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VandersRenalPhysiology,8e>

Chapter4.BasicTransportMechanisms
Objectives
Identifythemajormorphologicalcomponentsofanepithelialtissueincludinglumen,interstitium,apical
andbasolateralmembranes,andtightjunctions.
Statehowtransportmechanismscombinetoachieveactivetranscellularreabsorptioninepithelial
tissues.
Defineisoosmotictransport.
Defineparacellulartransportanddifferentiatebetweentranscellularandparacellulartransport.
Definetheterms:channel,transporter,uniporter,multiporter,symporter,andantiporter.
Describequalitativelytheforcesthatdeterminemovementofreabsorbedfluidfromtheinterstitiuminto
peritubularcapillaries.
ExplainwhyvolumereabsorptionintheproximaltubuledependsonactivityoftheNaKATPase.
ComparetheStarlingforcesgoverningglomerularfiltrationwiththosegoverningperitubularcapillary
absorption.
CompareandcontrasttheconceptsofTmandgradientlimitedtransport.

TransepithelialTransport
Asshouldbeclearbynow,thekidneysaretransportmachines,movingalargearrayofsubstancesbetweenthe
renaltubulesandthenearbynetworkofbloodvessels.Thebasicprocessofmovingthesesubstances
(secretionandreabsorption)requiresthatsolutesandwatercross2celllayers:(1)theepitheliumthatmakes
upthewallsofthetubulesand(2)theendotheliumthatmakesupthevascularwalls.Substancesmustalso
traversethethinregionofinterstitialfluidbetweenthem.Inthecortex,wherethefluxesofmanyfiltered
substancesareenormous,thevascularendothelium(peritubularcapillaries)isfenestrated.Thefenestraeand
thelooseunderlyingbasementmembraneoffervirtuallynoresistancetothepassivemovementofwaterand
smallsolutes.Thisfacilepermeationhas2consequences.First,therateoftransportisgovernedalmost
exclusivelybyeventsinthetubularepitheliumratherthanthevascularendotheliumsecond,thecortical
interstitium,whichisthemediumfacedbythebasolateralmembranesofthetubularepithelia,hasan
osmolalityandconcentrationofsmallsolutesveryclosetothoseinplasma.Incontrast,bothbloodflowand
transporteventsarelessrapidinthemedulla.Onlysomeregionsofthemedullaryvasculaturearefenestrated,
sothat(1)overalltransportdependsonboththepropertiesofthevascularendotheliumandtubularepithelium,
and(2)themedullaryinterstitiumismostdefinitelynotplasmalikeinitscomposition.Intherestofthis
chapterwewilldescribetheprinciplesofepithelialtransportthatapplytoallpartsofthekidney,with
particularemphasisoneventsinthecortex.Wewillthenseehowtheseprinciplesapplytothemedullain
subsequentchapters.
Imagenotavailable. Crossingthetubularepitheliumcanoccureitherthroughthecellsoraroundthecells.
Theparacellularrouteiswhenthesubstancegoesaroundthecells,thatis,throughthematrixofthetight
junctionsthatlinkeachepithelialcelltoitsneighbor.Inmostcases,however,asubstancetakesthe
transcellularroute,a2stepprocessthroughthecells.Forreabsorption,thisisentranceacrosstheapical
membranefacingthetubularlumen,throughthecellcytosol,andthenexitacrossthebasolateralmembrane
facingtheinterstitium.Forsecretiontheprocessisreversed.Thesestructuresandpathwaysaredepictedin
Figures41AandB.
Figure41.

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Transcellularandparacellularreabsorption.Transcellularreabsorptionisatwostepprocesswithseparate
influxandeffluxsteps,utilizingtransportersorchannels.Paracellularreabsorptionisalwaysapassiveprocess
throughthetightjunctions.(ReproducedwithpermissionfromMcKinleyM,O'LoughlinVD.Human
Anatomy,2nded.NewYork:McGrawHill,2008.)
Transcellulartransport:throughcellsinonesideandouttheotherParacellulartransport:aroundcells
throughtightjunctions
Anarrayofmechanismsexistsbywhichsubstancescrossthevariousbarriers.Thesearenodifferentfrom
transportmechanismsusedelsewhereinthebody.Wecanviewthesemechanismsasaphysiologicaltoolbox.
Renalcellsusewhicheversetoftoolsismostsuitableforthetask.Thegeneralclassesofmechanismsfor
traversingthebarriersaredepictedinFigure42.
Figure42.

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Mechanismsoftransmembranesolutetransport.Withtheexceptionofsimplediffusionthroughthelipid
bilayer,alltransportinvolveschannelsandtransportersthatareregulatedbysignalingpathways.
Thepresenceorabsenceofagiventransportproteinendowsthetubularepitheliumwithselectivity,thatis,the
abilitytochoosewhichsubstanceispermittedtomove.Selectivity,obviously,appliestocellmembranes
containingdifferenttransportproteins.Italsoappliestoparacellularfluxthroughtightjunctions.Keytight
junctionproteins,membersoftheclaudinfamily,determinethedegreetowhichvarioussubstancescantravel
paracellularly.Intheproximaltubule,smallionssuchassodiumandpotassium,water,andureacanmoveby
theparacellularroute.Inthethickascendinglimb,sodiumandpotassium,butnotwaterorurea,canmove
paracellularly.Neitherlocationpermitstheparacellularmovementofglucose.

