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Renin, endothelial no synthase and endothelin gene expression in the 2Kidney-1clip goldblatt model of long-term renovascular hypertension

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Description

Objective Numerous reports have shown the influence of renin, nitric oxide (NO) and the endothelin (ET) systems for regulation of blood pressure and renal function. Furthermore, interactions between these peptides have been reported. Aim of our study was to investigate the relative contribution of these compounds in long-term renovascular hypertension/renal ischemia. Methods Hypertension/left-sided renal ischemia was induced using the 2K1C-Goldblatt rat model. Renal renin, ET-1, ET-3 and endothelial NO synthase (eNOS) gene expression was measured by means of RNAse protection assay at different timepoints up to 10 weeks after induction of renal artery stenosis. Results Plasma renin activity and renal renin gene expression in the left kidney were increased in the clipped animals while eNOS expression was unchanged. Furthermore, an increase in ET-1 expression and a decrease of ET-3 expression was detected in early stenosis. Conclusions While renin is obviously involved in regulation of blood pressure and renal function in unilateral renal artery stenosis, ET-1, ET-3 and endothelium derived NO do not appear to play an important role in renal adaptation processes in long-term renal artery stenosis, although ET-1 and ET-3 might be involved in short-term adaptation processes.

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Publié par
Publié le 01 janvier 2009
Nombre de lectures 8
Langue English
Poids de l'ouvrage 1 Mo

.3eRniohdlU_bmruchvorlage28.11.0910:03Seite520520
EuRoPEanJouRnalofMEdIcalRESEaRcH
december14,2009
EurJMedRes(2009)14:520-525©I.HolzapfelPublishers2009

R
EnIn
,E
ndotHElIal
noS
yntHaSEand
E
ndotHElIn
G
EnE
E
xPRESSIonIntHE
2K
IdnEy
-1
clIP
G
oldBlatt
M
odElof
l
onG
-
tERM
R
EnovaSculaR
H
yPERtEnSIon
S.W.Reinhold
1
*,d.c.uihlein
1
*,c.a.Böger
1
,S.Kloiber
1
,K.frölich
1
,t.Bergler
1
,B.Banas
1
,
f.Schweda
2
,B.K.Krämer
3
1
Klinikun
2
dInPstoiltiuktlifnüikrfPühryIsinonleorgeie,MeudniizvienrsIiIt,yuonfivReergseitnysbofurRg,egReengsebnusrbgu,rRg,egGeenrsmbuarngy,,Germany,
3
MarienhospitalHerne,Ruhr-universityBochum,Germany

bstract
Objective:
numerousreportshaveshowntheinfluence
ofrenin,nitricoxide(no)andtheendothelin(Et)
systemsforregulationofbloodpressureandrenal
function.furthermore,interactionsbetweenthese
peptideshavebeenreported.aimofourstudywasto
investigatetherelativecontributionofthesecom-
poundsinlong-termrenovascularhypertension/re-
nalischemia.
Methods:
Hypertension/left-sidedrenalischemiawas
inducedusingthe2K1c-Goldblattratmodel.Renal
renin,Et-1,Et-3andendothelialnosynthase
(enoS)geneexpressionwasmeasuredbymeansof
Rnaseprotectionassayatdifferenttimepointsupto
10weeksafterinductionofrenalarterystenosis.
Results:
Plasmareninactivityandrenalreningeneex-
pressionintheleftkidneywereincreasedinthe
clippedanimalswhileenoSexpressionwasun-
changed.furthermore,anincreaseinEt-1expression
andadecreaseofEt-3expressionwasdetectedin
earlystenosis.
Conclusions:
Whilereninisobviouslyinvolvedinregu-
lationofbloodpressureandrenalfunctioninunilater-
alrenalarterystenosis,Et-1,Et-3andendothelium
derivednodonotappeartoplayanimportantrolein
renaladaptationprocessesinlong-termrenalartery
stenosis,althoughEt-1andEt-3mightbeinvolved
inshort-termadaptationprocesses.
Keywords:
bloodpressure,reninangiotensinsystem,
nitricoxide,endothelins,long-termrenalarterysteno-
sis,Rnaseprotectionassay
I
ntRoductIon
therenin-angiotensinsystem(RaS)hasgenerally
beenacceptedtoplayanimportantroleinbloodpres-
surehomeostasis.ReninformsangiotensinIfroman-
giotensinogenandangiotensinIisthereaftertrans-
*Bothauthorscontributedequallytothispaper.

