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H Y P E RT E N S I O N I N 2 0 1 7 was also blunted in Tcrδ−/− mice. In a cohort

of people with or without coronary artery

Novel mechanisms of hypertension disease and/or hypertension, a multiple lin‑

ear regression model showed similar, additive

and vascular dysfunction correlations between TCRγ constant region

Ernesto L. Schiffrin
New findings in 2017 enhanced our understanding of the mechanisms that
regulate blood pressure. Key studies provided insights into immune
mechanisms, the role of the gut microbiota, the adverse effects of perivascular
fat and inflammation on the vasculature, and the contribution of rare variants
in renin–angiotensin–aldosterone system genes to salt sensitivity.
The year 2017 saw the publication of many
basic and clinical studies in the field of
hypertension as well as new American
Heart Association and American College of
Cardiology guidelines for the management
of high blood pressure in adults1. Here, I focus
on key studies that advanced understanding of
basic mechanisms of blood pressure regula‑
tion and vascular dysfunction, including three
studies that provide new insights into the salt
sensitivity of blood pressure.
Research into immune mechanisms of
hypertension has grown substantially in recent
years and 2017 was no exception. As angio‑
tensin II (ANGII) infusion increases blood
pressure via a mechanism involving increased
production of IL‑17 from T helper 17 (TH17)
cells in mice2, and salt induces TH17 cells via
a serum and glucocorticoid-regulated kinase 1
(SGK1)-dependent pathway 3, Norlander
et  al. evaluated whether SGK1 signalling
in T cells contributes to salt-induced blood
pressure elevation and end-organ damage4.
They report that in mice, T cell-specific dele‑
tion of Sgk1 blunted blood pressure elevation
and abrogated endothelial dysfunction and
renal injury in response to ANGII infusion.
Deoxycorticosterone acetate–salt-induced
blood pressure elevation and vascular inflam‑
mation were also attenuated in these mice.
The basolateral Na+/K+/2Cl− cotransporter 1
(NKCC1; also known as solute carrier family 12
member 2) was upregulated in CD4+ T cells cul‑
tured in TH17‑polarizing conditions and medi‑
ated a salt-induced increase in the expression of
SGK1 and the IL‑23 receptor (which has a role
in TH17 cell differentiation). Thus, T cell SGK1
and NKCC1 are novel mediators of the effects
expression in blood, age and sex; the addition
of coronary artery disease to the model did not
improve these correlations. Thus, γδT cells
might contribute to the development of
­hypertension and are a novel target for therapy.
of salt on blood pressure and are ­potential
targets for the treatment of hypertension.
Wilck et al. also reported a novel mech­
anism by which salt increases blood pressure
and induces TH17 cells5. They found that
in mice, high salt intake results in changes in
bacterial species in the gut, particularly deple‑
tion of Lactobacillus murinus. Moreover,
treating mice with L. murinus prevented a
salt-­induced increase in TH17 cell numbers,
hypertension and the worsening of experimen‑
tal auto­immune encephalomyelitis. In healthy
men, a high-salt diet led to a reduction in
intestinal Lactobacillus spp. and increases
in TH17 cell numbers and blood pressure.
These results establish a link between salt
intake and the gut microbiome, and between
the gut microbiome and the immune system.
The researchers propose that the gut micro­
biome might be a potential therapeutic tar‑
get to counteract salt-sensitive conditions,
including hypertension.
A role of another lymphocyte subset
— γδT cells — in blood pressure elevation
was demonstrated by Caillon et al.6 These
unconven­tional, innate-like T cells comprise
only 1–4% of all lymphocytes in the circulation
but are very abundant in some tissues such as
the intestinal wall and the skin. In wild-type
mice, ANGII infusion increased systolic blood
pressure, increased splenic γδT cell numbers
and activation, and decreased endothelial
function. These effects on blood pressure and
endothelial function were abrogated in mice
that lacked γδT cells owing to genetic knockout
of the δ-subunit or antibody-­induced γδT cell
depletion. ANGII‑induced T cell activation
in the spleen and perivascular adipose tissue
The incidence of aortic aneurysms is
increased in patients with hypertension and
athero­sclerosis compared with the general
popu­lation. In 2017, increasing evidence
for a role of perivascular fat and inflamma‑
tion in vascular remodelling led to a study
of the potential role of perivascular visceral
adipose tissue (VAT) in aneurysm forma‑
tion. Sakaue et al.7 tested the hypothesis that
genetic deletion of type  1a angiotensin II
receptor (AGTR1A) in VAT could blunt the
development of aortic aneurysms in apolipo­
protein  E-deficient (Apoe −/−) mice. They
found that, compared with transplantation
of VAT from Apoe−/− mice, transplantation of
VAT from Apoe−/−/Agtr1a−/− mice to around the
abdominal aorta of Apoe−/− recipients reduced
Key advances
• Serum and glucocorticoid-regulated kinase 1
(SGK1) signalling in T cells contributes to
salt-induced blood pressure elevation and
end-organ damage via a mechanism involving
upregulation of Na+/K+/2Cl− cotransporter 1
(NKCC1) and polarization to a T helper 17
(TH17) cell phenotype4
• A high-salt diet alters the gut microbiome of
humans and mice, resulting in depletion of
Lactobacillus spp. and an increase in TH17 cell
numbers and blood pressure5
• In mice, γδT cells contribute to angiotensin
II‑induced hypertension and endothelial
dysfunction and might also have a role in
human hypertension and end-organ damage6
• AGTR1A and osteopontin mediate the
polarization of macrophages to an
inflammatory phenotype in perivascular fat,
resulting in inflammation and potentially
contributing to the formation of aortic
aneurysms7
• Rare variants in seven renin–angiotensin–
aldosterone system (RAAS)-related genes,
including APLN and RENBP, are associated
with salt sensitivity of blood pressure8