MovementbyDiffusion
Imagenotavailable. Diffusionisthefrenziedrandommovementoffreemoleculesinsolution(likethe
PingPongballsinalotterydrawing).Netdiffusionoccursacrossabarrier(ie,moremoleculesmovingone
waythantheother)ifthereisdrivingforce(aconcentrationgradientor,forchargedmolecules,apotential
gradient)andifthebarrierispermeable.Thisappliestoalmostallsubstancescrossingtheendothelialbarrier
liningtheperitubularcapillaries.Itappliestosubstancestakingtheparacellularroutearoundthetubular
epitheliumandtosomesubstancestakingthetranscellularroutethroughmembranes.Smallneutralmolecules
thatarelipidsoluble,suchasthebloodgases,alcohol,andsteroids,candiffusedirectlythroughthelipid
bilayer.

MovementthroughChannels
Mostsubstancesofbiologicalimportancecannotpenetratelipidmembranesfastenoughtomeetcellular
needs.Tospeeduptheprocesstheirtransmembranefluxismediatedbyintegralmembraneproteins,whichare
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dividedintocategoriesofchannelsandtransporters(seeFigure42).Channelsaresmallpores(proteinswith
a"hole"throughtheinterioroftheprotein)thatpermit,dependingontheirstructure,waterorspecificsolutes
todiffusethroughthem.Thus,weusethetermssodiumchannelandpotassiumchanneltodesignatechannels
thatpermitdiffusionofthesemolecularspecies.Aquaporinsarechannelsthatarepermeabletowater.Some
speciesofaquaporinalsopermitdiffusionofsmallneutralmoleculesincludingcarbondioxide(CO2)and
nitricoxide(NO).Channelstypicallyflickeropenandclosedlikecamerashutters,sothatthepermeabilityofa
membranecontainingmanychannelsisproportionaltothenumberofchannelsandtheprobabilityoftheir
beingopen.Movementthroughchannelsispassive,thatis,noexternalenergyisrequired.Theenergytodrive
thediffusionisinherentintheconcentrationgradientor,strictlyspeaking,theelectrochemicalgradient,
becausechargedionsaredriventhroughchannelsandaroundcellsviatheparacellularroutenotonlyby
gradientsofconcentrationbutalsobygradientsofvoltage.Channelsrepresentamechanismforrapid
movementofspecificsubstancesacrossmembranes,whichwouldotherwisediffuseslowlyornotatall.
Acharacteristicofchannelscriticalforrenalfunctionistheregulationoftheirpermeabilitybyanumberof
environmentalfactorsandsignalingcascades(Figure43).First,manychanneltypescanbegated,meaning
thattheprobabilitythatthechannelisopencanbeincreasedordecreased.Thetopicofchannelgatingisa
wholestorybyitself,butseveralwaysofgatingchannelsincludereversiblebindingofsmallmoleculesthat
arecomponentsofsignalingcascades(ligandgatedchannels),changesinmembranepotential(voltagegated
channels),andmechanicaldistortion(stretchgatedchannels).Second,manychanneltypeshave
phosphorylationsitessuchthatphosphorylationeitherlocksthechannelshutorallowsittobegatedbyone
themechanismsabove.Third,somechannelspeciescanbemovedbackandforthbetweenthesurface
membraneandintracellularvesicles,therebyregulatingthenumberoftheexistingchannelsactually
functioningaspermeabilitypathways.Finally,andonaslowertimescale,thegenomicexpressionofchannels
isregulatedsothatthetotalnumberofchannels,whetherinthemembraneorsequesteredinvesicles,isaltered
upordown.Channelandtransporterproteinsarenotpermanentfixturesinthemembrane.Theirlifetimesin
themembranearegenerallyintherangeofafewhours.Alloftheseregulatoryprocessesarecontrolledby
intricatesignalingcascadesthatarethesubjectofcurrentresearch.
Figure43.