formedbytheangiotensinconvertingenzymeinthe
biologicallyactiveangiotensinII(at-II).at-IIis
knowntobevasoconstrictiveandstimulatesthere-
leaseofaldosterone,therebycausingsodiumreten-
tion.theupregulationofrenininrenalarterystenosis
duetotheactivationoftherenalbaroreceptoris
thoughttocauserenalhypertensionbyactivatingthe
renin-angiotensinsystem.
noisknownasvasorelaxingmolecule.Inthemod-
elof2K1crenovascularhypertensionnohasbeen
proventobeinvolvedinmaintainingbloodflow.no
isthoughttoactasavasodilatatorandtherebytoan-
tagonisethehighlevelsofat-IIinbothkidneys[1].
nomeasurementshaveshownthatendogenousno
productionisincreasedinthecontralateralkidneyof
2K1cratsthreeweeksafterclipping[2].
theEtscompriseagroupofthree21-aminoacid
peptides,havingvasoactive,inotropicandmitogenic
properties[3].Et-1actsonvascularmusclecellscaus-
ingalong-lastingvasoconstriction[4].Short-termrenal
arterystenosisinthe2K1cmodelofrenovascularhy-
pertensionhasresultedinanupregulationofrenalEt-
1intheclippedkidney.Et-2wasnotfoundinratkid-
neys[5].furthermoreEt-1andEt-3seemtoberegu-
latedinoppositewaysasshowninaratrenalischemia
reperfusionmodel6hoursafterreperfusion[5].
Inaddition,manyinteractionsbetweentheseabove
compoundshavebeenfound:noforinstancedown-
regulatestheEt-1expressionandat-IIisaknown
stimulatorofEt-1expression[6,7].
Sincethecontributionofthesedifferentmediators
inrenovascularhypertensionespeciallywithregardto
long-termregulationisunclear,theaimofourstudy
wastoinvestigatetheeffectsofunilateralrenalartery
clipping,usingthe2K1c-model,onrenalrenin,
enoS,Et-1andEt-3geneexpression.
M
EtHodS
allanimalexperimentswereconductedaccordingto
thenationalInstitutesofHealthguidelinesforthe
careanduseofanimalsinresearch.

