aof the procedure on
role for the short-loopplasma renin levels in
feedback mechanism to alterpatients who did or
the sensitiv-ity of baroreceptordid not have a
or MD mechanisms would be
consis-tent with current data. significant reduction
in blood pressure.

Role of Sympathetic
Nerve Activity

The capacity for sympathetic

nerve activation to stimulate
renin has been long recognized.
For example, -adrenoceptors
are abundant in the JGA of
kidneys 233 from
various
species.
Furthermore,
numerous
stud-ies
have
demonstrated that -adrenergic
agonists stim234

ulate renin release. Chronic

renal nerve activation also
235,236
stimulates renin,
along
with its affects to
modulate renal blood flow and
tubular
function.
In

Regulation of
Cellular Release
of Renin
At the JGA, renin
is
stored
in
cytoplasmic granules
within granular cells.
In
response
to
activating
stimuli,
renin is released into
the circulation by
exocytosis.
This
process
of
renin
secretion is carried out
by
fusion
events
between the secretory
granules and cell
membrane of afferent
241
arterioles.
Furthermore,
the
extent of secre-tory
activity or exocytosis
can be assessed using
electrophysiological
techniques
that
directly measure cell
membrane
capacitance of single
242
mouse JG cells.
The
control
mechanisms for renin,
described above, act
by triggering this
exocytotic pathway.
Compared to the
relative wealth of
available information
about physio-logical
regulation of renin,
much less is known
about the precise
intracellular pathways
involved in renin
secretion, and how
these mechanisms are
controlled
in
the
granular cell. The
general consensus is
that the environmental
signals
regulating
renin act through a
limited number of
intracellular
second
messengers, including
calcium and cyclic
214,243
AMP.
The cyclic AMP
pathway appears to be
the major trigger for
cellular release of

renin. In a variety of By
contrast,
in
experimental
models,increases
calcium
maneuvers
causing
anintracellular
levels may inhibit
elevation
renin release. For
of intracellular concentrationsexample, experimental
of cyclic AMP cause rapid maneuvers that reduce
stimulation
of
reninintracellular calcium
243,244
concentra-tion
secretion.
In this
stimulate
renin
regard,
most
of
therelease.243 Moreover,
documented secretagogues forseveral
med-iators
renin, including PGE2, PGI2,with putative actions
inhibit
renin
dopamine, and -adrenor-to
such
as
eceptor,
act
via
7release,
II, transmembrane
receptorsangiotensin
receptor
agonists,
linked to Gs-proteins thatvasopressin,
and
have
increase cyclic AMP levels inendothelins,
244
receptors that couple
JG cells.
The specific
Gq-pro-teins, and
biochemical pathways byto
activation of these
which cyclic AMP acts toreceptors by ligand
stimulate renin secretion are
intracellular
unclear, but likely involveincreases
calcium
protein kinase A, since inhi-concentrations in JG
bition of protein kinase Acells.214,243
The
attenuates the stimulatoryinhibitory effect of
effect of -adrenoreceptors oncalcium on renin
190
renin secretion.
release appears to be

I. EPITHELIAL AND
NONEPITHELIAL
TRANSPORT AND
REGULATION

mediated by protein
kinase
C,
since
stimulation of protein
kinase C inhibits renin
245247
secretion,
whereas blockade of
protein
kinase
C
attenuates
the
inhibitory effect on
245247
renin secretion.
There is also evidence
that the effects of
calcium on renin
release are mediated
in
part
by
a
calmodulindependent
process,
since inhibition of
calmodulin activ-ity
stimulates
renin
248,249
secretion.
Antagonistic interactions between the
cyclic AMP and
intracellular

REGULATION OF RENIN

process.
For
calcium may ultimately determine the example, in cell
final conse-quences of extracellularsystems, cAMP
243,250
signals on renin release.
has only a modest
effect in inducing
renin
gene
Regulation of Renin Gene
transcription of
Expression
the renin gene,
but nonetheless it
The steady-state activity of the RAS
causes
marked
is generally reflected by renin mRNA
induction of renin
levels in the kidney. During chronic
262
stimulation of the RAS, for example, mRNA levels.
upregulation of renin gene expressionThis
is required to sustain over time theaugmentation is
enhanced release of renin protein by theassociated with
JGA. Understanding of tissue-specificenhanced stability
renin
control of renin gene expression hasof
263
mRNA.
cAMP
been complicated by the dif-ficulty of
increases
developing tractable cell culturealso
levels
of
RNApreparations derived from JG cells.
binding
proteins
Thus, transgenic mice have been
the
used extensively to assess in vivotargeting
regulation
of
renin
gene30UTR of the
251,252
expression.
Using this approach,human
renin
minimal
264
gene,
segments of the human renin gene
sufficient to recapitsuggesting
a
poten-tial
ulate temporal- and cell-specific
patterns of gene expression have beenmechanism for its
251,252
identified.
effects to promote
There
is
strong
sequencerenin
mRNA
0
conservation of 5 proximal promoterstability.
regions between the renin genes of the
253
human, rat, and mouse.
This region
contains a cyclic AMP (cAMP)
254256
response element (CRE),
which isControl of
required for cAMP stimulation of Renal
254,257
transcription.
In addition, thereHemodynami
are at least seven transcription factor-cs by the
binding sites within the proximalRAS
promoter, including a binding site for
HOX proteins that play critical roles in Angiotensin II,
specifying positional information alongacting via its AT1
receptor, is a
embryonic
potent
253
axes.
The renin promoter isvasoconstrictor.
254,257,258Stimulation
of
relatively weak in isola-tion,
but is strengthened up to 80-fold
by
a
AT
receptors
in
1
259,260
distal enhancer element.
Thisvascular smooth
enhancer contains at least
muscle
cells
eleven transcription factor-binding sitesinitiates
a
responsive to a variety of signal signaling
261
transduction pathways.
Inhibitory
factors,
including
endothelin-1,
angiotensin II, mechani-cal stretch, and
inflammatory cytokines, may act
through target sequences within the
261
enhancer.
Post-transcriptional
mechanisms
also play a key role in determining
steady-state renin mRNA levels. cAMP
appears to be a critical mediator in this

cascade including
increased
intracellular
calcium
concentration
and
alterations
in
cytoskeleton,
inducing
contraction with
consequent
increases
in
vascular
265
resistance.
Studies in mice
deficient in both
the
AT1A and AT1B
receptor isoforms
have confirmed
the importance of
AT1 receptors in
this
102,100
response.
The
pressor response
to
acute
angiotensin
II
infusion
is
completely
abolished in these
double-knockout
100
animals ;
whereas response
to another pressor
agent,
epinephrine,
is
not
affected.
These
vasoconstrictor
actions
of
angiotensin
II
play a central role
in main-taining
circulatory
homeostasis in a
number
of
tissues, including
the kidney. In the
kidney,
the
hemodynamic
actions
of
angiotensin
II
impact
renal
blood flow, glomerular filtration
rate, excretion of
salt and water,
and progression
of renal damage
in disease states.
Glomerular

437

Microcirculation

exclusively
by
AT1A
The coordinated regulation of
275
receptors.
resistances in the afferent and efferent The
overall
arterioles plays a critical role ineffect
of
determining and maintaining theangiotensin II on
glomerular filtration rate (GFR). The glomerular
RAS has potent effects on glomerularhemodyamics is a
hemodynamics. Angiotensin II causespredominant
constriction of both the afferent andincrease in postefferent arterioles. However, the effectglo-merular
of high levels of angiotensin II is to resistance,
induce a more profound constriction ofresulting in an
increase
in
266268
the efferent arteriole.
The reasons
glomeru-lar
for this disproportionate effect ofhydrostatic
angiotensin II on the efferent arteriolepressure. These
are not clear, but may includeactions serve to
differences in levels of AT1 receptorprotect GFR in
269
expression,
modulating actions ofstates
of
vasodilaintravascular
volume depletion.
tors such as prostaglandins and nitric
270,271Because
oxide on pre-glomerular vessels
angiotensin
II
or differences in calcium
also
responses to angiotensin II in the
272274simultaneously
afferent versus efferent arterioles.
reduces
renal
In mice, the AT1A and AT1B
blood
flow,
there
receptor isoforms have distinct actions
be
a
in the glomerular circulation. Bothwill
AT1A and AT1B receptors contribute tocoincident
the afferent arteriolar response toincrease
in
angio-tensin II, whereas the efferent
arteriolar
response
is
mediatedfiltration fraction,

and a decrease in
peritubular capil276
lary pressure
promoting
an
increase
in
sodium
reabsorption in the
proximal
277,278
tubule.
The
importance
of angiotensin II
in
maintaining
GFR when renal
perfu-sion
is
threatened
is
illustrated by the
effect of ACE
inhibitors
in
patients
with
critical bilateral
renal
artery
stenosis or critical
stenosis in the
renal artery of a
single functioning
kidney.
When
blood pressures in
such patients are
reduced
to
equivalent levels
with

I. EPITHELIAL AL TRANSPORT
AND
AND
NONEPITHELI REGULATION

438

15. THE RENINANGIOTENSIN SYSTEM

These
observations
a non-specific vasodilator,formed the basis of
such
as
nitroprusside,the rationale for using
compared to an ACE inhibitor,ACE inhibi-tors or
the ACE inhibitor
angiotensin receptor
blockers in chronic
causes a much more
kidney
diseases.
marked deterioration in
Reduction
of
279,280
GFR.
glomerular
The
glomerular
hemodynamic preshemodynamic responses tosure may be a key
angio-tensin II may bemechanism explaining
modified significantly bythe renoproother circu-lating factors. Fortective effects of these
example, the vasoconstrictoragents in diseases
such
as
diabetic
actions of angiotensin II may
11,13,14
nephropathy.
be substantially augmented in
the presence of elevatedRenal Medullary
281285
adenosine levels.
ThisCirculation
can occur in pathologic states Along with its
on
the
including
malignanteffects
glomerular circulation
hypertension, renal arteryangiotensin II, acting
stenosis, and in some exper-through AT1 receptors,
important
imental models of renalhas
286288
ischemia.
When bothregulatory functions in
the renal circulation in
angiotensin II and adenosinegeneral. In the mouse,
are present at high con-regulation of renal
flow
by
centrations, there is a dramaticblood
angiotensin
II
is
increase in preglomeru-larprimarily mediated by
296
resistance that does not occur AT1A
receptors.
Moreover,
effects
of
with either agent alone. Other
AT
receptors
to
mediators,
such
as 1
modulate blood flow
289
prostanoids
and
nitricin
the
medulla
oxide, may also modulate thesignificantly impact
actions of angioten-sin II inthe kidneys excretory
capacity
for
the
glomerularsodium.297 In this
microcirculation, particularlyregard, it has been
that
in disease states such as suggested
regulation
of
290
diabetes.
In angiotensin II-medullary blood flow
induced hypertension, forby angiotensin II
example, nitric oxide attenu-represents a
ates
afferent
arteriolarcritical pathway for
modulating
the
291
constriction.
pressure-natriure-sis
discussed
In
kidney
disease,response
in
the
abnormal activation of theearlier 161,276
RAS and coincident increaseschapter.
Thus, regulation of
in glomerular hydrostatic
pressure have been suggestedmedullary blood flow
to contribute to progres-siveby the RAS is likely
292,293
renal
injury.
Forto be a key pathway
example, in the remnant
used by the kidney to
kidney model of chronicmaintain
blood
kidney disease, post-glomeru-pressure homeostasis.
lar resistances are increased, The mechanisms
and this is associated withcontrolling medullary
increased
glomerularblood flow in the
294,295kidney are complex.
hydrostatic
pressures.
This abnormal glomerularAs in the glomerulus,
hemodynamic
pattern
is
reversed with RAS blockade.

vasodilator effects of
mediators such as
nitric
oxide
and
prostanoids act to
counterbalance
the
actions of angiotensin
II. For example, a
subpressor dose of
angiotensin II, which
by itself has a
negligible effect on
the
medullary
circulation,
significantly reduces
medul-lary blood flow
when combined with
the NO inhibitor L298
NAME.
Cortical
blood
flow
is
unaffected in this
circumstance. Nitric
oxide also protects
medullary blood flow
during
chronic
infusion
of
299
angiotensin II.
In
the outer medulla,
angiotensin
II
stimulates NO production by tubular
epithelium, potentially
as a com-pensatory
mechanism, and this
may be an example of
tubulo-vascular
cross-talk, whereby
the
effects
of
angiotensin II on
tubular
epithelium
may
modify
its
vasoconstrictor
300
actions.
Similarly,
renal prostaglan-dins
also
appear
to
modulate
pressure
natriuresis by altering
renal
medullary
301
hemodynamics.
These hemodynamic
changes from the
inhibition of prostaglandin
production
lead to increased
chloride reab-sorption
in the loop of Henle
and
collecting
302,303
duct.
Alterations in the
balance of angiotensin
II and NO in the
medulla may have

significant consequences on Along with its

systemic
blood
pressurehemodynamic actions,
angiotensin II may
regulation. For example,
angiotensin II-stimulated NOmodulate fluid and
excretion
production is impaired insolute
Dahl-sensitive hypertensivethrough two distinct
263,304,305
pathways: (1) an
rats,
and attenpathway
uated generation of NO inindirect
kidneys of these animals isinvolving stimulation
associated
with
reducedof aldosterone release
306,307 from
the
adrenal
medullary blood flow.
gland;
and
(2)
through
Furthermore, delivery of LNAME directly into the renaldirect effects of AT1
medulla of Dahl salt-sensitivereceptors expressed by
rats reverses the hypertensiverenal epithelia.162
305
actions of angiotensin II, as In the adrenal
does intra-venous infusion of
cortex, activation of
308
L-arginine.
AT1
receptors
stimulates the release
119
of
aldosterone
RENAL
which
in
turn
EPITHELIAL
promotes
sodium
ACTIONS
reabsorption
by
OF
binding to mineraloTHE corticoid receptors in
RAS
the mineralocorticoidresponsive segments

of
the
distal
125
nephron.
The
biology
of
the
aldosterone system is
described elsewhere,
and histori-cally was
thought to be the
major effector system
used by the RAS to
control renal sodium
123
handling.
Direct
actions of angiotensin
II in the kidney were
defined later using
isolated
perfused
309314
tubules
and
micropunc-ture
315318
studies.
Using
these
approaches,
renal
epithe-lial
responses
to
angiotensin II were
documented in several
nephron
segments.
However, it has been