Commonmechanismsforregulatingchannelandtransporteractivity.1.Transportproteinsareshuttledback
andforthbetweenthesurfacemembrane,wheretheyfunctionnormally,andsitesofsequestrationatthebase
ofmicrovilliorinintracellularvesicles.2.Transportproteinsaresynthesizedandinsertedinthemembrane,or
removedanddegraded.3.Transportproteinsareactivatedorinhibitedbyattachingligands,eithercovalently
(eg,phosphorylation),orreversibly(eg,ATP).
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MovementbyTransporters
Ourgenomecodesforalargearrayofproteinsthatfunctionastransporters,allwithnamesandacronymsthat
suffusethephysiologicalliterature.Transporters,likechannels,permitthetransmembranefluxofasolutethat
isotherwiseimpermeableinthelipidbilayer.Channelscanmovelargeamountsofmaterialsacross
membranesinashortperiodoftime,butmosttransportershavealowerrateoftransportbecausethe
transportedsolutesbindmuchmorestronglytothetransportprotein.Furthermore,theproteinmustundergoa
moreelaboratecycleofconformationalchangetomovethesolutefromonesideofthemembranetotheother.
However,overallfluxratedependsnotonlyonthekineticsofindividualtransporters,butalsoonthedensity
oftransportersinthemembrane.Totalfluxviatransporterscanbeveryhighifthetransporterdensityishigh.
Asisthecaseforchannels,theamountofsubstancemovedviatransportersishighlyregulated.Theregulation
includeschangesinphosphorylationofthetransporter(therebyturningitsactivityonoroff),sequestration
intovesicles,andofcourse,changesingenomicexpression.Asdescribednext,wegrouptransportersinto
categoriesaccordingtobasicfunctionalproperties.
Uniporters
Uniporterspermitmovementofasinglesolutespeciesthroughthemembrane.Thebasicdifferencebetweena
channelandauniporteristhatachannelisatinyhole,whereasauniporterrequiresthatthesolutebindtoa
sitethatisalternatelyavailabletoonesideandthentheothersideofthemembrane(likeenteringavestibule
throughanoutsidedoorandthenleavingthevestibuletoenterahallwaythroughaninsidedoor).Movement
throughauniporterisoftencalledfacilitateddiffusionbecause,likediffusion,itisdrivenbyconcentration
gradients,butthetransportedsolutemovesthroughtheuniporterproteinratherthanthemembranelipid.Aset
ofuniporterscrucialforallcellsincludesthosethatfacilitatethemovementofglucoseacrosscellmembranes.
ThesearemembersoftheGLUT(glucosetransporter)familyofproteinsthatpermit,inthekidney'sproximal
tubuleepithelialcells,glucosetomovefromthecytosolacrossthebasolateralmembraneintotheinterstitium.
Multiporters:SymportersandAntiporters
Multiportersmove2ormoresolutespeciesacrossamembranesimultaneously.Symportersmovethem
togetherinthesamedirection.Antiportersmovetheminoppositedirections.Intheliterature,symportersare
sometimescalledcotransporters,andantiportersarecalledexchangers.Importantsymportersforthehandling
ofglucosemovesodiumandglucosetogetherintocells(membersoftheSGLTproteinfamily).Eachtransport
cyclemoves1glucosemoleculeandeither1or2sodiumionsdependingontheparticularspeciesofSGLT.
Anotherkeysymporterinthekidneyisonethatmovessodium,potassium,andchloridealltogetherintoacell
(NK2Cl).Importantantiportersinthekidneysandmanyotherorgansmovesodiumintoacellandprotons
outofacell,oftencalledsodiumhydrogenexchangers,membersoftheNHE(sodiumhydrogenexchange)
proteinfamily.Yetanotherfamilyofantiportersinmanycells,includingthekidney,moveschlorideinone
directionandbicarbonateintheoppositedirection.Inlaterchapters,wewillseehowtheseandother
transportersplaydefinedrolesinspecificnephronsegments.
Channelsareholestransportersbindsolutesandthenmovethembychangingconformation
Allmoleculartransportrequiresenergy.Inthecaseofdiffusionthroughachannelormovementviaa
uniporter,theenergyisinherentintheelectrochemicalgradientofthesolute.Withsymportersandantiporters,
atleast1ofthesolutesmovesdownitselectrochemicalgradientandprovidestheenergytomove1ormoreof
theothersolutesupitselectrochemicalgradient(likeapulleysystemwhereaweightisraisedbythe
downwardmovementofaheavierweightontheothersideofthepulley).Movementofanysoluteupits
electrochemicalgradientiscalledactivetransport.Inthecaseofsymportersandantiportersthatdonot
hydrolyzeadenosinetriphosphate(ATP),theactivetransportiscalledsecondaryactivetransportbecausethe
energyisprovidedindirectlyfromthetransportofanothersoluteratherthandirectlyfromachemicalreaction.
Inalargenumberofcases,sodiumis1ofthesolutesmovedbyasymporterorantiporter.Theelectrochemical
gradientofsodiuminallcellsfavorsentrance.Passivemovementofsodiumisthereforealwaysinward.When
sodiummovementiscoupledtothatofanothersolute,asinsodiumprotonantiport(exchange),sodiumwill
normallyenter.Thestoichiometryisimportanthere.Theenergyavailablefromagradientismultipliedbythe
numberofmoleculesthatmovepertransportcycle.Forexample,sodium/calciumantiportersmove3sodium
ionspercalciumion.Calciumhasalargerelectrochemicalgradientthansodium,butthisdifferenceis
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overcomebymoving3sodiumionspercycleoftheantiporter.
Anotherexamplewherethestoichiometryplaysanessentialroleisthecoupledtransportofbicarbonateand
sodium.AnimportantsymporterintheproximaltubuleistheNBCetransporter,whichmoves3bicarbonate
ionsand1sodiumionoutofthecell,pertransportcycle.Theelectrochemicalgradientforbicarbonateis
directedoutward,andtheenergygainedfrommoving3bicarbonateionsoutwardisgreaterthantheenergyit
takestomove1sodiumionoutwardagainstitselectrochemicalgradient.Therefore,thistransportermoves
bothsolutesoutward,uptheelectrochemicalgradientforsodium.Thisisararecaseofsodiumremovalby
somethingotherthananATPase.
PrimaryActiveTransporters
Primaryactivetransportersaremembraneproteinsthatmove1ormoresolutesuptheirelectrochemical
gradientsusingtheenergyobtainedfromthehydrolysisofATP.Alltransportersthatmovesolutesinthis
mannerareATPases,thatis,theirstructureisboththatofanenzymethatsplitsATP,andatransporterthathas
bindingsitesthatalternatelyareopentoonesideandthentheothersideofthemembrane.Amongthekey
primaryactivetransportersinthekidneyistheubiquitousNaKATPase,oftencalledthe"sodiumpump,"
someisoformofwhichispresentinvirtuallyallcellsofthebody.Thistransportersimultaneouslymoves
sodiumagainstitselectrochemicalgradientoutofacellandpotassiumagainstitsgradientintoacell.The
stoichiometryis3sodiumionsoutand2potassiumionsforeveryATPmoleculehydrolyzed.Othercrucial
primaryactivetransportsystemsareHATPases,whichmoveprotonsoutofcells,andCaATPases,which
movecalciumoutofcells.AlloftheseATPasesbelongtoalargefamilyofhomologoustransporterproteins.
Yetanotherimportantclassofprimaryactivetransportersarethemultidrugresistanceproteins(MDR,also
calledATPbindingcassetteproteins),namedfortheirabilitytoremovetherapeuticdrugsfromcells.Unlike
theinorganicionATPases,whicharequiteselectivefortheionspeciestheymove,theMDRtransporters
unselectivelytransportawidevarietyoforganicanions.