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YEAR IN REVIEW

low-frequency variants identified associations

↑ Blood pressure
Renal Vasoconstriction
sodium
retention
IL-23R ↑ IL-17
TH17 Priming γδT
Abdominal aortic
↓ Lactobacillus spp. aneurysm
• ↑ Numbers • ↑ Numbers
• ↑ Activation • ↑ Activation
• ↑ SGK1
• ↑ NKCC1 AGTR1A
RAAS gene ? discovery of novel biomarkers and therapeutic
Salt ANGII ↑ Osteopontin
variants
Visceral adipose
tissue
Figure 1 | Novel mechanisms of hypertension and aortic aneurysm formation. Salt induces
Naturekinase
activation of T helper 17 (TH17) cells via a serum and glucocorticoid-regulated Reviews | Nephrology
1 (SGK1)-
dependent pathway that enhances the activity of Na+/K+/2Cl− cotransporter 1 (NKCC1). High salt
intake also results in depletion of Lactobacillus spp. in the intestinal microbiome, leading to
stimulation of TH17 cells. Angiotensin II (ANGII) stimulates γδT cells, which in turn prime other
immune cells, including TH17 cells. Activated TH17 and γδT cells produce IL‑17, which stimulates
renal sodium retention and vasoconstriction, resulting in increased blood pressure. Rare renin–
angiotensin–aldosterone system (RAAS) gene variants increase the salt sensitivity of blood pressure,
potentially via a mechanism involving ANGII. In perivascular visceral adipose tissue, binding of ANGII
to type 1a angiotensin II receptor (AGTR1A) leads to increased production of pro-inflammatory
osteopontin, which contributes to the formation and progression of abdominal aortic aneurysms.
the formation of aortic aneurysms, infiltration be complete without the inclusion of a genetic
of macrophages and gelatinolytic activity in study. Genome-wide association studies
the abdominal aorta. In addition, AGTR1A (GWAS) and candidate gene studies have iden‑
activation polarized VAT macrophages to an tified common genetic variants that influence
inflammatory phenotype, and AGTR1A defi‑ the salt sensitivity of blood pressure, including
ciency resulted in a reduction in the expression numerous single-nucleotide polymorphisms in
of pro-inflammatory o ­ steopontin in VAT and renin–angiotensin–aldosterone system (RAAS)
in ANGII‑induced osteopontin production genes8. However, these common vari­ants
by cultured adipose cells. Moreover, treat‑ explain only a small part of the heritability of
ment with an osteopontin-neutralizing anti‑ blood pressure sensitivity to salt. In 2017, Kelly
body reduced ANGII‑induced macrophage et al. conducted a resequencing study in which
migration. Consistent with these findings, the they evaluated the associations of rare variants
researchers showed that transplantation of VAT of seven RAAS genes with blood pressure salt
from osteopontin-deficient Apoe−/− mice was sensitivity in the 300 most salt-­sensitive and
more effective in reducing formation of aortic 300 most salt-resistant participants of the
aneurysms than was transplantation of Apoe−/− GenSalt study 9. The seven genes (RENBP,
VAT. They conclude that VAT AGTR1A has a ACE2, AGTR1, HSD11B1, HSD11B2, NR3C2
role in the formation of abdominal aortic aneur­ and APLN) were selected based on their poten‑
ysms via a mechanism involving osteopontin. tial roles in the regulation of blood pressure.
These findings could potentially prompt use The researchers found that individuals with
of inhibitors of the renin–­angiotensin system rare variants in these genes had 1.5‑fold greater