I. EPITHELIAL
TRANSPORT AND
AND
REGULATION
NONEPITHELIAL

RENAL EPITHELIAL ACTIONS OF THE RAS

although
difficult, in the intact animal, toangiotensin II is
separate the effects of AT1 receptors inthought to regurenal epithelium from other renal andlate renal water
systemic effects of angiotenson II, and handling
to determine their contribution toprimarily through
integrated control of blood pressure. actions in the
Nonetheless, recent studies using renal
cross-transplantation and regionalcollecting tubule
genetic deletion clearly indicate(discussed
significant,
non-redundantbelow), data are
emerging
to
contributions of AT1
suggest
that
AT
1
receptors within the kidney to
determining the level of bloodreceptor
232,319
pressure.
Activation of AT1activation
also
receptors in the
modulates
nephron can have physiologic orproximal tubular
pathophysiologic effects depending onexpression of the
the clinical context. For example, aqua-porin
1
stimulation of AT1 receptors in thechannel,
proximal tubules helps to preventheretofore
circulatory collapse at baseline by pro- considered to be
319
moting sodium retention,
whereasconstitu-tively
324
the accumulated stimulation of AT1expressed.
receptors on tubular cells that occurs The capacity
over the span of a normal lifetimefor
proximal
downregulates
pro-survival
genestubular actions of
RAS
to
including sirtuin 3, such that AT1the
influence
blood
receptor deficiency is associated with
pressure was first
320
enhanced longevity in mice.
In thedemonstrated in
next section, we will provide an elegant
overview of tubular actions of the RAS. experiments by
Sigmund
and
325
associates.
In
these
studies,
Tubular Effects of Angiotensin isolated
coII
expression
of
human renin and
Proximal Tubule
angiotensinogen
Direct actions of angiotensin II inin the proximal
tubule
caused
the proximal tubule are perhaps the best
hypertension
characterized. These actions were firstwithout
any
321323
implied in whole animal studies,
detectable
and then were specifically definedincrease in circuusing in vitro perfused proximallating angiotensin
II levels. In more
313
tubules
and
micro-puncturerecent work from
317
studies. Taken together, these studies this
group,
sug-gest that angiotensin II, actingoverexpression of
through AT1 receptors on thethe type AT1
basolateral surface of proximal tubules,receptor in the
proximal tubule
pro-motes sodium reabsorption byraised
baseline
coordinately stimulat-ing the sodium-blood
pressure
326
proton anti-porter on the luminal
levels.
membrane along with the sodium-Inversely, Gurley
colleagues
potassium-ATPase
on the basolateraland
310,313,317
surface.
These actions result showed that
in enhanced basolateral sodium
310
bicarbonate flux.
In addition,

deletion of AT1
receptors
selectively from
the
proximal
tubular
epithelium using
a
Cre/loxp
approach reduces
the baseline level
of blood pressure
by
diminishing
fluid reabsorption
from the proximal
tubule, and protects
from
angiotensin
IIinduced
hypertension by
miti-gating
sodium
319
reabsorption.
These studies also
illustrated
that
angiotensin
II
regulates
the
abundance of key
apical membrane
sodium
transporters, as
AT1
receptor
deletion in the
proximal tubule
allowed
the
downregulation
of the NHE3
exchanger and the
NaPi2
cotransporter,
thereby
facilitating
hypertensioninduced
319
natriuresis.
Complementary
studies in a rat
model
demonstrated that
angotensin
II
directs
these
transporters
to
redistribute
within
the
luminal
membrane microvilli
of the proximal
tubular cell to
promote sodium
and
water

439

327

tubule appears to
be
neutral.
AT1 receptors are also present on theCoordinating
luminal brush border of the proximal with
its
328330
tubular epithelium.
Moreover,stimulation of the
angiotensin II is secreted into, andapical mem-brane
endocy-tosed from, the proximalsodium-proton
tubular lumen where its levels may not exchanger,
correlate with plasma angiotensin II angiotensin
II
331333
levels.
It has been suggested thatenhances
the
control of angiotensin II gener-ation inactivity of the
this luminal compartment mightsodiumprovide separate regulation of epithelialbicarbonate cofunction that is independent of thetransporter on the
334
systemic RAS. Moreover, activationbasolateral
of AT1 receptors on the luminalsurface of the
early prox-imal
membrane of the proximal tubular cell
310,313
tubule.
As
can
such, angiotensin
promote sodium reabsorption, in partII acts as a
through
a
Gi-pro-tein-mediatedpotent stimulus
313,317,333for proximal
reduction in cyclic AMP.
acidification,
There is
some evidence for an independent coupled to
of
regulation of luminal concentrations ofreclamation
angiotensin II. For example, althoughbicarbonate from
the
early
both whole kidney and proximalproximal
tubular angiotensin II levels are tubule.310,337,338
elevated in response to reduced renal Nevertheless, the
335
perfu-sion,
angiotensin II levels inresulting
reduction
proximal tubular fluid are
not suppressed with acute volumein delivery of
expansion, and may even increase inbicarbonate to the
335,336
this setting.
late
proximal
The net effect of angiotensin II ontubule leads to
bicarbonate han-dling in the proximal less bicarbonate
reabsorption.

I. EPITHELIAL

reabsorption
in
that
segment.
Moreover,
at
higher
concentrations,
angiotensin
II
par-adoxically
inhibits sodiumbicarbonate
transporter
339
activity,
such
that overall the
bicarbonate
concentra-tion in
the urinary filtrate
reaching
the
distal convo-luted
tubule is not
altered
by
angiotensin
II
340
stimulation.
Thus,
the
contribution
of
the
RAS
to
acidbase
regulation
is
primarily
mediated
by
aldoste-rone
in
the
distal
341345
nephron.

AND
TRANSPORT AND
NONEPITHELI REGULATION
AL

440

15. THE RENINANGIOTENSIN SYSTEM

effects in modulating
ion flux along the
Compared to the proximaldistal nephron. As in
nephron
tubule, the functions ofother
angiotensin II in the medullarysegments, all the
thick ascending limb (MTAL) elements of the RAS
are not as well-characterized.
are present along the
AT1 receptors
distal nephron, and
are expressed on both the
high
luminal
and
basolateralrelatively
membranes of the MTALconcen346,347
epithelium.
In vitro
trations of angiotensin
studies addressing the role ofII can be detected in
angiotensin II in MTAL ionthe tubular fluid of
transport suggest that cellularthese
171,330,332
segments.
responses may differ, depending on the localAngiotensin II, acting
concentrations of angioten-sinvia AT1 receptors,
348,349
II.
At
lowerstimulates
concentrations of angiotensinsodiumhydrogen
II,
exchange
in
the
inhibition of the sodium-cortical and outer
potassium-chloride co-transporter348,349
(NKCC2) may bemedullary collecting
seen,
whereas stimula- tubule by increasing
tion of NKCC2 can be seen at the density of the
348
higher concentrations.
Invacuolar
sodiumvivo
microperfusionhydrogen-ATPase in
experiments have also demon-the apical membrane
strated
physiologicalof
consequences of angiotensin IIthe type A intercalated
in the MTAL, includingcell, which in turn
leads to an increase in
increased
bicarbonatebicarbonate
transport out of the urinaryreabsorption.315,316,352
350
filtrate.
This heightened,353
the
apical
bicarbon-ate flux is likely dueOn
membrane
of
the
to
an
increase
in
principal
cells
in
the
sodiumhydro-gen exchange,
collecting
as has been observed in thecortical
duct
(CCD),
luminal
proximal tubule, suggesting
angiotensin
II
that angiotensin II increases
stimulates
amiloridesodium reabsorption from the
sensitive
sodium
MTAL. These data are
transport
by
consistent with the findingincreasing activity of
that in vivo administration ofthe epithelial sodium
angio-tensin II leads tochannel
(ENaC)
heightened expression of both
through
an
AT1
the
receptor-dependent
312,318
NHE3
sodium-hydrogenmecha-nism.
exchanger and NKCC2 in theFurthermore,
351
MTAL.
activation of AT1
receptors
on
the
basolateral
membrane
Distal Nephron
of
CCD
cells
SOLUTE TRANSPORT
stimulates the activity
Although angiotensin IIof potassium channels
indirectly influences distal andvia a nitric oxidecollecting tubular functiondependent pathway.354
through the generation ofAs the distal nephron
aldosterone,
more
recentulti-mately determines
studies have demonstrated thaturine
flow
and
angiotensin II also has directcomposition, actions
Loop of Henle

of angiotensin II to modulate and -2.359 In the

sodium handling at this site medullary collecting
may impact blood pressure
164,312
duct, angiotensin II
homeostasis.
upregulates
gene
expression for the V2
WATER HANDLING
vasopressin receptor,
Recent studies suggest aand the expression
role for the RAS in the con- and apical membrane
trol of urinary concentrating
of
the
mechanisms and free watertar-geting
aquaporin-2
handling. For example, the
complete
absence
ofchannel.360363 These
angiotensinogen, ACE oreffects are mediated
AT1A/AT1B receptors in mice through a protein
is associated with atrophy of kinase A-dependent
the renal papilla and a marked
360
Thus,
urinary
concentratingpathway.
230,355,356
direct
effects
of
defect.
Mice
lacking AT1A receptors areangiotensin II on
also unable to generateexpression of water
maximally concentrated urine, channels and perhaps
despite having appar-entlyvasopressin receptors
357
normal renal papillae. may contribute to its
These
animals
generateactions on renal water
vasopressin
normally
inhandling.
response to water restriction,
357
but are resistant to dDAVP.
Administration of an AT1References
receptor-antagonist to wild-[1] Tiret L, Bonnardeaux
type mice, and even selective
A, Poirier O, Ricard S,
deletion of AT1 receptors from
Marques-Vidal
P,
Evans A, et al.
the collecting duct using a
Synergistic effects of
Cre/loxp
approach,
angiotensin converting
recapitulates this uri-nary
enzyme
and
357,358
concentrating
defect.
angiotensin II type I
receptor
Similarly,
AT1
receptor
polymorphisms on risk
blockade also blunts the
of
myocardial
maximal urine concentrating
infarction.
Lancet
1994;344:9103.
capacity
in
DDAVPX,
challenged rats, and this effect[2] Jeunemaitre
Soubrier F, Kotelevtsev
is associated with reduced
YV,
Lifton
RP,
expression of aquaporins-1
Williams CS, Charru

basis
of
human
hypertension: role of
angiotensinogen. Cell
1992;71(1):16980.
[3] Bonnardeaux A, Davies
E, Jeunemaitre X, Fe
ry I, Charru A, Clauser
E, et al. Angiotensin II
type 1 receptor gene
polymorph-isms
in
human
essential
hypertension.
Hypertension
1994;24:639.

[4] Benetos

A, Gautier S,
Ricard S, Topouchian
J, Asmar R, Poirier O,
et al. Angiotensinconverting
enzyme
inhibitors: influence of
angiotensin-converting
enzyme
and
angiotensin II type 1
receptor
gene
polymorphisms
on
aortic
stiffness
in
normotensive
and
hypertensive patients.
Circulation
1996;94:698703.

[5] Wang

J, Staessen J.
Genetic
polymorphisms
in
the
reninangiotensin
system: relevance for
susceptibility to cardiovascular disease. Eur J
Pharmacol
2000;410:289302.

[6] Yoshida

H, Kon V,
Ichikawa
I.
Polymorphisms of the
reninangiotensin
system
genes
in
progressive
renal
diseases. Kidney Int
1996;50:73244.

A, et al. Molecular
I. EPITHELIAL
TRANSPORT AND
AND
REGULATION
NONEPITHELIAL

REFERENCES

[18]
[7] Husain A, Drugs Graham R. Enzymes and
Receptors of the Renin-Angiotensin
System: Celebrating a Century of
Discovery. Sidney: Harwood Academic;
2000.
[8] Investigators TS. Effect of enalapril on
survival in patients with reduced left
ventricular
ejection
fractions
and
congestive heart failure. The SOLVD
Investigators.
N
Engl
J
Med
1991;325:293302.

[9] Investigators

Veniant M,
Menard
J,
Bruneval
P,
Morley
S,
Gonzales MF,
Mullins
J.
Vascular
damage without
hypertension in
transgenic rats
expressing prorenin
exclusively in
the liver. J Clin
Invest
1996;98(9):1966
70.

TS. Effect of enalapril on

mortality and the devel-opment of heart
failure in asymptomatic patients with
reduced left ventricular ejection fractions.
The SOLVD Investigators. N Engl J Med
[19] Peters J,
1992;327:7257.
Farrenkopf R,
[10] Yusuf S, Sleight P, Pogue J, Bosch J,
Clausmeyer S,
Davies R, Dagenais G. Effects of an
Zimmer
J,
angiotensin-converting-enzyme inhibitor,
Kantachuvesiri
ramipril, on cardiovascular events in highS, Sharp MG, et
risk patients. The Heart Outcomes
al. Functional
Prevention Evaluation Study Investigators.
significance of
N Engl J Med 2000;342(3):14553.
pro-renin
[11] Lewis EJ, Hunsicker LG, Bain RP,
internal-ization
Rohde RD. The effect of angiotensinin the rat heart.
converting-enzyme inhibition on diabetic
Circ
Res
nephrop-athy. The Collaborative Study
2002;90(10):113
Group. N Engl J Med 1993;329
541.
(20):145662.
Peach MJ.
[12] Dahlof B, Devereux RB, Kjeldsen SE,[20]
Reninangiotensi
Julius S, Beevers G, de Faire U, et al.
n
system:
Cardiovascular morbidity and mortality in
Biochemistry
the Losartan Intervention For Endpoint
and mechanisms
reduction in hypertension study (LIFE): a
of
action.
randomised trial against atenolol. Lancet
Physiol
Rev
2002;359(9311):9951003.
1977;57(2):3137
0.
[13] Lewis EJ, Hunsicker LG, Clarke WR,
Bock HA,
Berl T, Pohl MA, Lewis JB, et al. [21]
Hermle
M,
Renoprotective effect of the angiotensinBrunner
FP,
receptor antagonist irbesartan in patients
Thiel
G.
with nephropathy due to type 2 diabetes. N
Pressure
Engl J Med 2001;345(12):85160.
dependent
[14] Brenner BM, Cooper ME, de Zeeuw
modulation of
D, Keane WF, Mitch WE, Parving HH, et
renin release in
al. Effects of losartan on renal and
isolated
cardiovascu-lar outcomes in patients with
perfused
type 2 diabetes and nephropathy. N Engl J
glomeruli.
Med 2001;345(12):8619.
Kidney
Int
[15] Danser AH, Deinum J. Renin, pro1992;41(2):2758
renin and the putative (pro) renin receptor.
0.
Hypertension 2005;46(5):106976.
[16] Luetscher JA, Kraemer FB, Wilson[22] Carey RM,
McGrath
HE,
DM, Schwartz HC, Bryer-Ash M.
Pentz
ES,
Increased plasma inactive renin in diabetes
Gomez
RA,
melli-tus. A marker of microvascular
Barrett
PQ.
complications.
N
Engl
J
Med
Biomechanical
1985;312(22):14127.
coupling
in
renin-releasing
[17] Deinum J, Ronn B, Mathiesen E,
cells. J Clin
Derkx FH, Hop WC, Schalekamp MA.
Invest
Increase in serum pro-renin precedes onset
1997;100(6):156
of microalbuminuria in patients with
674.
insulin-dependent
diabetes
mellitus.
[23] Lorenz JN,
Diabetologia 1999;42(8):100610.
Weihprecht H,

Schnermann J,
Skott O, Briggs
JP.
Renin
release
from
isolated
juxtaglomerular
apparatus
depends
on
macula
densa
chloride
transport. Am J
Physiol
1991;260(4 Pt
2):F486493.