ReceptorMediatedEndocytosisandTranscytosis
Imagenotavailable. Almostallthesecretionandreabsorptionofsolutesdiscussedthroughoutthistextbook
usesomecombinationofthejustmentionedsetofmembranepermeabilitymechanisms.Oneothersolute
transportprocessofsomeimportanceisreceptormediatedendocytosis.Inthiscase,asolute,usuallyaprotein,
bindstoasiteontheapicalsurfaceofanepithelialcell,andthenapatchofmembranewiththesoluteboundto
itisinternalizedasavesicleinthecytoplasm.Subsequentprocessesthendegradetheproteinintoits
constituentaminoacids,whicharetransportedacrossthebasolateralmembraneandintotheblood.
Forafewproteins,particularlyimmunoglobulins,endocytosiscanoccurateithertheapicalorbasolateral
membranes,afterwhichtheendocyticvesiclesremainintactandaretransportedtotheoppositecellular
membrane,wheretheyundergoexocytosistoreleasetheproteinintact.Suchtranscytosisisveryimportantin
thehostdefensemechanismsofthekidneyandinthepreventionofurinarytractinfections.

OsmosisandOsmoticPressure
OsmoticVocabulary
Thevocabularyofosmoticmattersisoftenusedlooselyleadingtosomeconfusion,butthecentralconceptis
straightforward.Solutesdissolvedinwaterdisplacesomeofthewaterandloweritsconcentration.Therefore,
solutionsdifferinginsoluteconcentrationalsodifferinwaterconcentration.Giventheopportunitytodoso,
waterdiffusesfromwhereitsconcentrationishigher(dilutesolutions)intosolutionswhereitsconcentrationis
lower(concentratedsolutions),aprocesscalledosmosis.
Dissolvedsolutesthatdisplacewaterarecalledosmoles.Onemoleofanydissolvedsolute(anAvogadro
numberofitabout6.021023)is1osmole.Thesumofthemolesinamixturegivesusthetotalnumberof
osmoles.Forexample,onehalfmoleofureaandonehalfmoleofsucrosetogethermake1totalosmole.As
saltsdissociateinsolution,1moleofsaltmoleculesthatsplitinto2ions(eg,NaCl)becomes2osmoles,anda
moleofsaltthatsplitsinto3ions(eg,CaCl2)becomes3osmoles.
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Theconcentrationofosmolesisexpressedbythetermsosmolarityandosmolality.Osmolarityisthenumber
ofosmolesperliterofsolutionmostcommonly,itisexpressedin"milli"units(mOsm/L).Asolution
containing50mMureaand100mMNaClhasanosmolarityof250mOsm/L(50urea,100Na+,and100Cl
).Osmolarityisaconvenientunitbecausewecaneasilycalculateitfromtheknowningredientsinsolution.
Osmolalityistheconcentrationofosmolesperkgofwater,forexample,300mOsm/kgH2O.Asaliterof
solutioncontainsalmost1kgofwater,thevaluesofosmolarityandosmolalityarenearlythesame.
Alloftheaboveassumesthatsolutionsareideal(ie,anydissolvedsoluteparticleisthesameasanyotherand
isfullyactiveosmotically),butrealsolutionsarenotideal.Solutesinteractwitheachotherinmysteriousways
suchthatamoleofmostsolutes,whendissolved,resultsinlessthan1osmole.Itistherealosmolalitythat
determinesthemovementofwaterbetweenfluidcompartments.Theseconceptsareillustratedinthecaseof
physiologicalsaline(0.9%NaCl,or154mmol/LNaCl).Thissolutioniscommonlyusedasahospitalinfusion
solutionbecauseitmatchesthenormalosmolalityofhumanplasma(280290mOsm/kgH2O).The
osmolarityofthissolution,assumingideality,is154+154=308mOsm/L,butthemeasuredosmolalityis287
mOsm/kgH2O.Anysolutionwiththesamerealosmolalityasnormalhumanplasmaissaidtobeanisosmotic
solution.Forconvenience,physiologistsoftencalculateosmolarityassumingthesolutiontobeidealandthen
callitosmolality,andaccepttheerrorinthiscalculationasthepricepaidforconvenience.
Osmoticpressureisanotherconfusingconcept.Despiteitsname,osmoticpressureisnotapressureinthe
