白蛋白氧化損傷在CKD和心血管病變進(jìn)展中的作用

白蛋白氧化損傷在CKD和心血管病變進(jìn)展中的作用腎臟纖維化預(yù)示CKD的預(yù)后CKD是“全球公共健康問題”腎纖維化是各種CKD進(jìn)展的共同途徑揭示促進(jìn)腎纖維化和CKD進(jìn)展的致病因素及機(jī)制是防止CKD進(jìn)展的關(guān)鍵2021/4/272AOPP是蛋白質(zhì)氧化損傷的標(biāo)志AOPP是在氧化應(yīng)激中生成的一類含雙酪氨酸的氧化蛋白質(zhì)產(chǎn)物白蛋白在體外與次氯酸作用生成AOPP，體內(nèi)AOPP主要由白蛋白氧化生成血漿AOPP濃度與酪氨酸水平密切相關(guān)Witko-SarsatV,etal.KidneyInt1996;49:13042021/4/273AOPP潴留可能與CKD進(jìn)展相關(guān)AOPP血漿水平隨CKD患者腎臟病進(jìn)展而增加糖尿病或肥胖患者循環(huán)中AOPP水平增高AOPP血漿水平與ESRD患者的頸動脈內(nèi)膜中層厚度有關(guān)Witko-SarsatV,etal.

JImmunol1998;161:2524Martin-GallanP,etal.FreeRadicBioMed2003;34:1563YangXB.ChinInterMed,2005,44:342DruekeT,etal.Circulation2002;106:22122021/4/274研究假設(shè)AOPP潴留不僅是反映氧化應(yīng)激的標(biāo)志物，它可能與慢性腎臟病的進(jìn)展和心血管損傷有關(guān)2021/4/275要解決的問題AOPP潴留能否促進(jìn)CKD進(jìn)展？AOPP為何能促進(jìn)CKD進(jìn)展?干預(yù)AOPP潴留能否延緩CKD進(jìn)展？2021/4/276AOPP潴留增加5/6腎切除動物的腎臟炎癥AOPPs-RSALiHY,HouFF,etal.JAmSocNephrol2007;18:5285/6NxShamRSAvehicleRenalexpressionofMCP-1&M?influxatweek132021/4/277LiHY,HouFF,etal.JAmSocNephrol2007;18:5285/6NxShamAOPPsRSAvehicleRenalexpressionofTGF-β1atweek13AOPP潴留上調(diào)5/6腎切除動物腎TGF-β1表達(dá)2021/4/278AOPP潴留促進(jìn)5/6腎切除動物腎纖維化vehicleLiHY,HouFF,etal.JAmSocNephrol2007;18:528AOPPsRSAGlomerulosclerosisindexInterstitialfibrosisscore59135913Time(weeks)2021/4/279AOPP潴留加速5/6腎切除模型腎功能減退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+AOPPsM?MCP-1AOPP潴留促進(jìn)糖尿病腎臟的炎癥反應(yīng)M?influx&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潴留加重糖尿病的腎臟高濾過和白蛋白尿2021/4/2712AOPP慢性負(fù)荷加速高脂血癥家兔動脈粥樣硬化NormaldietCholesterolChol+RSAChol+AOPPsLiuSX,HouFF,etal.ArteriosclerThrombVascBiol2006;26:1156AOPPsincreasemacrophageinfiltrationinatheroscleroticplaques.vehicleRSAAOPPs2021/4/2713AOPP潴留是介導(dǎo)腎臟病和動脈粥樣硬化進(jìn)展的致病因素結(jié)論2021/4/2714要解決的問題AOPP潴留能否促進(jìn)CKD進(jìn)展？2.AOPP為何能促進(jìn)CKD進(jìn)展?干預(yù)AOPP潴留能否延緩CKD進(jìn)展？2021/4/2715AOPP處理的正常大鼠腎小球足細(xì)胞凋亡增加ZhouLL,HouFF,etal.KidneyInt2009;76:1148Normalratsweretreatedwithvehicle,RSAorAOPPs2021/4/2716AOPP潴留導(dǎo)致腎小球足細(xì)胞凋亡和缺失ZhouLL,HouFF,etal.KidneyInt2009;76:11482021/4/2717ZhouLL,HouFF,etal.KidneyInt2009;76:1148AOPP潴留減少腎小球足細(xì)胞數(shù)量和密度2021/4/2718AOPP導(dǎo)致足細(xì)胞缺失的受體和信號途徑LiLiZhou,etal.KidneyInt2012,82:759RAGE2021/4/2719AOPP上調(diào)系膜細(xì)胞細(xì)胞外基質(zhì)生成WeiXF,HouFF,etal.AmJPhysiolRenalPhysiol2009;296:F4272021/4/2720AOPP導(dǎo)致系膜細(xì)胞功能紊亂的信號途徑WeiXF,HouFF,etal.AmJPhysiolRenalPhysiol2009;296:F427PKC-αactivationAOPPsaccumulationNADPHoxidaseactivationO2-productionTGF-β1overexpressionECMoverproduction(FN,CollagenⅣ)2021/4/2721AOPP-白蛋白激活腎小管上皮細(xì)胞RASCaoW,etal.AntioxidRedoxSign2013,18(1):192021/4/2722AOPP活化單側(cè)腎切除大鼠腎內(nèi)RASCaoW,etal.AntioxidRedoxSign2013,18(1):192021/4/2723AOPP與CD36相互作用活化腎內(nèi)RASDeletionofCD36orinhibitionofNADPHoxidasesignificantlyblockAOPPs-triggeredintrarenalactivationofRASCaoW,etal.AntioxidRedoxSign2013,18(1):192021/4/2724AOPP誘導(dǎo)內(nèi)皮細(xì)胞粘附分子過度表達(dá)GuoZJ,etal.AntioxidRedoxSign2008;10:1699TheinflammatoryreactiontriggeredbyAOPPswaspreventedbyblockingofRAGEorinhibitionofNADPHoxidase2021/4/2725結(jié)論AOPP潴留通過促進(jìn)redox敏感的炎癥反應(yīng)導(dǎo)致腎臟和血管細(xì)胞的損傷和功能紊亂NADPH氧化酶活化是介導(dǎo)AOPP致病作用的重要細(xì)胞內(nèi)事件2021/4/2726要解決的問題AOPP潴留能否促進(jìn)CKD進(jìn)展？2.AOPP為何能促進(jìn)CKD進(jìn)展?3.干預(yù)AOPP潴留能否延緩CKD進(jìn)展？2021/4/2727阻斷AOPP致病作用的可能途徑抗氧化治療阻斷AOPP與其受體的相互作用抑制AOPP作用的信號分子（如NADPH氧化酶）2021/4/2728NADPH氧化酶抑制劑阻斷AOPP的致病作用AT1AngⅡACEAOPPAOPP+apocyninCaoW,etal.ARS2013,18:19ZhouLL,etal.KidneyInt2009;76:1148;WT-1TUNELMergeAOPPAOPP+apocynin2021/4/2729M?MCP-1DM+AOPPDM+AOPP+apocininShiXY,HouFF,etal.Endocriology,2008;149:1829抑制AOPP活化改善糖尿病腎臟炎癥STZ-induceddiabeticrats2021/4/2730HeLJ，etal.JEndocrinology,2009;200:347西藏胡黃連提取物EPS減少糖尿病腎臟炎癥反應(yīng)DM+AOPP2021/4/2731EPS改善AOPP引起的動脈粥樣硬化GuoZJ,HouFF,etal.IntJCardio,2009,136:315WithoutEPSWithEPSVehicleRSAAGEsAOPPs2021/4/2732結(jié)論