3.Reinhold_Umbruchvorlage28.11.0910:03Seite521december14,2009EuRoPEanJouRnalofMEdIcalRESEaRcH521
80maleWistarrats,weighing150g,havingfreeac-B
lood
P
RESSuRE
cesstotapwaterandstandardcommercialpelletchow
(altrominc1000,lage,Germany)wereused.unilat-Systolicbloodpressuresignificantlyincreasedinthe
eralrenovascularclippingwasinducedinatotalof402K1c-groupto162.5±8mmHgonday1,179±11
ratsandashamoperationin40controlrats.asteno-mmHgonday2and189±7mmHgonday20after
sisoftheleftrenalarterywasinducedbya0.2mmsil-clipping,thereafterlevellingoffatslightlylowerlevels
verclip.anaesthesiawasdoneusingmethohexital(75(155±7mmHgatday40and149±3mmHgatday
mg/kgIP).8animalsofeachgroupweresacrificed3,63).thecontrolgrouppresentedsignificantlylower
7,12,28and70daysaftersurgery.systolicbloodpressurevaluesateverypostoperative
Systolicbloodpressurewasmeasuredusingthetailtimepoint(fig.2).
cuffmethod(processcontrolbloodpressure209000;
tSE,Homburg/Saar,Germany)[8].Bloodwascol-
lectedformeasurementofplasmareninactivityafter
decapitation.thekidneyswereimmediatelyremoved,
weighedandfrozenusingliquidn
2
andstoredat
-80°c.
Renalrenin,enoS,Et-1and-3and-actingene
expressionfromwholekidneywasanalysedusing
Rnase-protectionassaysaspreviouslyreported[9].
-actinwasusedashousekeepinggene.Plasmarenin
activitywasmeasuredbyacommerciallyavailable
anG-I-radioimmunoassay(diasorin,Saluggia,Italy).
Resultsareexpressedasmean±SEM.theStu-
dent´st-testwasusedforstatisticalanalysisaftertest-
ingfornormaldistribution.Pvalues<0.05werecon-
sideredstatisticallysignificant.
R
ESultS
K
IdnEy
W
EIGHt
Kidneyweightoftheunclippedkidneysincreased
Fig.2.
Systolicbloodpressureafterclippingandsham-opera-
bytime.Itwassignificantlyhigherthantheclipped
tion.Systolicbloodpressuresignificantlyincreasedinthe
2K1c-groupto162.5±8mmHgonday1,179±11mmHg
kidneysstartingatday7.thecontralateral(unclipped)
onday2and189±7mmHgonday20afterclipping,there-
kidneyhadahigherweightcomparedtothecontrol
afterlevellingoffatslightlylowerlevels(155±7mmHgat
groupstartingatday28.theweightoftheclipped
day40and149±3mmHgatday63).thecontrolgroup
kidneyswassignificantlylowerthancontrolstarting
presentedsignificantlylowersystolicbloodpressurevalues
atday3anddidnotchangesignificantlyovertime
ateverypostoperativetimepoint(significantvs.control*,
(fig.1).
p<0.05).

Fig.1.
Kidneyweightinthe2K1cgroupandcontrolgroupatdifferenttimepointsaftersurgery.Kidneyweightoftheun-
clippedkidneysincreasedbytime.Itwassignificantlyhighercomparedtotheclippedkidneysstartingatday7.thecontralateral
(unclipped)kidneyhadahigherweightcomparedtothecontrolgroupstartingatday28.theweightoftheclippedkidneyswas
significantlylowerthancontrolstartingatday3anddidnotchangesignificantlyovertime(significantvs.control*;significant
vs.contralateralside#,p<0.05).

3.Reinhold_Umbruc225

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Fig.3.
Plasmareninactivityintheclippedandunclipped
group.Plasmareninactivityinthe2K1c-groupwassix
timeshigherthaninthecontrolgroupatday3.Plasma
reninactivitythendecreasedtoabout3.5foldondays7,12
and28andtoabout2foldofcontrolgrouponday70(sig-
nificantvs.control*,p<0.05).

Fig.4.
Geneexpressionofreninintheclipped
andunclippedkidneys(K)atdifferenttime-
pointsaftersurgery.Renalreningeneexpression
washigheratalltimepointsintheclippedkidney
comparedwiththeunclippedkidneyandatday
3to28comparedtocontrol,whereasthecon-
tralateralkidneydisplayedreningenesuppres-
sionto~50%ofcontrolatday3to12(signifi-
cantvs.control*;significantvs.contralateral
side#,p<0.05).