senseofhydrostaticpressureitjustmeansosmolality.Abeakerofwaterandabeakerofglucosesolution
withahighosmolality,bothhavethesamehydrostaticpressure,butdifferentosmoticpressures.Bydefinition,
osmoticpressureisthepressurethattheoreticallywouldhavetobeappliedtoasolutiontopreventthe
movementofwaterbyosmosisacrossasemipermeablebarrierfrompurewaterintothesolution.(A
semipermeablebarrierispermeabletowater,butnotsolute.)Numerically,itisthejustrealosmolality
expressedinpressureunits.Thisequivalenceisexpressedbythevan'tHoffequationwhereistheosmotic
pressure,RandTarethegasconstantandabsolutetemperature,andCistheosmolality(osmolarityisusually
usedasanapproximationforosmolality).
=RTC
TocalculateanumericalvalueforosmoticpressureinunitsofmmHg,multiplytheosmolalityby19.3.Thus,
anosmolalitydifferenceofonly1mOsm/kgH2Oisactuallyasignificantdrivingforceforthemovementof
water.
WaterMovementAcrossSemipermeableBarriers
Imagenotavailable. Ifthesolutionsoneithersideofasemipermeablebarrierdifferinosmolality,water
movesbyosmosistowardthesolutionwiththehigherosmolality.Althoughwaterisdrivenbyitsown
concentrationgradient,itisconvenienttothinkofsoluteas"pulling"water.Thekidneysmakeuseofthis
conceptbyreabsorbingsolutesacrosstherenaltubules(fromlumentotheinterstitium)andallowingwaterto
follow,thatis,"waterfollowstheosmoles."Differencesinosmolalityareonlyeffectiveindrivingosmosis
whenthebarrierislesspermeabletosolutesthantowater,thatis,itissemipermeable.(Imagineabarriermade
ofchickenwire.Regardlessofosmolalities,therewouldbenoosmosisbecausetherewouldbenorestriction
onthediffusionofsolute.)
Wateristransportedby"followingtheosmoles"
Imagenotavailable. Inthefenestratedendothelialbarriersofglomerularcapillariesandperitubular
capillaries,mostofthesolutesareaspermeablethroughthefenestraeaswaterandthusdonotinfluencewater
movement.However,thelargeplasmaproteinsarenotpermeable,andtheydoindeedinfluencewater
movement.Theosmoticpressureresultingfromtheproteinsonly(ignoringeverythingelse)iscalledthe
colloidosmoticpressureoroncoticpressure.ColloidosmoticpressureisacomponentoftheStarlingforces
governingfiltrationandabsorptionacrossendotheliallayers.Inotherbarriers,specificallytheepitheliallining
oftherenaltubules,thepermeabilitiesofallsolutesaregenerallylowerthanwaterpermeability.Therefore,all
solutescontributetodrivingawaterflux.Here,alloftheosmolality,notjustthecomponentresultingfrom
proteins,isimportant.
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ProximalTubuleReabsorption
Virtuallyallofthe180LofwaterandseveralpoundsofsaltandothersolutesfilteredeachdayintoBowman's
spacearereabsorbed,alongwithlargeamountsofmanyothersubstances.Mostofthisreabsorptionoccursin
theproximaltubule.Almostallsolutes(exceptlargeplasmaproteins)arefilteredfromplasmaintoBowman's
spaceinthesameproportionaswaterthus,theirconcentrationsintheglomerularfiltratearethesameasin
theplasma.Bytheendoftheproximaltubule,abouttwothirdofthewaterandsoluteshavebeenreabsorbed.
Theratesofreabsorption,andthusconcentrationsinthelumenattheendoftheproximaltubule,varyfrom
solutetosolute,butthesummedtotalofsolutes(osmoles)reabsorbedisproportionaltowaterreabsorbed.This
iscalledisoosmoticreabsorption.Inthelaterportionsofthenephron,beyondtheproximaltubule,
reabsorptionisgenerallynotisoosmotic,meaningthatwaterandtotalsolutereabsorptionareusuallynot
proportional.Thisiscrucialforourabilitytoindependentlyregulatesoluteandwaterbalance.

