肾髓质PGE2及肾素受体在糖尿病肾病和高血压中的作用课件

InteractionbetweenRenalMedullaryPGE2and(P)RRinDiabeticNephropathyandHypertensionTianxinYang1,2andWeidongWang11InstituteofHypertension,SunYat-senUniversitySchoolofMedicine;2DepartmentofInternalMedicine,UniversityofUtahPrevalenceofCKDCDC2010ESRDCostsNIDDK2010DiabetesMellitusandDiabeticNephropathyNearly26millionAmericanshavediabetes,accordingtonewestimatesfromtheCentersforDiseaseControlandPrevention(CDC).Inaddition,anestimated79millionU.S.adultshaveprediabetes,aconditioninwhichbloodsugarlevelsarehigherthannormal,butnothighenoughtobediagnosedasdiabetes.Prediabetesraisesaperson'sriskoftype2diabetes,heartdiseaseandstroke.Diabetesaffects8.3percentofAmericansofallages,and11.3percentofadultsaged20andolder,accordingtotheNationalDiabetesFactSheetfor2011.About27percentofthosewithdiabetes—7millionAmericans—donotknowtheyhavethedisease.Prediabetesaffects35percentofadultsaged20andolder.NationalDiabetesFactSheetfor2011,CDCAnnualNumber(inThousands)ofNewCasesofDiagnosedDiabetesAmongAdultsAged18–79Years,UnitedStates,1980–2010From1980through2010,thenumberofadultsintheUnitedStatesaged18–79withnewlydiagnoseddiabetesmorethantripledfrom493,000in1980toover1.7millionin2010.Thenumberofnewcasesofdiabeteshasincreasedsincetheearly1990s.From2008through2010,thenumberofnewcasesofdiagnoseddiabeteshasshownlittlechange.NationalDiabetesFactSheetfor2011,CDCNumber(inMillions)ofCivilian,NoninstitutionalizedAdultswithDiagnosedDiabetes,UnitedStates,1980–2010From1980through2010,thenumberofU.S.adultsaged18yearsorolderwithdiagnoseddiabeteshasmorethantripled(from5.5millionto20.7million).NationalDiabetesFactSheetfor2011,CDCEpidemiology

Diabeticnephropathyisthemostcommoncauseofchronickidneyfailureandend-stagekidneydiseaseintheUnitedStates,accountingfor44%ofallnewcasesofkidneyfailureintheUnitedStatesin2008.Peoplewithbothtype1andtype2diabetesareatrisk.Theriskishigherifblood-glucoselevelsarepoorlycontrolled.Furthermore,oncenephropathydevelops,thegreatestrateofprogressionisseeninpatientswithpoorcontroloftheirbloodpressure.Alsopeoplewithhighcholesterollevelintheirbloodhavemuchmoreriskthanothers.糖尿病肾病在西方国家是导致慢性肾病和终末期肾病的最主要病因，在我们国家主要病因仍为原发性肾小球疾病，但糖尿病肾病的发病率有逐年增高的趋势。以肾小球病变为特征的糖尿病肾病大约在糖尿病诊断之后15至20年出现，病程呈进展性大约1/3的糖尿病病人有肾脏受累

糖尿病肾病Diabeticnephropathy,alsoknownasnodulardiabeticglomerulosclerosisandintercapillaryglomerulonephritis,isaprogressivekidneydiseasecausedbyangiopathyofcapillariesinthekidneyglomeruli.Itischaracterizedbynephroticsyndromeanddiffuseglomerulosclerosis.Itisduetolongstandingdiabetesmellitus,andisaprimeindicationfordialysisinmanyWesterncountries.(Pro)reninReceptorandDiabeticNephropathy图1.肾素-血管紧张素系统与糖尿病肾病的治疗策略(Pro)ReninReceptor(PRR)：ANewComponentoftheRASBatenburgWW,JanDanserAH.EurJPharmacol.2008May118.Review.SystemicRASSchematicpresentationofthemainstepsintheRAAScascadeandsitesofactionoftheRAASinhibitors(Pro)reninReceptorandHypertensionCollectingDuctReninSystemAngIIAngIIStmulates(P)RRExpressioninPrimaryRatIMCDCellsControlAngIIPRR43kDaβ-Actin43kDaP<0.05AngIIStimulatesCOX-2ExpressioninPrimaryRatIMCDCellsControlAngII(4hr)AngII(12hr)AngII(8hr)43kDaCOX-2P<0.05MediumReninActivityP<0.05P<0.05EffectofExogenousPGE2onPRRExpression

PRRVehiclePGE2P<0.0143kDaEffectsofStructurallyDistinctEP4AntagonistsCTRCTRAngIIAngIIAngII+ONO-AE3-208AngII+L-16198243kDa43kDaEffectofEP4AgonistonPRRExpressionCTRCAY10598RoleofcAMP-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<0.05ContAngIIAn