白蛋白氧化损伤在CKD和心血管病变进展中的作用

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2021/4/272AOPP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;49:13042021/4/273AOPP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;161:2524Martin-GallanP,etal.FreeRadicBioMed2003;34:1563YangXB.ChinInterMed,2005,44:342DruekeT,etal.Circulation2002;106:22122021/4/274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2021/4/275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？2021/4/276AOPP潴留增加5/6肾切除动物的肾脏炎症AOPPs-RSALiHY,HouFF,etal.JAmSocNephrol2007;18:5285/6NxShamRSAvehicleRenalexpressionofMCP-1&MØinfluxatweek132021/4/277LiHY,HouFF,etal.JAmSocNephrol2007;18:5285/6NxShamAOPPsRSAvehicleRenalexpressionofTGF-β1atweek13AOPP潴留上调5/6肾切除动物肾TGF-β1表达2021/4/278AOPP潴留促进5/6肾切除动物肾纤维化vehicleLiHY,HouFF,etal.JAmSocNephrol2007;18:528AOPPsRSAGlomerulosclerosisindexInterstitialfibrosisscore59135913Time(weeks)2021/4/279AOPP潴留加速5/6肾切除模型肾功能减退ChangesinCcrChangesinalbuminuriaLiHY,HouFF,etal.JAmSocNephrol2007;18:528AOPPsRSAvehicle●▲■Ccr(ml/min/100gBW)Urinaryproteinexcretion(mg/24hours)Time(weeks)2021/4/2710ShiXY，HouFF,etal.Endocrinology,2008;149:1829DM+vehicleDM+RSADM+AOPPsMøMCP-1AOPP潴留促进糖尿病肾脏的炎症反应MØinflux&MCP-1expressioninSTZ-induceddiabeticrats2021/4/2711ParameterWeek5(n=6)Week10b(n=6)Ccr(ml/min/KgBW)cGroup1(DM+vehicle)7.16±0.23d8.05±0.34dGroup2(DM+RSA)7.18±0.23d8.01±0.27dGroup3(DM+AOPPs)7.55±0.288.89±0.17eGroup4(DM+AOPPs+apocynin)5.89±0.19f6.34±0.27fGroup5(DM+apocynin)5.58±0.19g5.96±0.31gGroup6(control+vehicle)3.41±0.283.59±0.16Urinaryalbuminexcretion(mg/24h)b,cGroup1(DM+vehicle)0.78×/÷1.16d1.20×/÷1.17dGroup2(DM+RSA)0.78×/÷1.14d1.17×/÷1.17dGroup3(DM+AOPPs)1.17×/÷1.16e1.95×/÷1.15eGroup4(DM+AOPPs+apocynin)0.51×/÷1.15f0.72×/÷1.20fGroup5(DM+apocynin)0.45×/÷1.13g0.55×/÷1.17gGroup6(control+vehicle)0.17×/÷1.150.19×/÷1.12ShiXY，HouFF,etal.Endocrinology,2008;149:1829AOPP潴留加重糖尿病的肾脏高滤过和白蛋白尿2021/4/2712AOPP慢性负荷加速高脂血症家兔动脉粥样硬化NormaldietCholesterolChol+RSAChol+AOPPsLiuSX,HouFF,etal.ArteriosclerThrombVascBiol2006;26:1156AOPPsincreasemacrophageinfiltrationinatheroscleroticplaques.vehicleRSAAOPPs2021/4/2713AOPP潴留是介导肾脏病和动脉粥样硬化进展的致病因素结论2021/4/2714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？2021/4/2715AOPP处理的正常大鼠肾小球足细胞凋亡增加ZhouLL,HouFF,etal.KidneyInt2009;76:1148Normalratsweretreatedwithvehicle,RSAorAOPPs2021/4/2716AOPP潴留导致肾小球足细胞凋亡和缺失ZhouLL,HouFF,etal.KidneyInt2009;76:11482021/4/2717ZhouLL,HouFF,etal.KidneyInt2009;76:1148AOPP潴留减少肾小球足细胞数量和密度2021/4/2718AOPP导致足细胞缺失的受体和信号途径LiLiZhou,etal.KidneyInt2012,82:759RAGE2021/4/2719AOPP上调系膜细胞细胞外基质生成WeiXF,HouFF,etal.AmJPhysiolRenalPhysiol2009;296:F4272021/4/2720AOPP导致系膜细胞功能紊乱的信号途径WeiXF,HouFF,etal.AmJPhysiolRenalPhysiol2009;296:F427PKC-αactivationAOPPsaccumulationNADPHoxidaseactivationO2-productionTGF-β1overexpressionECMoverproduction(FN,CollagenⅣ)2021/4/2721AOPP-白蛋白激活肾小管上皮细胞RASCaoW,etal.AntioxidRedoxSign2013,18(1):192021/4/2722AOPP活化单侧肾切除大鼠肾内RASCaoW,etal.AntioxidRedoxSign2013,18(1):192021/4/2723AOPP与CD36相互作用活化肾内RASDeletionofCD36orinhibitionofNADPHoxidasesignificantlyblockAOPPs-triggeredintrarenalactivationofRASCaoW,etal.AntioxidRedoxSign2013,18(1):192021/4/2724AOPP诱导内皮细胞粘附分子过度表达GuoZJ,etal.AntioxidRedoxSign2008;10:1699TheinflammatoryreactiontriggeredbyAOPPswaspreventedbyblockingofRAGEorinhibitionofNADPHoxidase2021/4/2725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2021/4/2726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？2021/4/2727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）2021/4/2728NADPH氧化酶抑制剂阻断AOPP的致病作用AT1AngⅡACEAOPPAOPP+apocyninCaoW,etal.ARS2013,18:19ZhouLL,etal.KidneyInt2009;76:1148;WT-1TUNELMergeAOPPAOPP+apocynin2021/4/2729MøMCP-1DM+AOPPDM+AOPP+apocininShiXY,HouFF,etal.Endocriology,2008;149:1829抑制AOPP活化改善糖尿病肾脏炎症STZ-induceddiabeticrats2021/4/2730HeLJ，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+AOPP2021/4/2731EPS改善AOPP引起的动脉粥样硬化GuoZJ,HouFF,etal.IntJCardio,2009,136:315WithoutEPSWithEPSVehicleRSAAGEsAOPPs2021/4/2732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2021/4/2733动物实验的结果是否有临床意义?2021/4/2734AOPP在人类CKD肾组织沉积LiuBY,etal.FreeRadicRes.2011;45:662Immunohistologicstainingwithmonoclonalanti-AOPPNormalkidneytissueDiabeticNephrologyIgANephrologyMembranousNephrology2021/4/2735NormalkidneyAnti-AOPPIgAnephropathyAnti-AOPPIgAnephropathyAnti-AOPPIgAnephropathyAnti-AOPPIgAnephropathyAnti-AOPPIgAnephropathyMousenonimmunoIgGIgAnephropathyAnti-AOPPpretreatedbyAlbIgAnephropathyAnti-AOPPpretreatedbyAOPPXuJ,HouFF,etal.PapersubmittedIgA肾病患者肾组织中AOPP沉积2021/4/2736Anti-AOPPAnti-TGF-β1AngⅡNormalIgANXuJ,HouFF,etal.PapersubmittedImmunohistochemicalstaininginserialsectionsAOPP表达伴TGF-β和AngⅡ上调2021/4/2737XuJ,HouFF,etal.PapersubmittedAOPPTGF-β1MergeAOPPAngⅡMergeAOPP表达伴TGF-β和AngⅡ上调Doublestainingwithanti-AOPPandanti-TGF-β1oranti-AngⅡ2021/4/2738AOPP表达水平与肾组织细胞炎症程度相关XuJ,HouFF,etal.PapersubmittedDependentvariablesIndependentvariablesβP肾小球AOPP染色积分