SodiumandWater
Sodiumaccountsfornearlyhalfofthetotalsoluteloadappearingintheglomerularfiltrate,andmostofthe
restconsistsoftheanions(primarilychlorideandbicarbonate)thatmustaccompanysodiumtomaintain
electroneutrality.Similarly,sodiumanditsaccompanyinganionsaccountforthevastmajorityofsolutes
reabsorbedintheproximaltubule.Thelargeamountofsodiumandanionstransferredfromlumento
interstitiumsetsupanosmoticgradientthatfavorstheparallelmovementofwater.Theproximaltubule
epitheliumisverypermeabletowater,whichfollowstheosmolesacrossinequalproportions.Thus,boththe
fluidremovedfromthelumenandthatremainingbehindareessentiallyisoosmoticwiththeoriginalfiltrate.
Wesay"essentially"becausetheremustbesomedifferenceinosmolalitytoinducewatermovement,butfor
anepithelialbarrierliketheproximaltubulethatisverypermeabletowater,adifferenceoflessthan1
mOsm/kgissufficienttodrivereabsorptionofwater.(Recallthatanosmolalitydifferenceof1mOsm/kgis
equalindrivingforceto19.3mmHgofhydrostaticpressure).Onceintheinterstitium,thesolutesandwater
movefrominterstitiumintotheperitubularcapillariesandarereturnedtothesystemiccirculationTable41.
Table41.EstimatedForcesInvolvedintheMovementofFluidfromInterstitiumintoPeritubularCapillaries*
Forces
mmHg
1.Favoringuptake
a.Interstitialhydraulicpressure,PInt
3
b.Oncoticpressureinperitubularcapillaries,PC 33
2.Opposinguptake
a.Hydraulicpressureinperitubularcapillaries,PPC 20
b.Interstitialoncoticpressure,Int
3.Netpressureforuptake(12)

6
10

*Thevaluesforperitubularcapillaryhydraulicandoncoticpressuresarefortheearlyportionsofthe
capillary.Theoncoticpressure,ofcourse,decreasesasproteinfreefluidentersit(ie,asabsorptionoccurs)
butwouldnotgobelow25mmHg(thevalueofarterialplasma)evenifallfluidoriginallyfilteredatthe
glomeruluswereabsorbed.
Intheproximaltubulethetransportofwaterandeverysoluteistieddirectlyorindirectlytotheactive
transportofsodiumbytheNaKATPase
Epithelialtransportrequiresthatthecellsbepolarized,thatis,theproteinspresentintheapicalandthe
basolateralmembranesarenotthesame.Inthecaseofsodium,polarizationoftheproximaltubuleepithelium
promotesnetfluxfromlumentointerstitium.Movementofsodiumisthelinchpinaroundwhichthetransport
ofvirtuallyeveryothersubstancedepends.Figure44showsthemorphologyofageneralizedproximaltubule
epitheliuminwhichsaltandwatertransportcanbeviewedasamultistepprocess.
Figure44.

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Epithelialsaltandwaterreabsorption.Seetextforexplanationofeachindividualstep.(1)Sodiumisactively
extrudedintotheinterstitium.(2)Sodiumenterspassivelyfromthetubularlumen.(3)Anionsfollowthe
sodium(transcellularlyandparacellularly).(4)Waterfollowsthesolute(transcellularlyandparacellularly).(5)
Waterandsolutesmovebybulkflowintotheperitubularcapillary.
Step1istheactiveextrusionofsodiumfromepithelialcelltointerstitiumacrossthebasolateralmembrane.
Step2isthepassiveentranceofsodiumfromthetubularlumenacrosstheapicalmembraneintothecellto
replacethesodiumremovedinstep1.Step3istheparallelmovementofanionsthatmustaccompanythe
sodiumtopreserveelectroneutrality.Step4istheosmoticflowofwaterfromtubularlumentointerstitium.
Finally,step5isthebulkflowofwaterandsolutefrominterstitiumintotheperitubularcapillary.Letus
examinethesestepsmoreclosely.
Theactiveextrusionofsodiuminstep1isviatheNaKATPase,whichisthemajorenergyconsumerinthe
cell.TheactionoftheNaKATPasehasseveralconsequences,thekeyonebeingthatitkeepsthe
concentrationofsodiumwithinthecelllowenoughtofavorthepassiveentranceofsodiumfromlumentocell
inalltheprocessesofstep2.
Theentranceofsodiumintothecellinstep2isviamultiplepathways.Quantitatively,mostofsodiumenters
viathesodiumprotonantiporter(NHE3isoform).Aswewillseelater,regulationofthistransporterisakey
playerinregulatingsodiumexcretion.
Step3,themovementofanionsismorecomplex,asitinvolves2ions(chlorideandbicarbonate)andavariety
oftranscellularandparacellularprocesses.Wewillexaminethedetailslater,butfornow,weemphasizethat
themovementofsodium,whichisacation,mustbematchedquantitativelybytheequalmovementofanions.
Step4istheosmoticmovementofwater.Thetubularcellspossessacomplementofaquaporinsinboththe
apicalandbasolateralmembranes,andthetightjunctionsarealsopermeabletowater.Therefore,assteps1to
3lowerthelocalluminalosmoticconcentrationbyevenafewmilliosmolesperliter,waterflowsosmotically
fromlumentointerstitium.
Themovementofwaterintotheinterstitiuminstep4promotesstep5.Thisisthebulkflowoffluidfrom
interstitiumtoperitubularcapillarydrivenbyStarlingforces(hydrostaticandoncoticpressuregradients).The
capillaryhydraulicpressureopposestheuptakeofinterstitialfluids,butitsvalueof15to20mmHgismuch
lowerthanthe60mmHgintheglomerularcapillaries,wherethereisnetfiltration.Meanwhile,theplasma
oncoticpressurehasrisentomorethan30mmHgbecauselossofwaterbyfiltrationintheglomerular
capillariesconcentratesthelargeplasmaproteins.Thereisalsoasmallbutsignificant,interstitialpressure.
ThesumoftheseStarlingforcesisanetabsorptivepressure,anditdrivesfluidmovementintotheperitubular
capillaries.ThereadercanappreciatethefactthatifcorticalStarlingforcesareabnormal(eg,lowplasma
oncoticpressureaswhenliverdiseasepreventsnormalproductionofserumalbumin),absorptionoffluidfrom
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thecorticalinterstitiumcanbeslowed,causingabackupoffluidthatinhibitsfluidmovementfromtubular
lumentointerstitium.Ultimately,thiscanleadtoincreasedexcretionofwaterandelectrolytesfromthebody.
Waterreabsorptionintheproximaltubuleconcentratesalltheremainingunreabsorbedsolutes

ConsequencesforOtherSolutes
Imagenotavailable. Theeventsjustdescribedhaveconsequencesforalltheothersolutesfilteredalong
withsodiumanditsanions.Aswaterfollowssodiumanditsanionsacrosstheepithelium,theluminalvolume
decreases,therebyconcentratingallremainingsolutes.Iftwothirdsofthewaterisremoved,anysolutenot
previouslyremovedwillincreaseinconcentrationbyafactorof3.Asitsluminalconcentrationrises,this
generatesaconcentrationgradientacrossthetightjunctionsbetweenthelumenandtheinterstitium(The
interstitialconcentrationoftransportedsubstancesisessentiallyclampedtotheplasmavaluebecauseofthe
highperitubularbloodflowandhighpermeabilityofthefenestratedcapillaries.).Ifthetightjunctionsare
permeabletothesubstanceinquestion("leaky"),thesubstancediffusesfromthelumentotheinterstitiumand
thenintotheperitubularcapillariesalongwithsodiumandwater.Thisispreciselywhathappenstomany
solutes(eg,urea,potassium,calcium,andmagnesium)intheproximaltubule.Theexactfractionsthatare
reabsorbeddependonthepermeabilityofthetightjunctions,butaregenerallyintherangeofonehalftotwo
thirds.Asindicatedearlier,onesubstancethatdoesnotmovebytheparacellularrouteisglucose,whichis
impermeableinthetightjunctions.WewilldescribethefateoffilteredglucoseinChapter5.

LimitsonRateofTransport:TMandGradientlimitedSystems
Imagenotavailable. Eventhoughthetransportcapacityoftherenaltubulesishuge,itisnotinfinite.There
areupperlimitstotherateatwhichanygivensolutecanbereabsorbedorsecreted.Insituationsinwhich
unusuallylargeamountsofasubstancearefiltered,theselimitsarereachedwiththeconsequencethatlarger
thannormalamountsofsolutearenotreabsorbed(ie,leftinthelumenandpassedontothenextnephron
segment).Ingeneral,transportmechanismscanbeclassifiedbythepropertiesoftheselimitsaseither(1)
tubularmaximumlimited(Tm)systemsor(2)gradientlimitedsystems.
Theclassificationisbasedontheleakinessofthetightjunctions.Considerfirstgradientlimitedsystems.
Whenthetightjunctionsareveryleakytoagivensubstance,forexample,sodium,itisimpossibleforthe
removalofthesubstancefromthelumentoreduceitsluminalconcentrationverymuchbelowthatinthe
corticalinterstitium.Asthesubstanceisremovedandtheluminalconcentrationstartstofall,thegradient
betweenthese2mediaincreases,causingthesubstancetoleakbackasfastasitisremoved(likebailingavery
leakyboat).Thusforsodiumandallothersubstanceswhosereabsorptionischaracterizedbyagradient
limitedsystem,theluminalconcentrationremainsclosetotheinterstitialconcentration.Beawarethatthe
existenceofalimitingratedoesnotstopreabsorptioninnormalcircumstancesbecausewaterisbeing
reabsorbedsimultaneously.Eventhoughtheluminalconcentrationdoesnotdecreaseverymuch,large
amountsarestillbeingremoved.Incontrast,ifunusualosmoticconditionsretardwaterreabsorption,then
removalofthesubstanceisnotaccompaniedbyacorrespondingamountofwater.Consequentlyits
concentrationdoesdecrease,thelimitinggradientisindeedreached,andnowthesubstanceleaksback,leaving
unusuallyhighamountsofthesubstanceinthelargevolumeofunreabsorbedwater.
Therateofreabsorptionforanysubstanceislimitedbythecapacityofthetransporters(Tmsystems)orby
paracellularbackleak(gradientlimited)
NowconsiderTmlimitedsystems.Inthiscasethetightjunctionsareimpermeabletothesolutesinquestion.
Thereisnobackleakandnolimitonthesizeofthedifferenceinconcentrationbetweenlumenand
interstitium.Thelimitontransportrateinsteadisplacedonthecapacityofthetransporterstoremovethe
substance(theinherentkineticpropertiesofthetransportproteinsandtheirdensityinthemembrane).Asthe
filteredloadrises,theamountreabsorbedincreasesinparalleluptothepointofsaturatingthetransporters.For
loadsbelowtheTm,virtuallyallisreabsorbed.ButanyincreaseinfilteredloadabovetheTmdoesnot
increasetransportoutofthelumen.Consequently,theexcessisleftbehind.Inmostcases,theamountthat
escapesreabsorptionintheproximaltubuleisexcreted.
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ThefunctionalreasonfordifferentiatingbetweenTmandgradientlimitedsystemsisthatsoluteshandledby
Tmsystemswill,ifthefilteredloadisbelowtheTm,bereabsorbedessentiallycompletely,whereassolutes
handledbygradientlimitedsystemsareneverreabsorbedcompletely,thatis,asubstantialamountalways
remainsinthetubuletobepassedontothenextnephronsegment.