to prevent the development or progression of odds of being salt sensitive than those without
aortic aneurysms in at‑risk patients, including rare variants. In addition, the APLN gene was
those with hypertension. associated with salt sensitivity and rare APLN
Finally, a discussion of recent advances in variants conferred 2.2‑fold increased odds of
the understanding of hypertension would not salt sensitivity. Analyses of 50 common and
between single markers of the remaining six
RAAS genes and salt-sensitive phenotypes.
After adjustment for multiple testing, how‑
ever, only the RENBP variant rs78377269 was
associated with salt sensitivity. Each copy of
the minor allele of this variant resulted in a
1.6 mmHg greater blood pressure response to
increased dietary sodium and was associated
with a doubling of the odds of salt sensitiv‑
ity. This study provides the first evidence of
a potential contribution of rare RAAS gene
­variants to the salt sensitivity of blood pressure.
In summary, key studies published dur‑
ing 2017 open new vistas into mechanisms of
blood pressure elevation and aortic aneurysm
formation that bring together salt, immunity,
genetics, the RAAS and the vasculature (FIG. 1).
These advances provide opportunities for the
targets for hypertension.
Ernesto L. Schiffrin is at the Hypertension and Vascular
Research Unit, Lady Davis Institute for Medical
Research and Department of Medicine, Sir Mortimer
B. Davis-Jewish General Hospital, McGill University,
3755 Côte-Ste-Catherine Road, Montréal,
Québec H3T 1E2, Canada.
ernesto.schiffrin@mcgill.ca
doi:10.1038/nrneph.2017.178
Published online 2 Jan 2018
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AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the
prevention, detection, evaluation, and management of
high blood pressure in adults: a report of the American
College of Cardiology/American Heart Association Task
Force on Clinical Practice Guidelines. Hypertension
http://dx.doi.org/10.1161/HYP.0000000000000065
(2017); J. Am. Coll. Cardiol. http://dx.doi.org/
10.1016/j.jacc.2017.11.005 (2017).
2. Madhur, M. S. et al. Interleukin 17 promotes
angiotensin II‑induced hypertension and vascular
dysfunction. Hypertension 55, 500–507 (2010).
3. Wu, C. et al. Induction of pathogenic TH17 cells by
inducible salt-sensing kinase SGK1. Nature 496,
513–517 (2013).
4. Norlander, A. E. et al. A salt-sensing kinase in
T lymphocytes, SGK1, drives hypertension and
hypertensive end-organ damage. JCI Insight 2, e92801
(2017).
5. Wilck, N. et al. Salt-responsive gut commensal
modulates TH17 axis and disease. Nature 551,
585–589 (2017).
6. Caillon, A. et al. Gamma/delta T cells mediate
angiotensin II‑induced hypertension and vascular injury.
Circulation 135, 2155–2162 (2017).
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II type 1 receptor promotes vascular inflammation and
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8. He, J. et al. Genome-wide association study identifies
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598–607 (2013).
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Acknowledgements
The work of the author was funded by Canadian Institutes
of Health Research (CIHR) First Pilot Foundation Grant
143348 and a tier 1 Canada Research Chair on Hypertension
and Vascular Research by the Canada Research Chair
CIHR/Government of Canada Program.
Competing interests statement
The author declares no competing interests.

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