[24]

Bell PD,
Lapointe
JY,
Sabirov
R,
Hayashi S, PetiPeterdi
J,
Manabe K, et al.
Macula densa
cell
signaling
involves ATP

441

release through a maxi anion channel. Proc

Natl Acad Sci USA 2003;100(7):43227.
[25] Lorenz JN, Weihprecht H, He XR,
Skott O, Briggs JP, Schnermann J. Effects
of adenosine and angiotensin on macula
densa-stimulated renin secretion. Am J
Physiol 1993;265(2 Pt 2): F187194.

[26]

Kurauchi-Mito
A, et al. The
(pro)renin
receptor/ATP6A
P2 is essential
1
for vacuolar H ATPase
assembly
in
murine cardiomyocytes. Circ
Res
2010;107(1):304
.

cyte
structure
and function. J
Am
Soc
Nephrol
2011;22
(12):220312.

[39]

Riediger F,
Quack I, Qadri
F, Hartleben B,
Park
JK,
Potthoff SA, et
al.
Pro-renin
receptor
is
essential
for
podocyte
autophagy and
survival. J Am
Soc
Nephrol
2011;22(12):219
3202.
[40] Gould AB,
Green
D.
Kinetics of the
human renin and
human substrate
reaction.
Cardiovasc Res
1971;5(1):869.
[41] Inoue I,
Nakajima
T,
Williams
CS,
Quackenbush J,
Puryear
R,
Powers M, et al.
A
nucleotide
substitution in
the promoter of
human
angiotensinogen
is
associated
with
essential
hyperten-sion
and affects basal
transcription in
vitro. J Clin
Invest 1997;99
(7):178697.

Admiraal PJ, van Kesteren CA,

Danser AH, Derkx FH, Sluiter W,
Schalekamp MA. Uptake and proteolytic
activation of pro-renin by cultured human
endothelial cells.
[36] Cruciat
CM, Ohkawara
10 Hypertens 1999;17(5):6219.
B, Acebron SP,
[27] Nguyen G, Delarue F, Burckle C,
Karaulanov E,
Bouzhir L, Giller T, Sraer JD. Pivotal role
Reinhard
C,
of the renin/pro-renin receptor in
Ingelfinger D, et
angiotensin II production and cellular
al. Requirement
responses to renin. J Clin Invest
of
pro-renin
2002;109(11):141727.
receptor
and
1
vacuolar
H ATPase[28] van Kesteren CA, Danser AH, Derkx
mediated
FH, Dekkers DH, Lamers JM, Saxena PR,
acidification for
et al. Mannose 6-phosphate recepWnt signaling.
tormediated internalization and activation
Science
of pro-renin by cardiac cells. Hypertension
2010;327(5964):
1997;30(6):138996.
45963.
[29] Nguyen G. Renin/pro-renin receptors.
Kidney Int 2006;69 (9):15036.
[37] Yanai K,
[30] Burckle C, Bader M. Pro-renin and its
Saito
T,
Kakinuma
Y,
ancient
receptor.
Hypertension
Kon Y, Hirota
2006;48(4):54951.
K, Taniguchi[31] Burckle CA, Jan Danser AH, Muller
Yanai K, et al.
DN, Garrelds IM, Gasc JM, Popova E, et
Reninal. Elevated blood pressure and heart rate in
dependent
human renin receptor transgenic rats.
cardiovascular
functions and
Hypertension 2006;47 (3):5526.
renin[32] Hirose T, Hashimoto M, Totsune K,
independent
Metoki H, Asayama K, Kikuya M, et al.
bloodbrain
Association of (pro)renin receptor gene
barrier functions
poly-morphism with blood pressure in
revealed
by
Japanese men: the Ohasama study. Am J
renin-deficient
Hypertens 2009;22(3):2949.
mice. J Biol
Chem
[33] Nguyen G, Muller DN. The biology of
the (pro)renin receptor.
2000;275(1):58.
10 Am Soc Nephrol 2010;21(1):1823. [38] Oshima Y,
[34] Ramser J, Abidi FE, Burckle CA,
Kinouchi
K,
Lenski C, Toriello H, Wen G, et al. A
Ichihara
A,
[42] Kim HS,
unique exonic splice enhancer mutation in a
Krege
JH,
Sakoda
M,
Kluckman KD,
family with X-linked mental retardation
Kurauchi-Mito
Hagaman
JR,
and epilepsy points to a novel role of the
A, Bokuda K, et
Hodgin JB, Best
renin
receptor. Hum Mol
Genet
al.
Pro-renin
CF,
et
al.
2005;14(8):101927.
receptor
is
Genetic control
of
blood
essential
for
[35] Kinouchi K, Ichihara A, Sano M, SunWada GH, Wada Y,
pressure and the
normal
podoI. EPITHELIAL AL TRANSPORT
AND
AND
NONEPITHELI REGULATION

442

15. THE RENINANGIOTENSIN SYSTEM

(35):2642834.
angiotensinogen locus. Proc
Natl Acad Sci USA 1995;92
(7):27359.

[52]

SayedTabatabaei FA, Oostra

BA, Isaacs A, van
Duijn CM, Witteman
[43] Dickson ME, Sigmund
JC.
ACE
CD.
Genetic
basis
of
polymorphisms. Circ
hypertension:
revi-siting
Res
angiotensinogen. Hypertension
2006;98(9):112333.
2006;48(1):1420.
[44] Ingelfinger JR, Zuo WM,[53] Rigat B, Hubert
C, Alhenc-Gelas F,
Fon EA, Ellison KE, Dzau VJ.
Cambien F, Corvol P,
In situ hybridization evidence
Soubrier
F.
An
for angiotensinogen messenger
insertion/deletion
RNA in the rat proximal tubule.
polymorphism in the
An hypothesis for the intrarenal
angio-tensin
Irenin angiotensin system. J Clin
converting
enzyme
Invest 1990;85(2):41723.
gene accounting for
[45] Kobori H, Harrisonhalf the vari-ance of
Bernard LM, Navar LG.
serum enzyme levels.
Expression of angiotensinogen
J
Clin
Invest
mRNA
and
protein
in
1990;86(4):13436.
angiotensin
II-depen-dent
Villard E, Tiret
hypertension. J Am Soc Nephrol[54]
L,
Visvikis
S,
2001;12(3):4319.
Rakotovao
R,
[46] Dzau VJ, Ellison KE,
Cambien F, Soubrier
Brody T, Ingelfinger J, Pratt RE.
F. Identification of
A com-parative study of the
new polymorphisms
distributions of renin and
of the angiotensin Iangiotensinogen
messenger
converting
enzyme
ribonucleic acids in rat and
(ACE) gene, and
mouse tissues. Endocrinology
study of their relation1987;120(6):23348.
ship to plasma ACE
[47] Corvol P, Williams TA,
levels by two-QTL
Soubrier F. Peptidyl dipeptidase
segregation-linkage
A: Angiotensin I-converting
analysis. Am J Hum
enzyme. Methods Enzymol
Genet
1995;248:283305.
1996;58(6):126878.
[48] Ehlers MR, Fox EA,
Takahashi
N,
Strydom DJ, Riordan JF.[55]
Smithies O. Human
Molecular cloning of human
genetics,
animal
testicular
angiotensinmodels and computer
converting enzyme: the testis
simulations
for
isozyme is identical to the Cstudying
terminal half of endothelial
hypertension. Trends
angio-tensin-converting
Genet
enzyme. Proc Natl Acad Sci
2004;20(3):13645.
USA 1989;86 (20):77415.
[56] Margolius HS.
Kallikreins
and
[49] Hubert C, Houot AM,
kinins.
Molecular
Corvol P, Soubrier F. Structure
characteristics
and
of the angiotensin I-converting
cellular and tissue
enzyme gene. Two alternate
promoters
correspond
to
responses. Diabetes
evolutionary
steps
of
a
1996;45(Suppl
1):
duplicated gene. J Biol Chem
S1419.
1991;266(23):1537783.
[50] Langford KG, Shai SY,[57] Campbell DJ,
Howard TE, Kovac MJ,
Alexiou T, Xiao HD,
Overbeek PA, Bernstein KE.
Fuchs S, McKinley
Transgenic mice demonstrate a
MJ, Corvol P, et al.
testis-specific pro-moter for
Effect of reduced
angiotensin-converting enzyme.
angiotensinJ
Biol
Chem
1991;266
converting
enzyme
(24):1555962.
gene expression and
[51] Beldent V, Michaud A,
angiotensinconverting
enzyme
Wei L, Chauvet MT, Corvol P.
inhibition
on
Proteolytic release of human
angiotensin
and
angiotensin-converting enzyme.
bradykinin
peptide
Localization of the cleavage
levels
in
mice.
site. J Biol Chem 1993;268
Hypertension

2004;43(4):8549.
Gainer
JV,
Morrow JD, Loveland
A, King DJ, Brown
NJ.
Effect
of
bradykinin-receptor
blockade
on
the
response to angiotensin-convertingenzyme inhibitor in
normotensive
and
hyperten-sive
subjects. N Engl J
Med
1998;339(18):128592.
[59] Donoghue M,
Hsieh F, Baronas E,
Godbout K, Gosselin
M, Stagliano N, et al.
A novel angiotensinconverting enzymerelated
carboxypeptidase
(ACE2)
converts
angiotensin
I
to
angiotensin 1-9. Circ
Res 2000;87(5):E19.

[58]

[60]

Tipnis SR, Hooper NM,

(8):221825.
Hyde R, Karran E, Christie G,
Oudit
GY,
Turner AJ. A human homolog of[67]
Herzenberg
AM,
angiotensin-converting enzyme.
Kassiri Z, Wong D,
Cloning
and
functional
Reich H, Khokha R,
expression as a captoprilet
al.
Loss
of
insensitive carboxypepti-dase. J
angiotensinBiol
Chem
converting enzyme-2
2000;275(43):3323843.
leads to the late
[61] Zhang H, Wada J, Hida K,
development
of
Tsuchiyama Y, Hiragushiet K,
angiotensin
IIShikata K, et al. Collectrin, a
dependent glomerulocollecting
duct-specific
sclerosis. Am J Pathol
transmem-brane glycoprotein, is
2006;168(6):180820.
a novel homolog of ACE2 and
Oudit GY, Liu
is devel-opmentally regulated in[68]
GC, Zhong J, Basu R,
embryonic kidneys. J Biol
Chow FL, Zhou J, et
Chem 2001;276(20):171329.
al.
Human
recombinant
ACE2
[62] Vickers C, Hales P,
reduces
the
Kaushik V, Dick L, Gavin J,
progression
of
Tang J, et al. Hydrolysis of
diabetic nephropathy.
biological peptides by human
Diabetes
angiotensin-con-verting
2009;59(2):52938.
enzyme-related
Wong
DW,
carboxypeptidase. J Biol Chem[69]
Oudit GY, Reich H,
2002;277 (17):1483843.
Kassiri Z, Zhou J, Liu
[63] Ferrario C, Brosnihan K,
QC, et al. Loss of
Diz D, Jaiswal N, Khosla MC,
angiotensinMilsted A, et al. Angiotensin-(1converting enzyme-2
7): a new hormone of the
(Ace2)
accelerates
angiotensin
system.
dia-betic
kidney
Hypertension 1991;18: [III-126injury. Am J Pathol
133]
[64] Santos RA, Simoes e Silva[70]2007;171(2):43851.
Wysocki J, Ye
AC, Maric C, Silva DM,
M,
Soler
MJ, Gurley
Machado RP, de Buhr I, et al.
SB,
Xiao
HD,
Angiotensin-(1-7)
is
an
Bernstein
KE,
et
al.
endogenous ligand for the G
ACE
and
ACE2
protein-coupled receptor Mas.
activity in diabetic
Proc Natl Acad Sci USA
mice.
Diabetes
2003;100(14):825863.
2006;55 (7):21329.
[65] Ferrario CM, Trask AJ,[71] Gurley
SB,
Jessup JA. Advances in
Coffman
TM.
biochemical and functional
Angiotensinroles of angiotensin-converting
converting enzyme 2
enzyme 2 and angio-tensin-(1gene targeting studies
7)
in
regulation
of
in
mice:
mixed
cardiovascular function. Am J
messages.
Exp
Physiol Heart Circ Physiol
Physiol
2005;289(6):H22812290.
2008;93(5):53842.
[66] Gurley SB, Allred A, Le TH,[72]
Zhong J, Guo D,
Griffiths R, Mao L, Philip N, et
Chen CB, Wang W,
al. Altered blood pressure
Schuster M, Loibner
responses and normal cardiac
H, et al. Prevention of
phenotype in ACE2-null mice. J
angiotensin
IIClin
Invest
2006;116
mediated
renal

I. EPITHELIAL AND
NONEPITHELIAL
TRANSPORT AND
REGULATION

oxidative
stress,
inflammation,
and
fibrosis
by
angiotensinconverting enzyme 2.
Hypertension
2010;57(2):31422.
[73] Zhang H, Wada
J,
Kanwar
YS,
Tsuchiyama
Y,
Hiragushi K, Hida K,
et al. Screening for
genes upregulated in
5/6 nephrec-tomized
mouse kidney. Kidney
Int 1999;56(2):54958.
[74] Malakauskas
SM, Quan H, Fields
TA, McCall SJ, Yu
MJ, Kourany WM, et
al. Aminoaciduria and
altered renal expression of luminal amino
acid transporters in
mice lacking novel
gene collectrin. Am J
Physiol Renal Physiol
2007;292(2):
F533544.