Fig.5.
GeneexpressionofEt-1intheclipped
andunclippedkidneys(K)atdifferenttime-
pointsaftersurgery.Et-1geneexpressiontend-
edtoincreasewithtimeinallgroupsandwas
significantlyhigherintheclippedkidneyonday
7comparedwiththecontralateralkidney(signifi-
cantvs.contralateralside*,90.4±6.7vs.71.2±
5.5,p<0.05).
P
laSMa
R
EnIn
a
ctIvIty
clippedkidneyandatday3to28comparedtocontrol,
whereastherightcontralateralkidneydisplayedrenin
Plasmareninactivityinthe2K1c-groupwassixtimesgenesuppressionto~50%ofcontrolatday3to12
higherthaninthecontrolgroupatday3.Plasmarenin(fig.4).
activitythendecreasedto~3.5foldondays7,12and
28andto~2foldofcontrolgrouponday70(fig.3).R
Enal
Et-1G
EnE
E
xPRESSIon
R
EnIn
G
EnE
E
xPRESSIon
Et-1tendedtoincreasewithtimeinallgroups.fur-
thermoreEt-1geneexpressionintheclippedkidney
Renalreningeneexpressionwashigheratalltime-washigheronday7comparedwiththecontralateral
pointsintheclippedkidneycomparedwiththeun-kidney(90.4±6.7vs.71.2±5.5;p=0.046)(fig.5).

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19:030eStie523EuRoPEanJouRnalofMEdIcalRESEaRcH

R
Enal
Et-3G
EnE
E
xPRESSIon
Et-3tendedtoincreasewithtimeinallgroups.Et-3
geneexpressionwassignificantlylowerintheclipped
kidneyscomparedwiththecontralateralkidneyatday
3(55.7±7.7vs.70.6±7.3;p=0.02)(fig.6).
enoSG
EnE
E
xPRESSIon
RenalenoSgeneexpression3daysafterclippingwas
255.5±17.0intheclippedkidneyvs.229.3±20.9in
thecontralateralkidney.onday7enoSgeneexpres-
sionwas135.3±12.6vs.138.4±22.6.onday12
enoSgeneexpressionwas274.2±31.5vs.275.9±
23.7.onday28enoSgeneexpressionwas358.0±
77.4vs.309.4±37.1.onday70enoSgeneexpres-
sionwas149.3±13.4vs.200.7±48.5.
allthesechangesdidnotreachstatisticalsignifi-
cance.
d
IScuSSIon
theaimofourstudywastodetermine-incontrastto
mostotherpublisheddatathatdealtwithshort-term
effects-thelong-termeffectsofexperimentalunilat-
eralrenalarterystenosisonbloodpressure,kidney
weightandrenalrenin,EtsandenoSexpression.
asignificantincreaseinbloodpressureafterclip-
pingiswellknownin2K1c-rats[2,10],makingthem
acommonlyusedmodelofrenovascularhyperten-
sion.ourdatafitswithotherfindingsshowingalow-
er,butstillincreasedbloodpressurefourweeksafter
clipping[1].furthermore,manyauthorsalsoshowan
increaseinweightofthecontralateralkidneywhilethe
weightoftheclippedkidneydecreasedwithtime[11,
12,13].Incontrastsomeauthorsfoundnochangein
theweightoftheclippedkidney,whiletheyalsofound
anincreaseinthecontralateralkidney[14,15].Sham-
operatedratsshowedasexpectednodifferenceinkid-
neyweight[16,17].
ourfindingsofappropriatechangesinkidney
weightandbloodpressureafterunilateralclipping
suggesteffectivecreationofunilateralrenalartery
stenosis.theapparentdecreaseinmeasuredsystolic

