白蛋白氧化损伤在CKD和心血管病变进展中的作用.ppt

白蛋白氧化损伤在CKD和心血管病变进展中的作用,肾脏纤维化预示CKD的预后,CKD是“全球公共健康问题”肾纤维化是各种CKD进展的共同途径揭示促进肾纤维化和CKD进展的致病因素及机制是防止CKD进展的关键,AOPP是蛋白质氧化损伤的标志,AOPP是在氧化应激中生成的一类含双酪氨酸的氧化蛋白质产物白蛋白在体外与次氯酸作用生成AOPP，体内AOPP主要由白蛋白氧化生成血浆AOPP浓度与酪氨酸水平密切相关,Witko-SarsatV,etal.KidneyInt1996;49:1304,AOPP潴留可能与CKD进展相关,AOPP血浆水平随CKD患者肾脏病进展而增加糖尿病或肥胖患者循环中AOPP水平增高AOPP血浆水平与ESRD患者的颈动脉内膜中层厚度有关,Witko-SarsatV,etal.JImmunol1998;161:2524,Martin-GallanP,etal.FreeRadicBioMed2003;34:1563,YangXB.ChinInterMed,2005,44:342DruekeT,etal.Circulation2002;106:2212,研究假设,AOPP潴留不仅是反映氧化应激的标志物，它可能与慢性肾脏病的进展和心血管损伤有关,要解决的问题,AOPP潴留能否促进CKD进展？,AOPP为何能促进CKD进展?干预AOPP潴留能否延缓CKD进展？,AOPP潴留增加5/6肾切除动物的肾脏炎症,AOPPs-RSA,LiHY,HouFF,etal.JAmSocNephrol2007;18:528,5/6Nx,Sham,RSA,vehicle,RenalexpressionofMCP-118:528,5/6Nx,Sham,AOPPs,RSA,vehicle,RenalexpressionofTGF-1atweek13,AOPP潴留上调5/6肾切除动物肾TGF-1表达,AOPP潴留促进5/6肾切除动物肾纤维化,vehicle,LiHY,HouFF,etal.JAmSocNephrol2007;18:528,AOPPs,RSA,Glomerulosclerosisindex,Interstitialfibrosisscore,5,9,13,5,9,13,Time(weeks),AOPP潴留加速5/6肾切除模型肾功能减退,ChangesinCcr,Changesinalbuminuria,LiHY,HouFF,etal.JAmSocNephrol2007;18:528,AOPPsRSAvehicle,Ccr(ml/min/100gBW),Urinaryproteinexcretion(mg/24hours),Time(weeks),ShiXY，HouFF,etal.Endocrinology,2008;149:1829,DM+vehicle,DM+RSA,DM+AOPPs,M,MCP-1,AOPP潴留促进糖尿病肾脏的炎症反应,Minflux149:1829,AOPP潴留加重糖尿病的肾脏高滤过和白蛋白尿,AOPP慢性负荷加速高脂血症家兔动脉粥样硬化,Normaldiet,Cholesterol,Chol+RSA,Chol+AOPPs,LiuSX,HouFF,etal.ArteriosclerThrombVascBiol2006;26:1156,AOPPsincreasemacrophageinfiltrationinatheroscleroticplaques.,vehicle,RSA,AOPPs,AOPP潴留是介导肾脏病和动脉粥样硬化进展的致病因素,结论,要解决的问题,AOPP潴留能否促进CKD进展？,2.AOPP为何能促进CKD进展?,干预AOPP潴留能否延缓CKD进展？,AOPP处理的正常大鼠肾小球足细胞凋亡增加,ZhouLL,HouFF,etal.KidneyInt2009;76:1148,Normalratsweretreatedwithvehicle,RSAorAOPPs,AOPP潴留导致肾小球足细胞凋亡和缺失,ZhouLL,HouFF,etal.KidneyInt2009;76:1148,ZhouLL,HouFF,etal.KidneyInt2009;76:1148,AOPP潴留减少肾小球足细胞数量和密度,AOPP导致足细胞缺失的受体和信号途径,LiLiZhou,etal.KidneyInt2012,82:759,RAGE,AOPP上调系膜细胞细胞外基质生成,WeiXF,HouFF,etal.AmJPhysiolRenalPhysiol2009;296:F427,AOPP导致系膜细胞功能紊乱的信号途径,WeiXF,HouFF,etal.AmJPhysiolRenalPhysiol2009;296:F427,PKC-activation,AOPPsaccumulation,NADPHoxidaseactivation,O2-production,TGF-1overexpression,ECMoverproduction(FN,Collagen),AOPP-白蛋白激活肾小管上皮细胞RAS,CaoW,etal.AntioxidRedoxSign2013,18(1):19,AOPP活化单侧肾切除大鼠肾内RAS,CaoW,etal.AntioxidRedoxSign2013,18(1):19,AOPP与CD36相互作用活化肾内RAS,DeletionofCD36orinhibitionofNADPHoxidasesignificantlyblockAOPPs-triggeredintrarenalactivationofRAS,CaoW,etal.AntioxidRedoxSign2013,18(1):19,AOPP诱导内皮细胞粘附分子过度表达,GuoZJ,etal.AntioxidRedoxSign2008;10:1699,TheinflammatoryreactiontriggeredbyAOPPswaspreventedbyblockingofRAGEorinhibitionofNADPHoxidase,结论,AOPP潴留通过促进redox敏感的炎症反应导致肾脏和血管细胞的损伤和功能紊乱NADPH氧化酶活化是介导AOPP致病作用的重要细胞内事件,要解决的问题,AOPP潴留能否促进CKD进展？,2.AOPP为何能促进CKD进展?,3.干预AOPP潴留能否延缓CKD进展？,阻断AOPP致病作用的可能途径,抗氧化治疗阻断AOPP与其受体的相互作用抑制AOPP作用的信号分子（如NADPH氧化酶）,NADPH氧化酶抑制剂阻断AOPP的致病作用,AT1AngACE,AOPP,AOPP+apocynin,CaoW,etal.ARS2013,18:19,ZhouLL,etal.KidneyInt2009;76:1148;,WT-1TUNELMerge,AOPP,AOPP+apocynin,M,MCP-1,DM+AOPP,DM+AOPP+apocinin,ShiXY,HouFF,etal.Endocriology,2008;149:1829,抑制AOPP活化改善糖尿病肾脏炎症,STZ-induceddiabeticrats,HeLJ，etal.JEndocrinology,2009;200:347,西藏胡黄连提取物EPS减少糖尿病肾脏炎症反应,DM+AOPP,EPS改善AOPP引起的动脉粥样硬化,GuoZJ,HouFF,etal.IntJCardio,2009,136:315,WithoutEPS,WithEPS,Vehicle,RSA,AGEs,AOPPs,结论,抑制NADPH氧化酶或抗氧化干预延缓AOPP诱导的肾脏病变和动脉粥样硬化进展,动物实验的结果是否有临床意义?,AOPP在人类CKD肾组织沉积,LiuBY,etal.FreeRadicRes.2011;45:662,Immunohistologicstainingwithmonoclonalanti-AOPP,Normalkidneytissue,DiabeticNephrology,IgANephrology,MembranousNephrology,NormalkidneyAnti-AOPP,IgAnephropathyAnti-AOPP,IgAnephropathyAnti-AOPP,IgAnephropathyAnti-AOPP,IgAnephropathyAnti-AOPP,IgAnephropathyMousenonimmunoIgG,IgAnephropathyAnti-AOPPpretreatedbyAlb,IgAnephropathyAnti-AOPPpretreatedbyAOPP,XuJ,HouFF,etal.Papersubmitted,IgA肾病患者肾组织中AOPP沉积,Anti-AOPP,Anti-TGF-1,Ang,Normal,IgAN,XuJ,HouFF,etal.Papersubmitted,Immunohistochemicalstaininginserialsections,AOPP表达伴TGF-和Ang上调,XuJ,HouFF,etal.Papersubmitted,AOPP,TGF-1,Merge,AOPP,Ang,Merge,AOPP表达伴TGF-和Ang上调,Doublestainingwithanti-AOPPandanti-TGF-1oranti-Ang,AOPP表达水平与肾组织细胞炎症程度相关,XuJ,HouFF,etal.Papersubmitted,98例eGFR80ml/min/1.73m2的IgAN患者，与肾脏AOPP表达相关的因素（多变量线性回归）,XuJ,HouFF,etal.Papersubmitted,28例接受重复肾活检的IgAN患者（重复肾活检的间隔时间平均3.5年），首次活检的AOPP染色积分与重复肾活检时肾纤维化指数增加与eGFR下降相关,肾AOPP表达水平预示IgAN肾纤维化进展,XuJ,HouFF,etal.Papersubmitted,首次肾活检AOPP表达水平中位数者在重复肾活检时肾小管间质纤维化和肾小球硬化指数明显增加,肾AOPP表达水平预示IgAN肾纤维化进展,XuJ,HouFF,etal.Papersubmitted,多因素回归分析,肾AOPP表达水平预示IgAN肾纤维化进展,血浆AOPP水平预示IgA肾病的肾脏存活率,Descamps-LatschaB,etal.KidneyInt.2004;66:1606,基线血浆AOPP水平40mol/L(N=84)或40mol/L(N=36)患者肾脏存活率的比较,PlasmaAOPPs,Proteinuria,血浆AOPP是内皮功能障碍的标志物,UAC30mg/d的新诊断的2型糖尿病患者（n=112例）,WangJ,FFHou,etal.PaperSubmitted,AOPP是促