[75]

Danilczyk
U,
Sarao R, Remy C,
Benabbas C, Stange
G, Richter A, et al.
Essential role for
collectrin in renal
amino acid transport.
Nature
2006;444(7122):1088
91.
[76] Timmermans
PB, Wong PC, Chiu
AT, Herblin WF,
Benfield P, Carini DJ,
et al. Angiotensin II
receptors
and
angiotensin
II
receptor antagonists.
Pharmacol
Rev
1993;45(2):20551.

[77]

Tharaux
P-L,
Coffman
TM.
Transgenic mice as a
tool to study
the reninangiotensin
system.
Contrib
Nephrol
2001;135:7291.

REFERENCES

fac-tor receptor
transactivation
Murphy
TJ,
Alexander
RW,
mediates
the
Griendling KK, Runge MS, Bernstein KE.
angiotensin IIIsolation of a cDNA encoding the vascular
induced
type-1 angiotensin II receptor. Nature
mitogen1991;351(6323):2336.
activated
[79] Sasaki K, Yamano Y, Bardhan S, Iwai
protein kinase
N, Murray JJ, Hasegawa M, et al. Cloning
activation
in
and expression of a comple-mentary DNA
vascular smooth
encoding a bovine adrenal angiotensin II
muscle cells. J
type-1
receptor.
Nature
Biol
Chem
1991;351(6323):2303.
1998;273(15):8
[80] Inagami T, Iwai N, Sasaki K, Yamamo
8906.
Y, Bardhan S, Chaki S, et al. Cloning,
Lautrette
expression and regulation of angiotensin II[92]
A, Li S, Alili R,
receptors. J Hypertens 1992;10(8):7136.
Sunnarborg SW,
[81] Sandberg K, Ji H, Clark AJ, Shapira
H, Catt KJ. Cloning and expression of a
Burtin M, Lee
novel angiotensin II receptor subtype. J
DC,
et
al.
Biol Chem 1992;267(14):94558.
Angiotensin II
[82] Iwai N, Inagami T. Identification of
and
EGF
two subtypes in the rat type I angiotensin
receptor crossreceptor. FEBS Letts 1992;298:25760.
talk in chronic
[83] Kakar S, Riel K, Neill J. Differential
kidney diseases:
expression of angiotensin II receptor
a
new
subtype mRNAs (AT-1A and AT-1B) in the
therapeutic
brain. Biochem Biophys Res Comm
approach. Nat
1992;185:68892.
Med
[84] Sasamura H, Hein L, Krieger JE, Pratt
2005;11(8):867
RE, Kobilka BK, Dzau VJ. Cloning,
74.
characterization, and expression of two
angiotensin receptor (AT-1) isoforms from[93]
Burson
the mouse genome. Biochem Biophys Res
JM, Aguilera G,
Commun 1992;185(1):2539.
Gross
KW,
[85] de Gasparo M, Catt KJ, Inagami T,
Sigmund CD.
Wright JW, Unger T. International union of
Differential
pharmacology. XXIII. The angiotensin II
expression
of
receptors.
Pharmacol
Rev
angiotensin
2000;52(3):41572.
receptor 1A and

[78]

[86]

1B in mouse.
Marrero M, Schieffer B, Paxton W,
Heerdt L, Berk BC,
Am J Physiol
Delafontaine P, et al. Direct stimulation of
1994;267(2 Pt
Jak/STAT pathway by the angiotensin II
1):E260267.
AT1 receptor. Nature 1995;375:24750.
[94] Iwai N,

[87]

Rakesh K,, Yoo B,, Kim IM,, Salazar

N,, Kim KS,, Rockman HA. beta-Arrestinbiased agonism of the angiotensin receptor
induced by mechanical stress. Sci
Signal.3(125):ra46.

[88]

Shenoy
SK,
Lefkowitz
RJ.
Angiotensin II-stimulated signaling through
G proteins and beta-arrestin. Sci STKE
2005;(311): cm14.

[89]

Ahn D, Ge Y, Stricklett PK, Gill P,

Taylor D, Hughes AK, et al. Collecting
duct-specific knockout of endothelin-1
causes hypertension and sodium retention. J
Clin Invest 2004;114 (4):50411.

[90]

Inagami
T,
Ohmichi
N,
Nakamura
Y,
Saeki
Y,
Kinoshita
M.
Differential
regulation of rat
AT1a and AT1b
receptor
mRNA.
Biochem
Biophys
Res
Commun
1992;188
(1):298303.

Yasuda N,, Akazawa H,, Ito K,,

Gasc JM,
Shimizu I,, Kudo-Sakamoto Y,, Yabumoto[95]
Shanmugam S,
C,, et al. Agonist-independent constitutive
Sibony
M,
activity of angiotensin II receptor promotes
Corvol
P.
cardiac remodeling in mice. Hypertension.
Tissue-specific
March;59(3):627-633.
expression
of
[91] Eguchi S, Numaguchi K, Iwasaki H,
type
1
Matsumoto T, Yamakawa T, Utsunomiya H,
angiotensin II
et al. Calcium-dependent epidermal growth

receptor
subtypes. An in
situ
hybridization
study.
Hypertension
1994;24(5):5317
.
[96] LlorensCortes
C,
Greenberg
B,
Huang
H,
Corvol
P.
Tissular
expression and
regulation
of
type
1
angiotensin II
receptor
subtypes
by
quantitative
reverse
transcriptasepolymerase
chain reaction
analysis.
Hypertension
1994;24(5):5384
8.

443

1996;271
Konishi H, Kuroda S, Inada Y,[107] Millan M,
Carvallo
P,
(36):2198592.
Fujisawa Y. Novel subtype of human
Izumi
S-I,
[111] Lehtonen
angiotensin II type 1 receptor: cDNA
Zemel S, Catt
JY, Daviet L,
cloning and expression. Biochem Biophys
K, Aguilera G.
Nahmias
C,
Res Commun 1994;199 (2):46774.
Novel sites of
Horiuchi
M,
expression of
Dzau
VJ.
[98] Chiu A, Dunscomb J, McCall D,
functional
Analysis
of
Benfield P, Baubonis W, Sauer B.
angiotensin II
functional
Characterization of angiotensin AT1A
receptors
in
domains
of
receptor iso-form by it ligand binding
the
late
angiotensin II
signature. Regul Pept 1993;44:1417.
gestation fetus.
type 2 recep[99] Oliverio MI, Best CF, Kim HS,
Science
tor involved in
Arendshorst WJ, Smithies O, Coffman
1989;244:1340
apoptosis. Mol
TM. Angiotensin II responses in AT1A
2.
Endocrinol
receptor-defi-cient mice: a role for AT1B
1999;13(7):105
receptors in blood pressure regula-tion.[108] Ichiki T,
Kambayashi Y,
160.
Am J Physiol 1997;272(4 Pt 2):F515520.
Inagami
T.
[112]
Carey RM,
[100] Oliverio MI, Kim HS, Ito M, Le T,
Multiple
Wang
ZQ,
Audoly L, Best CF, et al. Reduced growth,
growth factors
Siragy
HM.
abnormal kidney structure, and type 2
modulate
Role of the
(AT2) angiotensin receptor-mediated
mRNA
angiotensin
blood pressure regulation in mice lacking
expression of
type 2 receptor
both AT1A and AT1B receptors for
angiotensin II
in
the
angiotensin
type-2 receptor
regulation of
35.
Proc Natl Acad Sci USA
in R3T3 cells.
blood pressure
1998;95(26):15496501.
Circ
Res
and renal func[101] Davisson RL, Oliverio MI, Coffman
1995;77(6):10
tion.
TM, Sigmund CD. Divergent functions of
706.
Hypertension
angiotensin II receptor isoforms in the
[109]
Berry C,
2000;35(1 Pt
brain. J Clin Invest 2000;106(1):1036.
2):15563.
Touyz
R,
[102] Ito M, Oliverio MI, Mannon PJ, Best
Dominiczak
[113]
Siragy
CF, Maeda N, Smithies O, et al.
AF, Webb RC,
HM,
Carey
Regulation of blood pressure by the type
RM.
The
Johns
DG.
subtype-2
1A angio-tensin II receptor gene. Proc
Angiotensin
(AT2)
Natl Acad Sci USA 1995;92 (8):35215.
angiotensin
receptors:
receptor
Signaling,
regulates renal
[103] Matsusaka T, Nishimura H,
vascular
cyclic
Utsunomiya H, Kakuchi J, Nijmura F,
pathophysiolo
guanosine
Inagami T, et al. Chimeric mice carrying
gy,
and
0 0
regional targeted deletion of the
3 ,5 interactions
angiotensin type 1A receptor gene.
monophosphat
with ceramide.
Evidence against the role for local
e and AT1
Am J Physiol
angiotensin in the in vivo feedback
receptorHeart
Circ
regulation of renin synthesis in
mediated
Physiol
juxtaglomerular cells.
2001;281(6):H
prostaglandin
10 Clin Invest 1996;98(8):186777.
23372365.
E2 production
[104] Sugaya T, Nishimatsu S, Tanimoto K,[110] Hayashida
in
conscious
Takimoto E, Yamagishi T, Imamura K, et
W, Horiuchi
rats. J Clin
al. Angiotensin II type 1a receptorM, Dzau VJ.
Invest
deficient mice with hypotension and
Intracellular
1996;97(8):197
hyperreninemia. J Biol Chem 1995;270
third
loop
882.
(32):1871922.
domain
of
[114]
Dulin NO,
[105] Oliverio MI, Best CF, Smithies O,
angiotensin II
Alexander LD,
Coffman TM. Regulation of sodium
type-2
Harwalkar S,
balance and blood pressure by the AT(1A)
receptor. Role
Falck
JR,
receptor for angiotensin II. Hypertension
in mediating
Douglas
JG.
2000;35(2):5504.
Phospholipase
signal
[106] Grady E, Sechi L, Griffn C,
A2-mediated
transduction
activation
of
Schambelan M, Kalinyak J. Expression of
and
cellular
mitogenAT2 receptors in the developing rat fetus.
function.
J
activated
J Clin Invest 1991;88:92133.
Biol
Chem
AND
TRANSPORT AND
NONEPITHELI REGULATION
I. EPITHELIAL
AL

[97]

444

15. THE RENINANGIOTENSIN SYSTEM

Mitchell C, Wade
JB, Knepper MA.
protein kinase by angiotensin
AldosteroneII. Proc Natl Acad Sci USA
1998;95(14):8098102.
mediated regulation
[115] Hein L, Barsh GS, Pratt
of ENaC alpha, beta,
RE, Dzau VJ, Kobilka BK.
and gamma subunit
Behavioural
and
proteins
in
rat
cardiovascular
effects
of
kidney. J Clin Invest
disrupting the angiotensin II
1999;104 (7):R1923.
type-2 receptor in mice. Nature
1995;377(6551):7447.
[126] Asher C, Wald
[116] Ichiki T, Labosky PA,
H, Rossier BC,
Shiota C, Okuyama S,
Garty
H.
Imagawa Y, Fogo A, et al.
Aldosterone-induced
Effects on blood pressure and
increase
in
the
1
exploratory behaviour of mice
abundance of Na
lacking angiotensin II type-2
channel
subunits.
receptor.
Nature
Am
J
Physiol
1995;377(6551):74850.
1996;271(2
Pt
[117] Masaki H, Kurihara T,
1):C605611.
Yamaki A, Inomata N, Nozawa[127] Gumz ML, Stow
Y, Mori Y, et al. CardiacLR,
Lynch
IJ,
specific overexpression of
Greenlee
MM,
Rudin A, Cain BD,
angiotensin II AT2 receptor
et al. The circadian
causes attenuated response to
clock protein Period
AT1 receptor-mediated pressor
1
regu-lates
and chronotropic effects. J
expression of the
Clin
Invest
renal
epithelial
1998;101(3):52735.
sodium channel in
mice. J Clin Invest
[118] Steckelings UM, Larhed
2009;119(8):242334.
M, Hallberg A, Widdop RE,
Jones ES, Wallinder C, et al.[128] Naray-FejesToth A. Sgk: a new
Non-peptide
AT2-receptor
player (star?) in the
agonists.
Curr
Opin
early
action
of
Pharmacol 2011;11(2):18792.
aldosterone. News
[119] Aguilera G. Role of
Physiol
Sci
angiotensin
II
receptor
1999;14:2745.
subtypes on the regulation of
FE,
aldosterone secretion in the[129] Brennan
Fuller PJ. Rapid
adrenal glomerulosa zone in
upregulation
of
the rat. Mol Cell Endocrinol
serum and gluco1992;90(1):5360.
corticoid-regulated
[120] Okubo S, Niimura F,
kinase (sgk) gene
Nishimura H, Takemoto F,
expression
by
Fogo A, Matsusaka T, et al.
corticoster-oids
in
Angiotensin-independent
vivo.
Mol
Cell
mechanism for aldosterone
Endocrinol
synthesis
during
chronic
2000;166(2):12936.
extracellular fluid vol-ume
A,
depletion. J Clin Invest[130] Bhargava
Fullerton MJ, Myles
1997;99(5):85560.
K,
Purdy
TM,
[121] Quinn SJ, Williams GH.
Funder JW, Pearce
Regulation of aldosterone
D, et al. The serumsecretion. Annu Rev Physiol
and glucocorticoid1988;50:40926.
induced kinase is a
[122] Aguilera G. Factors
physiological
controlling
steroid
mediator
of
biosynthesis in the zona
aldosterone action.
glomerulosa of the adrenal. J
Endocrinology
Steroid Biochem Mol Biol
2001;142(4):158794.
1993;45(1-3):14751.
[123] Fuller PJ, Young MJ.[131] Zhang W, Xia X,
Reisenauer
MR,
Mechanisms
of
Rieg T, Lang F, Kuhl
mineralocorticoid
action.
D, et al.
Hypertension
Aldosterone-induced
2005;46(6):122735.
Sgk1 relieves Dot1a[124] Rogerson FM, Fuller PJ.
Af9-mediated tranMineralocorticoid
action.
scriptional
Steroids 2000;65(2):6173.
repression
of
1
[125] Masilamani S, Kim GH,
epithelial
Na

channel alpha. J Clin

Invest
2007;117(3):77383.
[132] McCormick JA,
Bhalla V, Pao AC,
Pearce D. SGK1: a
rapid
aldosteroneinduced regulator of
renal
sodium
reabsorption.
Physiology
(Bethesda)
2005;20:1349.
[133] Vallon V, Wulff
P,
Huang
DY,
Loffing J, Volkl H,
Kuhl D, et al. Role
of Sgk1 in salt and
potassium
homeostasis. Am J
Physiol Regul Integr
Comp
Physiol
2005;288(1):R410.