325

Fig.6.
GeneexpressionofEt-3intheclipped
andunclippedkidneys(K)atdifferenttime-
pointsaftersurgery.Et-3geneexpressionwas
significantlylowerintheclippedkidneyscom-
paredwiththecontralateralkidneyatday3(sig-
nificantvs.contralateralside*,55.7±7.7vs.
70.6±7.3,p<0.05).
bloodpressureonday20isthoughttobeduetoa
changeincuffsizeforbloodpressuremeasurement
withgrowthofrats.
Renalhypoperfusioniswell-knownasastimulator
ofbothrenalreningeneexpressionandplasmarenin
activity.Severalgroupsincludingourselveshave
shownanincreasedplasmareninactivityandin-
creasedipsilateralrenalreningeneexpressionafterin-
ductionofunilateralrenalarterystenosis[18].Renin
upregulationhasgenerallybeenacceptedasneurohu-
moralcounterregulationinrenalhypoperfusionto
maintainpost-stenoticrenalperfusionandrenalfunc-
itno.Inaccordancetoourfindingsmanygroupsreport
decreasing,butstillelevatedplasmareninlevelsinthe
morechronicphaseofrenovascularhypertension[19,
20,21],aswellasofincreasedreninRna-levelsinthe
clippedkidneyandsuppressedlevelsinthecontralat-
eralkidneyintheearlyphaseof2K1c-hypertension
[14,16,20].
Wedemonstratedthatrenalreningeneexpression
isupregulatedintheclippedkidneyasanearlyand
long-termadaptionprocesstorenalhypoperfusion.In
paralleldownregulationofthereningeneexpression
occursintheunclippedkidneymostpresumablydue
tosystemichypertensionagainasanearly-andlong-
termadaptionprocess.Hypertensionmostprobablyis
duetoanearlymarkedlyincreasedplasmareninactivi-
tythatdeclinesbytimebutstillisinadequatelyhigh
whenrelatedtosystemicbloodpressure,andpresum-
ablygoesalongwithsodiumretentioninadditionto
vasoconstriction.
Short-termrenalhypoperfusionhasresultedinan
upregulationofrenalEt-1andadownregulationof
renalEt-3[22].Studiesinpatientswithangioplastyof
renalarterystenosisshowedinconsistentresults.
WhileonereportfoundnochangeofplasmaEt-1
levelsafterrepair,anotherreportdescribedanin-
creasedlevelofEt-1[23,24].Inafurtherstudyno
differenceinplasmaEt-1levelssixweeksafterexper-
imental2K1c-clippingcomparedtobaselinewere
found[10].However,sinceendothelinsareknownto
actmainlyinanautocrine/paracrinemanner,plasma
levelsofendothelin-1maynotbesufficienttojudge

3.Reinhold_Umbruchvorlage28.11.0910:03Seite524524EuRoPEanJouRnalofMEdIcalRESEaRcHdecember14,2009
whethertheendothelinsystemisinvolvedi.e.inthebeconfirmedinfurtherstudies,usingpharmacological
pathophysiologyofunilateralrenalarterystenosis.anagonists/antagonistsand/orgeneticknockoutmodels.
additionalpapershowedthattheEt-systemseemedto
beactivatedinlow-renin,volume-dependent1K1c
R
EfEREncES
Goldblattrats[25],howeverthismodeldiffersinsev-
eralaspectstothe2K1cmodel,usedbyus.
1.SigmondH,BeierwaltesWH:Influenceofnitricoxidein
ourfindingsthatthereisnodifferenceinthegene
thechronicphaseoftwo-kidney,onecliprenovascular
expressionofEt-1andEt-3atday28and70sug-
hypertension.Hypertension1998;31:649-56.
2.turkstraE,BoerP,BraamB,KoomansHa:Increased
gest,thatEtsmightnottobeinvolvedinlong-term
availabilityofnitricoxideleadstoenhancednitricoxide
adaptationprocesses.IncontrastEt-1geneexpres-
dependencyoftubuloglomerularfeedbackinthecon-
sionbeingupregulatedintheclippedkidneyonday7
tralateralkidneyofratswith2-kidney,1-clipGoldblatt
andendothelin-3beingdownregulatedonday3,sug-
hypertension.Hypertension1999;34:679-84.
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matcheswellwithpreviousfindingsthatthereisno
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31.
differentexpressionpatternsinmedulla(down-regula-
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Received:April8,2009/Accepted:November4,2009

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fKrlainnizk-Juonsdef-PSotlriakluißn-ikalflüereI1n1nereMedizinII-nephrologie
93053Regensburg
tGeelr.:many+499419447301
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