肾髓质PGE2及肾素受体在糖尿病肾病和高血压中的作用.ppt

InteractionbetweenRenalMedullaryPGE2and P RRinDiabeticNephropathyandHypertension TianxinYang1 2andWeidongWang11InstituteofHypertension SunYat senUniversitySchoolofMedicine 2DepartmentofInternalMedicine UniversityofUtah PrevalenceofCKD CDC2010 IncidentRateofESRD NIDDK2010 ESRDCosts NIDDK2010 Diabetes Hypertension Glomerulonephritis PKD Kidneystones Drugs RAS Proteinuria Podocytedamage DiabetesMellitusandDiabeticNephropathy Nearly26millionAmericanshavediabetes accordingtonewestimatesfromtheCentersforDiseaseControlandPrevention CDC Inaddition anestimated79millionU S adultshaveprediabetes aconditioninwhichbloodsugarlevelsarehigherthannormal butnothighenoughtobediagnosedasdiabetes Prediabetesraisesaperson sriskoftype2diabetes heartdiseaseandstroke Diabetesaffects8 3percentofAmericansofallages and11 3percentofadultsaged20andolder accordingtotheNationalDiabetesFactSheetfor2011 About27percentofthosewithdiabetes 7millionAmericans donotknowtheyhavethedisease Prediabetesaffects35percentofadultsaged20andolder NationalDiabetesFactSheetfor2011 CDC Theoverallprevalencesoftotaldiabetes previouslydiagnosedpluspreviouslyundiagnoseddiabetes andprediabeteswere9 7 and15 5 respectively Inthemultivariable multinomial logitmodels malesex olderage afamilyhistoryofdiabetes overweight obesity centralobesity increasedheartrate elevatedsystolicbloodpressure elevatedserumtriglyceridelevel educationallevelbelowcollege andurbanresidencewereallsignificantlyassociatedwithanincreasedriskofdiabetesandprediabetes YangetalNEngJMed2010 EpidemiologyDiabeticnephropathyisthemostcommoncauseofchronickidneyfailureandend 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 RAS Pro ReninReceptor PRR ANewComponentoftheRAS BatenburgWW JanDanserAH EurJPharmacol 2008May118 Review SystemicRAS SchematicpresentationofthemainstepsintheRAAScascadeandsitesofactionoftheRAASinhibitors Pro reninReceptorandHypertension CollectingDuctReninSystem AngII 膜磷脂 花生四烯酸 ProstanoidSynthesisPathway mPGES 1 AngIIStmulates P RRExpressioninPrimaryRatIMCDCells AngIIStimulatesCOX 2ExpressioninPrimaryRatIMCDCells Control AngII 4hr AngII 12hr AngII 8hr 43kDa COX 2 P 0 05 PRRProteinExpressioninIMCDCellsafter12HoursofAngIITreatmentwithorwithoutNS 398 AngII P 0 05 P 0 01 PRR 43kDa AngII NS 398 Vehicle MediumReninActivity P 0 05 EffectofExogenousPGE2onPRRExpression ExogenousPGE2ReversestheEffectofNS 398 EffectsofStructurallyDistinctEP4Antagonists 43kDa 43kDa SummaryofResultswith3EPAntagonists AngII EffectofEP4AgonistonPRRExpression CTR CAY10598 RoleofcAMP PKAPathwayinControlofBaselinePRRProteinExpressioninIMCDCells CTR H89 CTR Forskolin 43kDa 43kDa PRR PRR PRRProteinExpressioninRatRenalMedullaafter2 WeeksofAngIIinfusionwithorwithoutCelecoxib AngII Coxib PRR Actin Circulatory RenalRegional andUrinaryReninActivityandTotalReninContent P 0 05 P 0 05 SystolicBloodPressure CelecoxibAttenuatesAlbuminuriainAngII InfusedMice Albuminexcretion g 24h p 0 05 p 0 05 Cont AngII AngII Celebrex AngII EP4a AngII Workingmodel CD PKA cAMP PRR EP4 Renin AGT AngI AngII ACE HypertensionCKD InstituteofHypertension SunYat senUniversitySchoolofMedicine Guangzhou China