[134]

Yoo D, Kim BY,

Campo C, Nance L,
King A, Maouyo D,
et al. Cell surface
expression of the
ROMK (Kir 1.1)
channel is

regulated by the aldosteroneAm J Physiol Renal

beta subunit of the
induced kinase, SGK-1, and
Physiol 2009;296(5):
epithelial
sodium
pro-tein kinase A. J Biol Chem
F11851193.
channel gene. J Clin
2003;278(25):2306675.
Invest
[135] Beesley AH, Hornby D,[142] Leite-Dellova
1996;97(7):17804.
White SJ. Regulation of distal
DC, Oliveira-Souza
1
M, Malnic G, Mellonephron K channels (ROMK)
[147] Rossier
BC,
Aires M.
mRNA
expression
by
Pradervand S, Schild
Genomic
and
aldosterone in rat kidney. J
L, Hummler E.
nongenomic dosePhysiol 1998;509(Pt 3):62934.
Epithelial
sodium
dependent biphasic
[136] Rozansky DJ. Cornwall T,
channel
and
the
effect of aldosterone
Subramanya AR, Rogers S,
1 1
control of sodium
on
Na /H
Yang YF, David LL, Zhu X,
balance: interaction
exchanger
in
Yang CL, Ellison DH.
between genetic and
proximal
S3
Aldosterone
mediates
environmental
segment: role of
activation of the thiazidefactors. Annu Rev
cytosolic calcium.
sensitive Na-Cl co-transporter
Physiol
Am J Physiol Renal
through an SGK1 and WNK4
2002;64:87797.
Physiol
2008;295
signaling pathway. J Clin
[148]
Rubera
I,
(5):F13421352.
Invest 2009;119(9):260112.
Loffing J, Palmer
[143]
Watts 3rd BA,
[137] Geller DS, Farhi A,
LG,
Frindt
G,
George T, Good DW.
Pinkerton N, Fradley M,
Fowler-Jaeger
N,
Aldosterone inhibits
Sauter D, et al.
Moritz M, Spitzer A, et al.
apical NHE3 and
2
Collecting
ductActivating mineralocorticoid
HCO3
absorption
specific
gene
receptor
muta-tion
in
via a nongenomic
inactivation
of
hypertension exacerbated by
ERK-dependent
alphaENaC in the
pregnancy.
Science
pathway
in
mouse kidney does
2000;289(5476):11923.
medullary
thick
not impair sodium
ascending limb. Am
and
potassium
[138] Geller DS, RodriguezJ Physiol Renal
balance.
J
Clin
Soriano J, Vallo Boado A,
Physiol
Invest
Schifter S, Bayer M, Chang
2006;291(5):F10051
2003;112(4):55465.
SS, et al. Mutations in the
013.
[149]
Biner HL, Arpinmineralocorticoid
receptor[144] Lifton
R.
Bott MP, Loffing J,
gene
cause
autosomal
Genetic
Wang X, Knepper
dominant pseudohypoaldosterdeterminants
of
M, Hebert SC, et al.
onism type I. Nat Genet
human hypertension.
Human
cortical
1998;19(3):27981.
PNAS
distal
nephron:
1995;92(19):854551.
[139] Berger S, Bleich M,
distribution
of
Schmid W, Cole TJ, Peters J,[145] Firsov D, Schild
Watanabe H, et al.
electrolyte and water
L,
Gautschi
I,
Mineralocorticoid
receptor
transport pathways. J
Merillat
A-M,
knockout
mice:
Am Soc Nephrol
Schneeberger
E,
1
Pathophysiology
of
Na
2002;13(4):83647.
Rossier Bernard C.
metabolism.
PNAS
[150] Greene EL, Kren
Cell
surface
1998;95(16):94249.
S, Hostetter TH.
expression of the
[140] Ronzaud C, Loffing J,
Role of aldosterone
epithelial Na channel
Bleich M, Gretz N, Grone HJ,
in
the
remnant
and a mutant causing
Schutz G, et al. Impairment of
kidney model in the
Liddle syndrome: a
sodium balance in mice
rat. J Clin Invest
quantitative
deficient in renal principal cell
1996;98 (4):10638.
approach.
PNAS
mineralocorticoid receptor. J
1996;93(26):153705.
Am
Soc
Nephrol[146] Tamura
H,
[151] Leopold JA,
2007;18(6):167987.
Schild L, Enomoto
Dam A, Maron BA,
Scribner AW, Liao
N,
Matsui
N,
[141] Pergher PS, Leite-Dellova
R, Handy DE, et al.
Marumo F, Rossier
D, de Mello-Aires M. Direct
Aldosterone impairs
BC. Liddle disease
vascular reactivity
action of aldosterone on
caused
by
a
by
bicarbonate reabsorption in in
missense mutation of
vivo cortical proximal tubule.
I. EPITHELIAL
TRANSPORT AND
AND
REGULATION
NONEPITHELIAL

REFERENCES

Nephrol
1999;10(Suppl
12):S258265.
[163] Hall JE,
Granger
JP.
[152] Jaffe IZ, Newfell BG, Aronovitz M,
Adenosine
Mohammad NN, McGraw AP, Perreault
alters
RE, et al. Placental growth factor
glomerular
mediates aldosterone-dependent vascular
injury in mice.
filtration
control
by
J Clin Invest 2010;120(11):3891900.
angiotensin II.
[153] Terada Y, Kobayashi T, Kuwana H,
Tanaka H, Inoshita S, Kuwahara M, et al.
Am J Physiol
Aldosterone stimulates proliferation of
1986;250(5 Pt
mesangial cells by activating mitogen2): F917923.
activated protein kinase 1/ 2, cyclin D1,
and cyclin A. J Am Soc Nephrol[164] Hall
JE.
2005;16(8):2296305.
Control
of
[154] Miyata K, Rahman M, Shokoji T,
sodium
Nagai Y, Zhang GX, Sun GP, et al.
excretion
by
Aldosterone stimulates reactive oxygen
angiotensin II:
species produc-tion through activation of
Intrarenal
NADPH oxidase in rat mesangial cells. J
mechanisms
Am Soc Nephrol 2005;16(10):290612.
and
blood
[155] Terada Y, Kuwana H, Kobayashi T,
pressure
Okado T, Suzuki N, Yoshimoto T, et al.
regulation. Am
Aldosterone-stimulated SGK1 activity
J
Physiol
mediates profibrotic signaling in the
1986;250(6 Pt
mesangium. J Am Soc Nephrol
2):R960972.
2008;19(2):298309.
[165] Campbell
[156] Shibata S, Nagase M, Yoshida S,
DJ. Extrarenal
Kawachi H, Fujita T. Podocyte as the
renin
and
target for aldosterone: roles of oxidative
blood pressure
stress
and
Sgk1.
Hypertension
regulation. An
2007;49(2):35564.
alternative
[157] Lee SH, Yoo TH, Nam BY, Kim DK,
viewpoint. Am
Li JJ, Jung DS, et al. Activation of local
J
Hypertens
aldosterone system within podocytes is
1989;2(4):2667
involved in apoptosis under diabetic
5.
conditions. Am J Physiol Renal Physiol[166] Sequeira
2009;297(5):F13811390.
Lopez
ML,
[158] Chrysostomou A, Pedagogos E,
Pentz
ES,
MacGregor L, Becker GJ. Double-blind,
Robert
B,
placebo-controlled study on the effect of
Abrahamson
the aldosterone receptor antagonist
DR,
Gomez
RA.
spironolactone in patients who have
Embryonic
persistent proteinuria and are on long-term
origin
and
angio-tensin-converting enzyme inhibitor
lineage
of
therapy, with or without an angiotensin II
juxtaglomerula
receptor blocker. Clin J Am Soc Nephrol
r cells. Am J
2006;1(2):25662.
Physiol Renal
Physiol
[159] Cowley Jr. AW, Roman RJ. The role
2001;281(2):F
of the kidney in hyperten-sion. Jama
345356.
1996;275(20):15819.
[160] Aperia AC, Broberger CG, Soderlund[167] Barajas L.
Anatomy
of
S. Relationship between renal artery
the
perfusion pressure and tubular sodium
juxtaglomerula
reabsorp-tion.
Am
J
Physiol
r
apparatus.
1971;220(5):120512.
Am J Physiol
[161] Guyton AC, Coleman TG, Cowley Jr.
1979;237(5):F
AV, Scheel KW, Manning Jr. RD, Norman
333343.
Jr. RA. Arterial pressure regulation.
Overriding dominance of the kidneys in[168] Taugner C,
Poulsen
K,
long-term regulation and in hypertension.
Hackenthal E,
Am J Med 1972;52(5):58494.
Taugner
R.
[162] Hall JE, Brands MW, Henegar JR.
Immunocytoch
Angiotensin II and long-term arterial
emical
pressure regulation: the overriding
localization of
dominance of the kidney. J Am Soc
decreasing glucose-6-phosphate
dehydrogenase activity. Nat Med
2007;13(2):18997.

renin in mouse
kidney.
Histochemistry
1979;62(1):192
7.
[169] Vander AJ.
Control
of
renin release.
Physiological
Review
1967;47(3):359
82.
[170] Sequeira
Lopez
ML,
Gomez
RA.
The role of
angiotensin II
in
kidney
embryogenesis
and
kidney
abnormalities.
Curr
Opin
Nephrol
Hypertens
2004;13(1):117
22.

445

[171]

regulation of
of
the
renin release.
reninangtiotens
Am J Physiol
in system in
1984;247(5 Pt
the
isolated
2):F706713.
perfused
rat
[188] Knoblich
kidney.
Circ
PR, Freeman
Res
RH, Villarreal
[172] Silver RB, Reid AC, Mackins CJ,
1974;:I193202.
D.
PressureAskwith T, Schaefer U, Herzlinger D, et[184] Tokumori
dependent
al. Mast cells: a unique source of renin.
Y, Kurahashi
renin release
Proc
Natl
Acad
Sci
USA
A, Murakami
during chronic
2004;101(37):1360712.
J, Mokuda GO,
blockade
of
[173] Mackins CJ, Kano S, Seyedi N,
Ikeda
T,
nitric
oxide
Schafer U, Reid AC, Machida T, et al.
Takeda A, et al.
synthase.
Cardiac mast cell-derived renin promotes
Biphasic renin
Hypertension
local
angiotensin
formation,
release
from
1996;28(5):738
perfused
rat
norepinephrine release, and arrhythmias in
42.
kid-ney. Horm
ischemia/reperfusion. J Clin Invest
[189] Persson
Metab
Res
2006;116 (4):106370.
PB, Baumann
1983;15(6):310
JE, Ehmke H,
1.
[174] Le TH, Coffman TM. A new cardiac
Hackenthal E,
MASTer switch for the reninangiotensin[185] Romero
Kirchheim HR,
system. J Clin Invest 2006;116(4):8669.
JC, Feldstein
Nafz
B.
[175] Tobian L, Tomboulian A, Janecek J.
AE,
EndotheliumThe effect of high perfu-sion pressures on
Rodriguezderived
NO
the granulation of juxtaglomerular cells in
Porcel
MG,
stimulates
an isolated kidney. J Clin Invest
Cases-Amenos
pressure1959;38(4):60510.
A.
New
dependent
[176] Skinner SL, McCubbin JW, Page IH.
insights
into
renin release in
Control of renin secretion. Circ Res
the
conscious
1964;15:6476.
pathophysiolog
dogs. Am J
[177] Kirchheim H, Ehmke H, Persson P.
y of renovasPhysiol
Physiology of the renal baroreceptor
cular
1993;264(6 Pt
mechanism of renin release and its role in
hypertension.
2):F943947.
congestive heart failure. Am J Cardiol
Mayo
Clin
[190] Kurtz A,
1988;62(8):68E71E.
Proc
Wagner
C.
[178] Nobiling R, Munter K, Buhrle CP,
1997;72(3):251
Role of nitric
Hackenthal E. Influence of pulsatile
60.
oxide in the
perfusion upon renin release from the[186] Fray JC.
control of renin
isolated per-fused rat kidney. Pflugers
Regulation of
secretion. Am J
Arch 1990;415(6):7137.
renin secretion
Physiol
[179] Hackenthal E, Paul M, Ganten D,
by calcium and
1998;275(6 Pt
Taugner R. Morphology, physiology, and
chemi-osmotic
2):F849862.
molecular biology of renin secretion.
forces: (Patho)
[191] Data JL,
physiological
Physiol Rev 1990;70(4):1067116.
considerations.
[180] Blaine EH, Davis JO, Witty RT. Renin
Gerber
JG,
Biochim
release after hemorrhage and after
Crump
WJ,
Biophys Acta
suprarenal aortic constriction in dogs
Frolich
JC,
1991;1097(4):2
without sodium delivery to the macula
Hollifield JW,
4362.
densa. Circ Res 1970;27 (6):10819.
Nies AS. The
[187] Osborn JL,
prostaglandin
Kopp
UC,
[181] Blaine EH, Davis JO, Prewitt RL.
system. A role
Thames MD,
Evidence for a renal vascular receptor in
in canine baroDiBona
GF.
control of renin secretion. Am J Physiol
receptor
Interactions
1971;220 (6):15937.
among
renal
control of renin
[182] Fray JC. Stretch receptor model for
nerves,
renin release with evidence from perfused
release. Circ
prostaglandins,
rat
kidney.
Am
J
Physiol
Res
and
renal
1976;231(3):93644.
1978;42(4):454
arterial pres[183] Hofbauer KG, Zschiedrich H,
8.
sure in the
Hackenthal E, Gross F. Function
AND
TRANSPORT AND
NONEPITHELI REGULATION
I. EPITHELIAL
AL
Rohrwasser A, Morgan T, Dillon HF,
Zhao L, Callaway CW, Hillas E, et al.
Elements of a paracrine tubular reninangioten-sin system along the entire
nephron.
Hypertension
1999;34
(6):126574.