OsmoticDiuresis
Ifthenormaltightcouplingbetweensodiumandwaterreabsorptionintheproximaltubuleisdisrupted,we
haveaphenomenonknownasosmoticdiuresis.Thetermdiuresissimplymeansincreasedurineflow,and
osmoticdiuresisdenotesthesituationinwhichtheincreasedurineflowisduetoanabnormallyhighamount
ofanysolutethatisnotreabsorbedatall(eg,mannitol)orisfilteredatsuchahighratethatmuchisleftinthe
tubule(eg,veryhighplasmaglucose),leavinglargeamountsofsolute(osmoles)inthelumen.Aswateris
reabsorbedfromthetubule,theconcentrationofanyunreabsorbedsoluterises.Itsosmoticpresenceretardsthe
furtherreabsorptionofwater,thatis,itis"holding"waterinthelumen.Ifthisoccursintheproximaltubule,it
alsoretardsnetsodiumreabsorption.Sodiumtransportpersecontinuesunabated.Butaswaterisbeingheldin
thelumen,thesodiumtransportcausesaninitialfallinluminalsodiumconcentration.Thisdrivesapassive
backleakofsodiumviatightjunctionsbecausethelimitinggradientforsodiumtransportisreached.Atthis
pointthereislittlenetsodiumtransportbecausetheamountreabsorbedismatchedbytheamountleaking
back.Theresultisthathighamountsofsodium,water,andtheunusualsolutepassontotheloopofHenle.
Osmoticdiuresiscanoccurinpersonswithuncontrolleddiabetesmellitus,inwhichthefilteredloadofglucose
exceedsthetubularmaximum(Tm),andtheunreabsorbedglucosethenactsasanosmoticdiuretic.Inother
cases,itcanbeduetoaninfusedsolutesuchasmannitolthatisfiltered,butnottransportedatall.

KeyConcepts
Imagenotavailable. Fluxfromlumentointerstitiumcanbetranscellularusingseparatetransport
stepsintheapicalandbasolateralmembranes,orparacellular,aroundthecellsthroughtightjunctions.
Imagenotavailable. Thekidneysmovesolutesacrossmembranesbymultipletransportmechanisms
includingchannels,uniporters,multiporters,andprimaryactivetransporters.
Imagenotavailable. Thekidneysregulateexcretionbyregulatingchannelsandtransportersin
epithelialcellmembranes.
Imagenotavailable. Watercrossesepithelialbarriersbymovementdownosmoticgradients(from
regionsoflowertohigherosmolality).
Imagenotavailable. Volumereabsorptionisamultistepprocessinvolvingtransportacrossepithelial
membranesfromlumentointerstitium,andbulkflowfrominterstitiumtoperitubularcapillariesdriven
byStarlingforces.
Imagenotavailable. Thereabsorptionofwaterconcentratesallremainingtubularsolutes,increasing
thedrivingforcefortheirpassivereabsorptionbydiffusion.
Imagenotavailable. Allreabsorptiveprocesseshavealimitonhowfasttheycanoccur,either
becausethesubstanceleaksbackintothelumen(gradientlimitedsystems),orbecausethetransporters
saturate(Tmsystems).
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Transcellularandparacellularreabsorption.Transcellularreabsorptionisatwostepprocesswithseparate
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influxandeffluxsteps,utilizingtransportersorchannels.Paracellularreabsorptionisalwaysapassiveprocess
throughthetightjunctions.(ReproducedwithpermissionfromMcKinleyM,O'LoughlinVD.Human
Anatomy,2nded.NewYork:McGrawHill,2008.)
Mechanismsoftransmembranesolutetransport.Withtheexceptionofsimplediffusionthroughthelipid
bilayer,alltransportinvolveschannelsandtransportersthatareregulatedbysignalingpathways.
Commonmechanismsforregulatingchannelandtransporteractivity.1.Transportproteinsareshuttledback
andforthbetweenthesurfacemembrane,wheretheyfunctionnormally,andsitesofsequestrationatthebase
ofmicrovilliorinintracellularvesicles.2.Transportproteinsaresynthesizedandinsertedinthemembrane,or
removedanddegraded.3.Transportproteinsareactivatedorinhibitedbyattachingligands,eithercovalently
(eg,phosphorylation),orreversibly(eg,ATP).
Epithelialsaltandwaterreabsorption.Seetextforexplanationofeachindividualstep.(1)Sodiumisactively
extrudedintotheinterstitium.(2)Sodiumenterspassivelyfromthetubularlumen.(3)Anionsfollowthe
sodium(transcellularlyandparacellularly).(4)Waterfollowsthesolute(transcellularlyandparacellularly).(5)
Waterandsolutesmovebybulkflowintotheperitubularcapillary.

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