腎髓質(zhì)PGE2及腎素受體在糖尿病腎病和高血壓中的作用

InteractionbetweenRenalMedullaryPGE2and(P)RRinDiabeticNephropathyandHypertensionTianxinYang1,2andWeidongWang11InstituteofHypertension,SunYat-senUniversitySchoolofMedicine;2DepartmentofInternalMedicine,UniversityofUtahPrevalenceofCKDCDC2021IncidentRateofESRDNIDDK2021ESRDCostsNIDDK2021DiabetesHypertensionGlomerulonephritisPKDKidneystonesDrugsRASProteinuriaPodocytedamageDiabetesMellitusandDiabeticNephropathyNearly26millionAmericanshavediabetes,accordingtonewestimatesfromtheCentersforDiseaseControlandPrevention(CDC).Inaddition,anestimated79millionU.S.adultshaveprediabetes,aconditioninwhichbloodsugarlevelsarehigherthannormal,butnothighenoughtobediagnosedasdiabetes.Prediabetesraisesaperson'sriskoftype2diabetes,heartdiseaseandstroke.Diabetesaffects8.3percentofAmericansofallages,and11.3percentofadultsaged20andolder,accordingtotheNationalDiabetesFactSheetfor2021.About27percentofthosewithdiabetes—7millionAmericans—donotknowtheyhavethedisease.Prediabetesaffects35percentofadultsaged20andolder.NationalDiabetesFactSheetfor2021,CDCTheoverallprevalencesoftotaldiabetes(previouslydiagnosedpluspreviouslyundiagnoseddiabetes)andprediabeteswere9.7%and15.5%,respectively.Inthemultivariable,multinomial,logitmodels,malesex,olderage,afamilyhistoryofdiabetes,overweight,obesity,centralobesity,increasedheartrate,elevatedsystolicbloodpressure,elevatedserumtriglyceridelevel,educationallevelbelowcollege,andurbanresidencewereallsignificantlyassociatedwithanincreasedriskofdiabetesandprediabetes.YangetalNEngJMed2021Epidemiology

Diabeticnephropathyisthemostcommoncauseofchronickidneyfailureandend-stagekidneydiseaseintheUnitedStates,accountingfor44%ofallnewcasesofkidneyfailureintheUnitedStatesin2021.Peoplewithbothtype1andtype2diabetesareatrisk.Theriskishigherifblood-glucoselevelsarepoorlycontrolled.Furthermore,oncenephropathydevelops,thegreatestrateofprogressionisseeninpatientswithpoorcontroloftheirbloodpressure.Alsopeoplewithhighcholesterollevelintheirbloodhavemuchmoreriskthanothers.糖尿病腎病在西方國(guó)家是導(dǎo)致慢性腎病和終末期腎病的最主要病因，在我們國(guó)家主要病因仍為原發(fā)性腎小球疾病，但糖尿病腎病的發(fā)病率有逐年增高的趨勢(shì)。以腎小球病變?yōu)樘卣鞯奶悄虿∧I病大約在糖尿病診斷之后15至20年出現(xiàn)，病程呈進(jìn)展性大約1/3的糖尿病病人有腎臟受累

糖尿病腎病Diabeticnephropathy,alsoknownasnodulardiabeticglomerulosclerosisandintercapillaryglomerulonephritis,isaprogressivekidneydiseasecausedbyangiopathyofcapillariesinthekidneyglomeruli.Itischaracterizedbynephroticsyndromeanddiffuseglomerulosclerosis.Itisduetolongstandingdiabetesmellitus,andisaprimeindicationfordialysisinmanyWesterncountries.(Pro)reninReceptorandDiabeticNephropathy圖1.腎素-血管緊張素系統(tǒng)與糖尿病腎病的治療策略RAS(Pro)ReninReceptor(PRR)：ANewComponentoftheRASBatenburgWW,JanDanserAH.EurJPharmacol.2021May118.Review.SystemicRASSchematicpresentationofthemainstepsintheRAAScascadeandsitesofactionoftheRAASinhibitors(Pro)reninReceptorandHypertensionCollectingDuctReninSystemAngII膜磷脂花生四烯酸ProstanoidSynthesisPathwaymPGES-1AngIIStmulates(P)RRExpressioninPrimaryRatIMCDCellsControlAngIIPRR43kDaβ-Actin43kDaP<0.05AngIIStimulatesCOX-2ExpressioninPrimaryRatIMCDCellsControlAngII(4hr)AngII(12hr)AngII(8hr)43kDaCOX-2P<0.05PRRProteinExpressioninIMCDCellsafter12HoursofAngIITreatmentwithorwithoutNS-398AngIIP<0.05P<0.01PRR43kDaAngII+NS-398VehicleMediumReninActivityP<0.05P<0.05EffectofExogenousPGE2onPRRExpression

PRRVehiclePGE2P<0.0143kDaExogenousPGE2ReversestheEffectofNS-398AngII

43kDaP<0.05P>0.05AngII+NS398AngII+NS398+PGE2PRREffectsofStructurallyDistinctEP4AntagonistsCTRCTRAngIIAngIIAngII+ONO-AE3-208AngII+L-16198243kDa43kDaSummaryofResultswith3EPAntagonistsP<0.01P<0.05P>0.05P<0.05VehicleControlEP1AEP3AEP4AAngIIEffectofEP4AgonistonPRRExpressionCTRCAY10598RoleofcAMP-PKAPathwayinControlofBaselinePRRProteinExpressioninIMCDCellsCTRH89CTRForskolin43kDa43kDaPRRPRRPRRProteinExpressioninRatRenalMedullaafter2-WeeksofAngIIinfusionwithorwithoutCelecoxibAngII+CoxibPRRControlAngII43kDaβ-ActinP<0.05P<0.05P<0.05P<0.05P<0.05P<0.05BACDHFGECirculatory,RenalRegional,andUrinaryReninActivityandTotalReninContentP<0.05P<0.05SystolicBloodPressureCelecoxibAttenuatesAlbuminuriainAngII-InfusedMiceAlbuminexcretion(μg/24h)p<0.05p<0.0