446

15. THE RENINANGIOTENSIN SYSTEM

[202] Goormaghtigh
N. Fact in favor of
Gerber JG, Keller RT, Nies
an
endocrine
AS. Prostaglandins and renin
function of the renal
release: the effect of PGI2,
arterioles. J. Pathol
PGE2, and 13,14-dihydro
Bacteriol
PGE2 on the baroreceptor
1945;57:392404.
mechanism of renin release in
K,
the
dog.
Circ
Res[203] Thurau
Schnermann
J,
1979;44(6):7969.
Nagel W, Horster M,
Wahl
M.
[193] Munter K, Hackenthal E.
Composition
of
The effects of endothelin on
tubular fluid in the
renovas-cular resistance and
macula
densa
renin release. J Hypertens
segment as a factor
Suppl 1989;7(6): S276277.
regulating
the
[194] Beierwaltes WH, Potter
function
of
the
DL, Shesely EG. Renal
juxtaglomerular
baroreceptor-stimulated renin
appara-tus. Circ Res
in the eNOS knockout mouse.
1967;21((1):Suppl
Am J Physiol Renal Physiol
2):7990.
2002;282(1):F5964.
[195] Fujino T, Nakagawa N,[204] Skott O, Briggs
JP.
Direct
Yuhki K, Hara A, Yamada T,
demonstration
of
Takayama K, et al. Decreased
macula
densasusceptibility to renovascular
mediated
renin
hypertension in mice lacking
secretion.
Science
the prostaglandin I2 receptor
1987;237(4822):161
IP.
J
Clin
Invest
820.
2004;114(6):80512.
[196] Francois H, Coffman TM.[205] Schlatter
E,
Salomonsson
M,
Prostanoids
and
blood
Persson AE, Greger
pressure: which way is up? J
R. Macula
Clin Invest 2004;114(6):7579.
densa cells sense
[197] Scholz H, Gotz KH,
luminal
NaCl
Hamann
M,
Kurtz
A.
concentration
via
Differential
effects
of
furosemide sensitive
1
2 1
extracellular anions on renin
Na 2Cl K
cosecretion from isolated pertransport. Pflugers
fused rat kidneys. Am J
Arch
1989;414
Physiol
1994;267(6
Pt
(3):28690.
2):F10761081.
[206] Martinez[198] Krattinger N, Capponi A,
Maldonado M, Gely
Mazzolai L, Aubert JF, Caille
R, Tapia E, Benabe
D, Nicod P, et al. Connexin40
JE. Role of macula
regulates renin production and
densa in diureticsblood pressure. Kidney Int
induced
renin
2007;72(7):81422.
release.
[199] Wagner C, de Wit C, Kurtz
Hypertension
L, Grunberger C, Kurtz A,
1990;16(3):2618.
Schweda F. Connexin40 is[207] Kotchen
TA,
essential for the pressure
Galla JH, Luke RG.
control of renin synthesis and
Failure of NaHCO3
secretion.
Circ
Res
and
KHCO3
to
2007;100(4):55663.
inhibit renin in the
[200] Schweda F, Kurtz L, de
rat. Am J Physiol
Wit C, Janssen-Bienhold U,
1976;231 (4):10506.
Kurtz
A,
Wagner
C.
Substitution of connexin40
with connexin45 pre-vents[208] Hanner
F,
Chambrey
R,
hyperreninemia and attenuates
Bourgeois S, Meer
hypertension.
Kidney
Int
E, Mucsi I, Rosivall
2009;75(5):4829.
L, et al. Increased
[201] Haefliger JA, Krattinger
renal renin content
N, Martin D, Pedrazzini T,
in mice lacking the
1 1
Capponi A, Doring B, et al.
Na /H
exchanger
Connexin43-dependent
NHE2. Am J Physiol
Renal
Physiol
mechanism modulates renin
2008;294(4):F93794
secretion and hypertension. J
4.
Clin
Invest
2006;116
[209] Ledoussal C,
(2):40513.
Lorenz JN, Nieman
[192]

ML, Soleimani M,
Schultheis PJ, Shull
GE.
Renal
salt
wasting in mice
1
lacking NHE3 Na /
1
H exchanger but
not in mice lacking
NHE2. Am J Physiol
Renal
Physiol
2001;281(4):F71872
7.
[210] Churchill PC,
Churchill MC. A1
and A2 adenosine
receptor activation
inhibits
and
stimulates
renin
secretion of rat renal
cortical slices. J
Pharmacol Exp Ther
1985;232(3):58994.

[211]

Harris

RC,

Breyer

MD.

Physiological
regulation

of

cyclooxy-genase-2
in the kidney. Am J
Physiol

Renal

Physiol

2001;281

(1):F111.

[212]

Schweda F, Klar J,
Fuson AL, Guan Y,
Narumiya S, Nusing RM,
Schneider A, Qi Z, et
Kurtz A. Stimulation of renin
al. Luminal NaCl
release by prostaglandin E2 is
delivery
regulates
mediated by EP2 and EP4
basolateral
PGE2
receptors in mouse kidneys.
release from macula
Am J Physiol Renal Physiol
densa cells. J Clin
2004;287(3):F427433.
Invest
[213] Schnermann J, Homer W.
2003;112(1):7682.
Smith Award lecture. The
juxtaglo-merular
apparatus:[221] Yang T, Endo Y,
from anatomical peculiarity to
Huang YG, Smart A,
physiologi-cal relevance. J Am
Briggs
JP,
Soc
Nephrol
Schnermann
J.
2003;14(6):168194.
Renin expression in
[214] Schweda F, Kurtz A.
COX-2-knockout
Cellular mechanism of renin
mice on normal or
release. Acta Physiol Scand
low-salt diets. Am J
2004;181(4):38390.
Physiol
Renal
[215] Facemire CS, Nguyen M,
Physiol 2000;279(5):
Jania L, Beierwaltes WH, Kim
F819825.
HS, Koller BH, et al. A major
role for the EP4 receptor in[222] Weihprecht H,
regula-tion of renin. Am J
Lorenz
JN,
Physiol
Renal
Physiol
Schnermann J, Skott
2011;301(5): F10351041.
O, Briggs JP. Effect
of
adenosine1[216] Beierwaltes WH, Schryver
receptor blockade on
S, Sanders E, Strand J, Romero
renin release from
JC. Renin release selectively
rabbit
isolated
stimulated by prostaglandin I2
perfused
in iso-lated rat glomeruli. Am J
juxtaglomerular
Physiol 1982;243(3):F276283.
apparatus. J Clin
[217] Webber PC, Larsson C,
Invest
Anggard E, Hamberg M,
1990;85(5):16228.
Corey EJ, Nicolaou KC, et al.[223] Kim SM, Mizel
Stimulation of renin release
D,
Huang
YG,
from rabbit renal cortex by
Briggs
JP,
arachidonic
acid
and
Schnermann
J.
prostaglandin endoperox-ides.
Adenosine as a
Circ Res 1976;39(6):86874.
mediator of macula
[218] Harding P, Sigmon DH,
densa-dependent
Alfie ME, Huang PL, Fishman
inhibi-tion of renin
MC, Beierwaltes WH, et al.
secretion. Am J
Cyclooxygenase-2
mediates
Physiol
Renal
increased renal renin content
Physiol 2006;290(5):
induced by low-sodium diet.
F10161023.
Hypertension 1997;29(1 Pt
2):297302.

[219]

[224]

Cheng H, Harris R.
Angiotensin
converting
enzyme
inhibitor-mediated
increases in renal renin
expression are not seen in
cyclooxygenase-2
knockout
mice. J Am Soc Nephrol
1999;10:343A.

[220]

Peti-Peterdi J, Komlosi P,

I. EPITHELIAL AND
NONEPITHELIAL
TRANSPORT AND
REGULATION

Mundel
P,
Bachmann S, Bader
M,
Fischer
A,
Kummer W, Mayer
B, et al. Expression
of
nitric
oxide
synthase in kidney
macula densa cells.
Kidney
Int
1992;42(4):10179.

[225]

Wilcox
CS,
Welch WJ. Macula
densa nitric oxide
synthase: expression,
regulation,
and
function. Kidney Int
Suppl
1998;67:S5357.
[226] He
XR,
Greenberg
SG,
Briggs
JP,
Schnermann
JB.
Effect of nitric oxide
on renin secretion.
II. Studies in the
perfused
juxtaglomerular
apparatus. Am J
Physiol 1995;268(5
Pt 2): F953959.

[227]

Tharaux
PL,
Dussaule JC, Pauti
MD, Vassitch Y,
Ardaillou
R,
Chatziantoniou
C.
Activation of renin
synthesis
is
dependent on intact
nitric
oxide
production. Kidney
Int
1997;51
(6):17807.

[228]

Castrop
H,
Schweda F, Mizel D,
Huang Y, Briggs J,
Kurtz A, et al.
Permissive role of
nitric
oxide
in
macula densa control
of renin secretion.
Am J Physiol Renal
Physiol 2004;286(5):
F848857.

[229]

Shricker
K,
Holmer S, Kramer
BK, Riegger GA,
Kurtz A. The role of
angiotensin II in the
feedback control of
renin
gene
expression. Pflugers
Arch
1997;434(2):16672.

REFERENCES

Physiol
1985;249(2):F
Oliverio MI, Madsen K, Best CF, Ito
175184.
M, Maeda N, Smithies O, et al. Renal
growth and development in mice lacking[244] Kurtz A,
Wagner
C.
AT1A receptors for angiotensin II. Am J
Cellular
Physiol 1998;274(1 Pt 2): F4350.
control of renin
secretion.
J
[231] Gomez RA, Chevalier RL, Everett
Exp
Biol
AD, Elwood JP, Peach MJ, Lynch KR, et
1999;202(Pt
al. Recruitment of renin gene-expressing
3):21925.
cells in adult rat kidneys. Am J Physiol
[245] Kurtz A,
1990;259(4 Pt 2):F660665.
Pfeilschifter J,
[232] Crowley SD, Gurley SB, Oliverio MI,
Hutter
A,
Pazmino AK, Griffiths R, Flannery PJ, et
Buhrle
C,
al. Distinct roles for the kidney and
Nobiling
R,
systemic
Taugner R, et
tissues in blood pressure regulation by the
al. Role of
reninangiotensin system. J Clin Invest
protein kinase
2005;115(4):10929.
C in inhibition
[233] Lew R, Summers RJ. The distribution
of beta-adrenoceptors in dog kidney: an
of renin release
autoradiographic
analysis.
Eur
J
caused
by
Pharmacol 1987;140(1):111.
vasoconstrictor
[234] Keeton TK, Campbell WB. The
s.
Am
J
pharmacologic alteration of renin release.
Physiol
Pharmacol Rev 1980;32(2):81227.
1986;250(4 Pt
[235] Holdaas H, DiBona GF, Kiil F. Effect
1):C563571.
of low-level renal nerve stimulation on
renin release from nonfiltering kidneys.[246] Churchill
Am J Physiol 1981;241(2):F156161.
MC, Churchill
[236] Holdaas H, Langard O, Eide I, Kiil F.
PC.
12-0Mechanism of renin release during renal
Tetradecanoylp
nerve stimulation in dogs. Scand J Clin
horbol
13Lab Invest 1981;41(7):61725.
acetate inhibits
[237] DiBona GF. Neural regulation of renal
renin secretion
tubular sodium reab-sorption and renin
of rat renal
secretion. Fed Proc 1985;44(13):281622.
cortical slices.
Journal
of
[238] Kirchheim HR, Gross R, Hackenberg
Hypertension
HM,
Hackenthal
E,
Huber
J.
1984;2(1):258.
Autoregulation of renin release and its
modification by renal sympathetic nerves[247] Churchill
PC, Rossi NF,
in conscious dogs. Kidney Inst
Churchill MC,
1981;20:152.
Ellis
VR.
Effect
of
[239] Blaine EH, Davis JO. Evidence for a
melittin
on
renal vascular mechanism in renin release:
renin
and
new observations with graded stimulation
prostaglandin
by aortic constriction. Circ Res
E2
release
1971;28((5):Suppl 2):11826.
from rat renal
[240] Esler MD, Krum H, Sobotka PA,
cortical slices.
Schlaich MP, Schmieder RE, Bohm M.
J
Physiol
Renal sympathetic denervation in patients
1990;428:2334
with treatment-resistant hypertension (The
1.
Symplicity HTN-2 Trial): a randomised
controlled trial. Lancet 2010;376[248] Park CS,
Honeyman
(9756):19039.
TW,
Chung
ES, Lee JS,
Sigmon
DH,
[241] Friis UG, Jensen BL, Hansen PB,
Fray
Andreasen D, Skott O. Exocytosis and
JC.
endocytosis in juxtaglomerular cells. Acta
Involvement of
Physiol Scand 2000;168(1):959.
calmodulin in
[242] Friis UG, Jensen BL, Aas JK, Skott O.
mediating
Direct demonstration of exocytosis and
inhibitory
endocytosis
in
single
mouse
action
of
juxtaglomerular
cells.
Circ
Res
intracellular
21
1999;84(8):92936.
Ca on renin
[243] Churchill PC. Second messengers in
secretion. Am J
renin secretion. Am J Physiol Renal
Physiol

[230]

1986;251 (6 Pt
2):F10551062.

[249]

Della
Bruna R, Pinet
F, Corvol P,
Kurtz
A.
Calmodulin
antagonists stimulate
renin secretion
and inhibit
renin synthesis
in vitro. Am J
Physiol
1992;262(3 Pt
2):F397402.
[250] Rasmussen
H, Barrett PQ.
Calcium
messenger
system:
an
inte-grated
view. Physiol
Rev
1984;64(3):938
84.