(R2=0.256)肾小球巨噬细胞数目0.3290.003系膜细胞增殖程度0.2530.023肾小管间质AOPP染色积分

(R2=0.410)间质巨噬细胞数目0.395＜0.001血浆AOPP水平0.409＜0.00198例eGFR＞80ml/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）2021/4/2739XuJ,HouFF,etal.Papersubmitted28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2021/4/2740XuJ,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2021/4/2741XuJ,HouFF,etal.Papersubmitted多因素回归分析VariablesattimeofdiagnosisMultivariateanalysisOR95%CIPGlomerularAOPPstainingscore<0.5(Reference)0.5-113.5001.473-123.7430.021>115.7501.754-141.4040.014TubulointerstitialAOPPstainingscore<1(Reference)1-2>230.0001.471-611.7970.027InterstitialinfiltratingcellswithAOPPexpression(present=1,absent=0)24.0002.394-240.6320.007肾AOPP表达水平预示IgAN肾纤维化进展2021/4/2742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＜40μmol/L(N=84)或≥40μmol/L(N=36)患者肾脏存活率的比较PlasmaAOPPsProteinuria2021/4/2743血浆AOPP是内皮功能障碍的标志物UAC<30mg/d的新诊断的2型糖尿病患者（n=112例）WangJ,FFHou,etal.PaperSubmittedMultivariateanalysisOR95%CIPSerumHDL-C(mmol/L)0.1840.048-0.7130.014HbA1c>7%(yes=1,no=0)5.1151.808-14.4690.002PlasmaAOPP>75μmol/L(yes=1,no=0)4.0281.320-12.2880.0142021/4/2744AOPP是促进血透患者CVD的独立危险因素Multi-centercohortstudy（HDpatients，n=1,539）UnivariatemultivariatevariablesOR95%CIPOR95%CIPAge≥50yr,(no=0,yes=1)2.3941.784-3.2130.0001.8681.315-2.6530.000Male(no=0,yes=1)1.0920.853-1.3980.485BMI≥24kg/m2,