447

Hypertension
[251] Sigmund CD, Jones CA, Kane CM, Wu C,
2005;45(1):38.
Lang JA, Gross KW. Regulated tissueand cell-specific expression of the human [262] Lang JA,
Ying
LH,
renin gene in transgenic mice. Circ Res
Morris
BJ,
1992;70 (5):10709.
Sigmund CD.
Transcriptional
[252] Fukamizu A, Hatae T, Kon Y,
and
Sugimura M, Hasegawa T, Yokoyama M,
posttranscriptio
et al. Human renin in transgenic mouse
nal
kidney is localized to juxtaglomerular
mechanisms
cells. Biochem J 1991;278(Pt 2):6013.
regulate human
renin
gene
[253] Pan L, Wang Y, Jones CA, Glenn ST,
expression in
Baumann H, Gross KW. EnhancerCalu-6 cells.
dependent inhibition of mouse renin
Am J Physiol
transcription by inflammatory cytokines.
1996;271(1 Pt
Am
J
Physiol
Renal
Physiol
2): F94100.
2005;288(1):F117124.
[263]
Chen M,
[254] Borensztein P, Germain S, Fuchs S,
Schnermann J,
Philippe J, Corvol P, Pinet
Smart
AM,
6. cis-Regulatory elements and transBrosius
FC,
acting factors directing basal and cAMPKillen
PD,
stimulated human renin gene expression
Briggs
JP.
in
chorionic
cells.
Circ
Res
Cyclic AMP
1994;74(5):76473.
selectively
[255] Smith DL, Morris BJ, Do YS, Law
increases renin
RE, Shaw KJ, Hseuh WA. Identification
mRNA
of cyclic AMP response element in the
stability
in
human renin gene. Biochem Biophys Res
cultured
Commun 1994;200 (1):3209.
juxtaglomerula
r
granular
[256] Paul M, Burt DW, Krieger JE,
cells. J Biol
Nakamura N, Dzau VJ. Tissue specificity
Chem
of renin promoter activity and regulation
1993;268(32):2
in mice. Am J Physiol 1992;262(5 Pt
413844.
1):E644650.
[257] Morris BJ, Smith DL, Law RE, Do[264] Morris BJ,
Adams
DJ,
YS, Shaw KJ, Hsueh WA. Function of
Beveridge DJ,
human renin proximal promoter DNA.
van
der
Kidney Int 1994;46(6):151621.
Weyden
L,
[258] Ying L, Morris BJ, Sigmund CD.
Mangs
H,
Transactivation of the human renin
Leedman PJ.
promoter by the cyclic AMP/protein
cAMP controls
kinase A pathway is mediated by both
human renin
cAMP-responsive element binding promRNA
tein-1 (CREB)-dependent and CREBstability
via
independent mechanisms in Calu-6 cells. J
specific RNABiol Chem 1997;272(4):241220.
binding
[259] Petrovic N, Black TA, Fabian JR,
proteins. Acta
Kane C, Jones CA, Loudon JA, et al. Role
Physiol Scand
of proximal promoter elements in
2004;181(4):36
regulation of renin gene transcription. J
973.
Biol Chem 1996;271(37):22499505.
[265]
Griendling
[260] Germain S, Bonnet F, Philippe J,
KK,
UshioFuchs S, Corvol P, Pinet F.
Fukai
M,
1 novel distal enhancer confers chorionic
Lassegue
B,
expression on the human renin gene. J
Alexander RW.
Biol Chem 1998;273(39):25292300.
Angiotensin II
[261] Pan L, Gross KW. Transcriptional
signaling
in
regulation
of
renin:
an update.
I. EPITHELIAL

vascular
smooth
muscle. New
con-cepts.
Hypertension
1997;29(1 Pt
2):36673.
[266] Blantz RC,
Konnen
KS,
Tucker
BJ.
Angiotensin II
effects
upon
the glomerular
microcirculatio
n
and
ultrafiltration
coefficient of
the rat. J Clin
Invest
1976;57(2):419
34.
[267] Dworkin
LD, Ichikawa
I, Brenner BM.
Hormonal
modulation of
glomerular
function. Am J
Physiol
1983;244(2):F
95104.
[268] Navar LG,
Inscho
EW,
Majid
SA,
Imig
JD,
HarrisonBernard LM,
Mitchell KD.
Paracrine
regulation of
the
renal
microcirculation. Physiol
Rev
1996;76(2):425
536.

[269]

Mendelsoh

n F, Dunbar M,
Allen A, Chou
S, Millan M,
Aguilera

G.

Angiotensin II
receptors in the
kidney.

Fed

Proc
1986;45:14205
.

AND
TRANSPORT AND
NONEPITHELI REGULATION
AL

448

15. THE RENINANGIOTENSIN SYSTEM

and the role of

sodium balance. Ann
Ito S, Johnson CS,
Intern
Med
Carretero OA. Modulation of
1985;103(2):2223.
angiotensin
II-induced
SC,
vasoconstriction
by[280] Textor
endothelium-derived relaxing
Tarazi RC, Novick
facAC, Bravo EL,
tor in the isolated
Fouad
FM.
microperfused rabbit afferent
Regulation of renal
arteriole.
hemodynamics and
10 Clin
Invest
glomerular filtration
1991;87(5):165663.
in patients with
[271] Olsen ME, Hall JE,
renovascular
Montani JP, Cornell JE.
hypertension during
Interaction between renal
converting enzyme
prostaglandins and angiotensin
inhibition
with
II in controlling glomer-ular
captopril. Am J Med
filtration in the dog. Clin Sci
1984;76 (5B):2937.
(Lond) 1987;72(4):42936.
[272] Fleming JT, Parekh N,[281] Miller
WL,
Steinhausen
M.
Calcium
Thomas RA, Berne
antagonists
preferentially
RM,
Rubio
R.
dilate preglomerular vessels of
Adenosine
hydronephrotic kidney. Am J
production in the
Physiol
1987;253(6
Pt
ischemic
kidney.
2):F11571163.
Circ
Res
[273] Carmines PK, Morrison
1978;43(3):3907.
TK, Navar LG. Angiotensin II
[282] Haddy FJ, Scott
effects
on
microvascular
JB.
Metabolically
diameters of in vitro bloodlinked
vasoactive
perfused
juxtamedullary
chemicals in local
nephrons. Am J Physiol
regulation of blood
1986;251(4 Pt 2): F610618.
flow. Physiol Rev
1968;48 (4):688707.
[274] Carmines PK, Navar LG.

[270]

Disparate effects of Ca channel

blockade on afferent and[283] Spielman WS,
Thompson CI. A
efferent arteriolar responses to
proposed role for
ANG II. Am J Physiol
adenosine in the
1989;256(6 Pt 2):F10151020.
regulation of renal
[275] Harrison-Bernard LM,
hemodynamics and
Monjure CJ, Bivona BJ.
renin release. Am J
Efferent arter-ioles exclusively
Physiol
express the subtype 1A
1982;242(5):F42343
angiotensin
receptor:
5.
functional
insights
from
[284]
Woodcock EA,
genetic mouse models. Am J
Loxley R, Leung E,
Physiol
Renal
Physiol
Johnston
CI.
2006;290(5):F11771186.
Demonstration
of
[276] Cowley AW, Roman RJ,
RA-adenosine
Fenoy FJ, Mattson DL. Effect
receptors in rat renal
of renal medullary circulation
papillae. Biochem
on
arterial
pressure.
J
Biophys
Res
Hypertens
Suppl
Commun
1992;10(7):S187193.
1984;121(2):43440.
[277] Earley LE, Friedler RM.
M,
Changes in renal blood flow[285] Miyamoto
Yagil Y, Larson T,
and pos-sibly the intrarenal
Robertson
C,
distribution of blood during
Jamison RL. Effects
the natriuresis accompanying
of
intrarenal
saline loading in the dog. J
adenosine on renal
Clin Invest 1965;44:92941.
function and medul[278] Earley LE, Friedler RM.
lary blood flow in
The effects of combined renal
the rat. Am J Physiol
vasodi-latation and pressor
1988;255(6 Pt 2):
agents on renal hemodynamics
F12301234.
and the tubular reabsorption of
sodium. J Clin Invest 1966;45
(4):54251.
[286] Mason J. The
pathophysiology of
ischaemic
acute
[279] Hricik DE. Captoprilrenal failure.
induced renal insufficiency
1 new hypothesis

about the initiation

phase. Ren Physiol
1986;9(3):12947.
[287] Osswald
H,
Schmitz HJ, Kemper
R. Tissue content of
adeno-sine, inosine
and hypoxanthine in
the rat kidney after
ische-mia
and
postischemic
recirculation.
Pflugers
Arch
1977;371(1-2):459.

[288]

Yagil
Y,
Miyamoto
M,
Jamison RL. Inner
medullary
blood
flow in postischemic
acute renal failure in
the rat. Am J Physiol
1989;256(3
Pt
2):F456461.

[289]

Purdy KE, Arendshorst

Nephrol
1999;10
WJ. Prostaglandins buffer
(12):262030.
ANG II-mediated increases in
cytosolic
calcium
in[297] Faubert
PF,
preglomerular VSMC. Am J
Chou SY, Porush JG.
Physiol
1999;277(6
Pt
Regulation
of
2):F850858.
papillary
plasma
[290] Jaimes EA, Hua P, Tian
flow by angiotensin
RX, Raij L. Human glomerular
II.
Kidney
Int
endo-thelium: interplay among
1987;32 (4):4728.
glucose, free fatty acids,
angiotensin II, and oxidative[298] Zou AP, Wu F,
stress. Am J Physiol Renal
Cowley Jr. AW.
Physiol
2010;298(1):
Protective effect of
F125132.
angiotensin
II[291] Ichihara A, Imig JD,
induced increase in
Inscho EW, Navar LG.
nitric oxide in the
Interactive
nitric
oxiderenal
medullary
angiotensin II influences on
circulation.
renal
microcirculation
in
Hypertension
angiotensin
II-induced
1998;31(1
Pt
hypertension.
Hypertension
2):2716.
[299] Szentivanyi Jr.
1998;31 (6):125560.
M,
Maeda
CY,
[292] Zatz R, Dunn B, Anderson
Cowley Jr. AW.
S, Rennke H, Brenner B.
Local
renal
medullary L-NAME
Prevention
of
diabetic
infusion
enhances
glomerulopathy
by
the effect of longpharmacological amelioration
term angiotensin II
of
glomerular
capillary
treatment.
hypertension. J Clin Invest
Hypertension
1986;77:192530.
1999;33(1
Pt
2):4405.
[293] Meyer TW, Anderson S,
JG,
Rennke HG, Brenner BM.[300] Dickhout
Mori T, Cowley Jr.
Reversing
glomerular
AW. Tubulovascular
hypertension
stabilizes
nitric
oxide
established glomerular injury.
crosstalk: buffering
Kidney Int 1987;31(3):7529.
of angiotensin II[294] Anderson S, Meyer T,
induced medullary
Rennke H, Brenner B. Control
vasoconstriction.
of glomerular hypertension
Circ
Res
limits renal injury in rats with
2002;91(6):48793.
reduced renal mass. J Clin
[301] Roman
RJ,
Invest 1985;76:6129.
Lianos E. Influence
[295] Simons JL, Provoost AP,
of prostaglandins on
De Keijzer MH, Anderson S,
papillary blood flow
Rennke HG, Brenner BM.
and
pressurePathogenesis of glomerular
natriuretic response.
injury
in the fawn-hooded rat:
Hypertension
effect of unilateral
1990;15(1):2935.
nephrectomy.
[302] Roman
RJ,
Kauker ML. Renal
J
Am
Soc
Nephrol
1993;4(6):136270.
effect
of
prostaglandin
[296] Ruan X, Oliverio MI,
synthe-tase
Coffman TM, Arendshorst WJ.
inhibition in rats:
Renal vascular reactivity in
Micropuncture
mice:
AngII-induced
studies.
Am
J
vasoconstriction in AT1A
Physiol
receptor null mice. J Am Soc

I. EPITHELIAL AND
NONEPITHELIAL
TRANSPORT AND
REGULATION

1978;235(2):F11111
8.
[303] Higashihara E,
Stokes JB, Kokko
JP, Campbell WB,
DuBose Jr. TD.
Cortical
and
papillary
micropuncture
examination of chloride transport in
segments of the rat
kidney
during
inhibition
of
prostaglandin
production. Possible
role
for
prostaglandins in the
chloruresis of acute
volume expansion. J
Clin
Invest
1979;64(5):127787.
[304] Chen
PY,
Sanders PW. Larginine abrogates
salt-sensitive
hypertension
in
Dahl/Rapp rats. J
Clin Invest 1991;
88(5):155967.

[305]

Szentivanyi Jr.
M, Zou AP, Mattson
DL,
Soares
P,
Moreno C, Roman
RJ, et al. Renal
medullary
nitric
oxide deficit of Dahl
S rats enhances
hypertensive actions
of angiotensin II.
Am J Physiol Regul
Integr Comp Physiol
2002;283(1):R26627
2.
[306] He H, Kimura S,
Fujisawa
Y,
Tomohiro
A,
Kiyomoto K, Aki Y,
et al. Dietary Larginine
supplementation
normalizes regional
blood flow in DahlIwai
salt-sensitive
rats. Am J Hypertens
1997;10(5
Pt
2):89S93S.

REFERENCES

Disruption of
the Ang II type
Hu L, Manning Jr. RD. Role of nitric
1
receptor
oxide in regulation of long-term pressurepromotes
natriuresis relationship in Dahl rats. Am J
longevity
in
Physiol 1995;268(6 Pt 2):H23752383.
mice. J Clin
[308] Rajapakse NW, Mattson DL. Role of
Invest
L-arginine uptake mechanisms in renal
2009;119(3):52
blood flow responses to angiotensin II in
430.
rats.
Acta
Physiol
(Oxf)
[321] Olsen ME,
2011;203(3):391400.
Hall
JE,
[309] Weiner I, New A, Milton A, Tisher C.
Montani
JP,
Regulation of luminal alkalinization and
Guyton
AC,
acidification in the cortical collecting duct
Langford HG,
by angiotensin II. Am J Physiol
Cornell
JE.
1995;38:F7308.
Mechanisms of
[310] Geibel J, Giebisch G, Boron WF.
1
1
angiotensin II
Angiotensin II stimulates both Na( )-H
1
2
natriuresis and
exchange and Na /HCO3 co-transport in
antithe rab-bit proximal tubule. Proc Natl
natriuresis. Am
Acad Sci USA 1990;87 (20):791720.
J
Physiol
1985;249(2 Pt
[311] Komlosi P, Fuson A, Fintha A, Peti2):F299307.
Peterdi J, Rosivall L, Warnock DG, et al.
JE,
Angiotensin I conversion to angiotensin II[322] Hall
Guyton
AC,
stimulates cortical collecting duct sodium
Smith Jr MJ,
transport. Hypertension 2003;42:1959.
Coleman TG.
[312] Peti-Peterdi J, Warnock DG, Bell PD.
Blood pressure
Angiotensin II directly stimulates ENaC
and
renal
activity in the cortical collecting duct via
function during
AT
chronic
(1) receptors. J Am Soc Nephrol
changes
in
2002;13(5):11315.
sodium intake:
[313] Schuster VL, Kokko JP, Jacobson HR.
role
of
Angiotensin II directly stimulates sodium
angiotensin.
transport in rabbit proximal convoluted
tubules. J Clin Invest 1984;73(2):50715.
Am J Physiol
[314] Tojo A, Tisher CC, Madsen
KM.
Renal Physiol
1
Angiotensin II regulates H ( )-ATPase
1980;239(3):
activity in rat cortical collecting duct. Am
F271280.
J Physiol 1994;267(6 Pt 2):F10451051.
[315] Barreto-Chaves ML, Mello-Aires M.[323] Hall JE,
Guyton
AC,
Effect of luminal angioJackson
TE,
tensin II and ANP on early and late
2
Coleman TG,
cortical distal tubule HCO3 reabsorption.
Lohmeier TE,
Am J Physiol 1996;271(5 Pt 2):F977984.
Trippodo NC.
[316] Levine DZ, Iacovitti M, Buckman S,
Control
of
Burns KD. Role of angio-tensin II in
glomerular
dietary modulation of rat late distal tubule
filtration rate
bicar-bonate flux in vivo. J Clin Invest
by
1996;97(1):1205.
reninangiotensi
[317] Cogan MG. Angiotensin II: a
n system. Am J
powerful controller of sodium transport in
Physiol
the early proximal tubule. Hypertension
1977;233(5):F
1990;15 (5):4518.
366372.
[318] Wang T, Giebisch G. Effects of[324] Bouley R,
Palomino
Z,
angiotensin II on electrolyte transport in
Tang
SS,
the early and late distal tubule in rat
Nunes
P,
kidney. Am J Physiol 1996;271(1 Pt
Kobori H, Lu
2):F143149.
HA, et al.
[319] Gurley SB, Riquier-Brison AD,
Angiotensin II
Schnermann J, Sparks MA, Allen AM,
and
Haase VH, et al. AT1A angiotensin
hypertonicity
receptors in the renal proximal tubule
modulate
regulate blood pressure. Cell Metab
proximal tubu2011;13(4):46975.
lar aquaporin 1
[320] Benigni A, Corna D, Zoja C,
expression. Am
Sonzogni A, Latini R, Salio M, et al.
J Physiol Renal

[307]

Physiol
2009;297(6):F
15751586.
[325] Davisson
R, Ding Y, Stec
D, Catterall J,
Sigmund
C.
Novel
mechanism of
hypertension
revealed
by
cell-specific
targeting
of
human
angiotensinoge
n in transgenic
mice. Physiol
Genomics
1999;1:39.

[326]

Li
H,
Weatherford
ET, Davis DR,
Keen
HL,
Grobe
JL,
Daugherty A,
et al. Renal
proximal
tubule
angiotensin
AT1A

449

potent
regulator
of
acidi-fication
in the rat early
proximal
convoluted
tubule. J Clin
Invest
1987;80(1):272
5.
[338] Liu FY,
Cogan
MG.
[328] Brown GP, Douglas JG. Angiotensin
Angiotensin II
II binding sites on iso-lated rat renal brush
stimulation of
border
membranes.
Endocrinology
hydrogen ion
1982;111(6):18306.
secretion in the
rat
early
[329] Brown GP, Douglas JG. Angiotensin
proximal
II-binding sites in rat and primate isolated
tubule. Modes
renal tubular basolateral membranes.
of
action,
Endocrinology 1983;112(6):200714.
mechanism,
[330] Harrison-Bernard LM, Navar LG, Ho
and kinetics. J
MM,
Vinson
GP,
el-Dahr
SS.
Clin
Invest
Immunohistochemical localization of
1988;82(2):601
ANG II AT1 receptor in adult rat kidney
7.
using a monoclonal anti-body. Am J
receptors regulate blood pressure. Am J
Physiol Regul Integr Comp Physiol
2011;301(4):R10671077.
[327] Riquier-Brison AD, Leong PK,
Pihakaski-Maunsbach K, McDonough
AA. Angiotensin II stimulates trafficking
of NHE3, NaPi2, and associated proteins
into the proximal tubule microvilli. Am J
Physiol Renal Physiol 2010;298(1):
F177186.

Physiol 1997;273(1 Pt 2):F170177.

[339] Li
Y,
Yamada
H,
Braam B, Mitchell KD, Fox J, Navar
Kita Y, Kunimi
LG. Proximal tubular secretion of
M, Horita S,
Suzuki M, et
angiotensin II in rats. Am J Physiol
al.
1993;264(5 Pt 2):F891898.
Roles of ERK

[331]

sodiumindependent
effect. J Clin
Invest
1983;72(1):778
3.

[342]

Weiner ID,
Hamm
LL.
Regulation of
intracellular
pH in the rabbit
cortical
collecting
tubule. J Clin
Invest
1990;85(1):274
81.
[343] Hays SR.
Mineralocortic
oid modulation
of apical and
basolat-eral
membrane
1
2
H /OH /HCO3
2
transport
processes
in
the rabbit inner
stripe of outer
medullary
collecting duct.
J Clin Invest
1992;90(1):180
7.
[344] Harrington
JT, Hulter HN,
Cohen
JJ,
Madias
NE.
Mineralocortic
oid-stimulated
renal
acidification:
the critical role
of
dietary
sodium.
Kidney
Int
1986;30(1):438
.
[345] Batlle DC.
Segmental
characterizatio
n of defects in
collecting
tubule
acidification.
Kidney
Int
1986;30(4):546
54.

and cPLA2 in
Navar LG, Lewis L, Hymel A, Braam
the angiotensin
B,
Mitchell
KD.
Tubular
fluid
II-mediated
concentrations and kidney contents of
biphasic
angiotensins I and
regulation of
1
2
35 in anesthetized rats. J Am Soc
Na -HCO3( )
Nephrol 1994;5(4):11538.
transport. J Am
[333] Li XC, Hopfer U, Zhuo JL. AT1
Soc Nephrol
receptor-mediated uptake of angiotensin II
2008;19(2):252
and NHE-3 expression in proximal tubule
9.
cells through a microtubule-dependent[340] Liu
FY,
endocytic pathway. Am J Physiol Renal
Cogan
MG.
Physiol 2009;297(5):F13421352.
Role
of
[334] Quan A, Baum M. Endogenous
angiotensin II
production of angiotensin II modulates rat
in
proximal tubule transport. J Clin Invest
glomerulotubul
1996;97 (12):287882.
ar balance. Am
[335] Boer WH, Braam B, Fransen R, Boer
J
Physiol
P, Koomans HA. Effects of reduced renal
1990;259(1 Pt
perfusion pressure and acute volume
2):F7279.
expan-sion on proximal tubule and whole [341] Stone DK,
kidney angiotensin II con-tent in the rat.
Seldin
DW,
Kidney Int 1997;51(1):449.
Kokko
JP,
[336] Thomson SC, Deng A, Wead L,
Jacobson HR.
Richter K, Blantz RC, Vallon
Mineralocortic
22.
An unexpected role for
oid modulation
angiotensin II in the link between dietary
of
rabbit
salt and proximal reabsorption. J Clin
medullary
Invest 2006;116 (4):11106.
collecting duct
acidification. A
[337] Liu FY, Cogan MG. Angiotensin II: a
AND
TRANSPORT AND
NONEPITHELI REGULATION
I. EPITHELIAL
AL

[332]

450

15. THE RENINANGIOTENSIN SYSTEM

[346]

[355]

Paxton WG, Runge M,

Horaist C, Cohen C, Alexander
RW,
Bernstein
KE.
Immunohistochemical
localization of rat angio-tensin
II AT1 receptor. Am J Physiol
1993;264(6 Pt 2): F989995.

[347]

Esther
C,
Howard T, Marino
E,
Goddard
J,
Capecchi
M,
Bernstein K. Mice
lacking angiotensin
converting enzyme
have low blood
pressure,
renal
pathology,
and
reduced male fertility.
Lab
Invest
1996;74:95365.

Poumarat JS, Houillier P,

Rismondo C, Rogues B, Lazar
G, Paillard M, et al. The
luminal membrane of rat thick
limb expresses AT1 receptor[356] Kihara
M,,
and aminopeptidase activities.
Umemura
S,,
Kidney Int 2002;62(2):43445.
Sumida
Y,,
[348] Amlal H, LeGoff C,
Yokoyama
M,,
Vernimmen C, Soleimani M,
Yabana M,, Nyui N,,
Paillard M, Bichara M. ANG II
et
al.
Genetic
1
1
1
2
deficiency
of
controls Na( )-K (NH4 )-2Cl
angiotensinogen
co-transport via 20-HETE and
produces
an
PKC in medullary thick
impaired
urine
ascending limb. Am J Physiol
concentrating ability
1998;274(4 Pt 1):C10471056.
in
mice.
[349] Lerolle N, Bourgeois S,
1998;53(3):548.
Leviel F, Lebrun G, Paillard
M, Houillier P. Angiotensin II
inhibits NaCl absorption in the
rat medullary thick ascending
limb. Am J Physiol Renal
Physiol 2004;287(3):F404410.

[350]

Capasso G, Unwin R,
Ciani F, De Santo NG, De
Tommaso G, Russo F, et al.
Bicarbonate transport along
the loop of
Henle. II. Effects of acidbase,
dietary, and neurohumoral
determinants. J Clin Invest
1994;94(2):8308.
[351] Kwon TH, Nielsen J, Kim
YH, Knepper MA, Frokiaer J,
Nielsen S. Regulation of
sodium transporters in the
thick ascending limb of rat
kidney:
response
to
angiotensin II. Am J Physiol
Renal
Physiol
2003;285(1):F152165.
[352] Rothenberger F, Velic A,
Stehberger PA, Kovacikova J,
Wagner CA. Angiotensin II
1
stimulates vacuolar H -ATPase
activity in renal acid-secretory
intercalated cells from the
outer medullary collecting
duct. J Am Soc Nephrol
2007;18 (7):208593.

[353]

Pech V, Zheng W, Pham

TD, Verlander JW, Wall SM.
1
Angiotensin II activates H ATPase in type A intercalated
cells. J Am Soc Nephrol
2008;19(1):8491.
[354] Wei Y, Wang W.
Angiotensin II stimulates
basolateral K chan-nels in rat
cortical collecting ducts. Am J
Physiol
Renal
Physiol
2003;284(1):F175181.

[357]

Oliverio
MI,
Delnomdedieu
M,
Best CF, Li P, Morris
M, Callahan MF, et
al. Abnormal water
metabolism in mice
lack-ing the type 1A
receptor for ANG II.
Am J Physiol Renal
Physiol
2000;278(1):F7582.
[358] Sparks
MA,
Parsons
KK,
Stegbauer J, Gurley
SB, VivekanandanGiri A, Fortner CN,
et al. Angiotensin II
type 1A receptors in
vas-cular
smooth
muscle cells do not
influence
aortic
remodeling
in
hypertension.
Hypertension
2011;57(3):57785.
[359] Kwon
T-H,
Nielsen J, Knepper
MA, Frokiaer J,
Nielsen
S.
Angiotensin II AT1
receptor
blockade
decreases
vasopressin-induced
water reabsorption
and AQP2 levels in
NaCl- restricted rats.
Am J Physiol Renal
Physiol
2005;288(4):F67368
4.
[360] Wong NL, Tsui
JK. Angiotensin II
upregulates
the
expression
of
vasopressin
V2
mRNA in the inner
medullary collecting
duct of the rat.
Metabolism
2003;52(3):2905.
[361] Wang W, Li C,
Summer S, Falk S,
Schrier
RW.
Interaction between
vasopressin
and
angiotensin II in
vivo and in vitro:
effect on aquaporins
and
urine
concentration. Am J
Physiol
Renal
Physiol
2010;299(3):F57758
4.
[362] Li C, Wang W,
Rivard CJ, Lanaspa
MA, Summer S,
Schrier
RW.
Molecular
mechanisms
of
angiotensin
II
stimulation on aqua-

porin-2
expression
and
Katsuya T, et al.
trafficking. Am J Physiol
Deletion
of
Renal
Physiol
angioten-sin2011;300(5):F12551261.
converting enzyme 2
accelerates pressure
[363] Stegbauer J, Gurley SB,
overload-induced
Sparks MA, Woznowski M,
cardiac dysfunction
Kohan DE, Yan M, et al. AT1
by increasing local
receptors in the collecting duct
angiotensin
II.
directly
modulate
the
Hypertension
concentration of urine. J Am
2006;47(4):71826.
Soc
Nephrol
2011;22
[366] Krattinger N,
(12):223746.
Capponi
A,
Mazzolai L, et al.
[364] Crackower MA, Sarao R,
Connexin40
reguOudit GY, et al. Angiotensinlates
renin
convert-ing enzyme 2 is an
production
and
essential regulator of heart
blood
pressure.
function.
Nature
Kidney Int 2007;72
2002;417(6891):8228.
(7):81422.
[365] Yamamoto K, Ohishi M,

[367]

Lubkemeier
I,
Machura K, Kurtz L,
et al. The connexin
40 A96S mutation
causes
renindependent
hypertension. J Am
Soc
Nephrol
2011;22(6):103140.
[368] Wagner C, de
Wit C, Kurtz L,
Grunberger C, Kurtz
A,
Schweda
F.
Connexin40
is
essential for the
pressure control of
renin synthesis and
secretion. Circ Res
2007;100(4):55663.

I. EPITHELIAL AND
NONEPITHELIAL
TRANSPORT AND
REGULATION