抑制NADPH氧化酶或抗氧化干預(yù)延緩AOPP誘導(dǎo)的腎臟病變和動脈粥樣硬化進(jìn)展2021/4/2733動物實(shí)驗(yàn)的結(jié)果是否有臨床意義?2021/4/2734AOPP在人類CKD腎組織沉積LiuBY,etal.FreeRadicRes.2011;45:662Immunohistologicstainingwithmonoclonalanti-AOPPNormalkidneytissueDiabeticNephrologyIgANephrologyMembranousNephrology2021/4/2735NormalkidneyAnti-AOPPIgAnephropathyAnti-AOPPIgAnephropathyAnti-AOPPIgAnephropathyAnti-AOPPIgAnephropathyAnti-AOPPIgAnephropathyMousenonimmunoIgGIgAnephropathyAnti-AOPPpretreatedbyAlbIgAnephropathyAnti-AOPPpretreatedbyAOPPXuJ,HouFF,etal.PapersubmittedIgA腎病患者腎組織中AOPP沉積2021/4/2736Anti-AOPPAnti-TGF-β1AngⅡNormalIgANXuJ,HouFF,etal.PapersubmittedImmunohistochemicalstaininginserialsectionsAOPP表達(dá)伴TGF-β和AngⅡ上調(diào)2021/4/2737XuJ,HouFF,etal.PapersubmittedAOPPTGF-β1MergeAOPPAngⅡMergeAOPP表達(dá)伴TGF-β和AngⅡ上調(diào)Doublestainingwithanti-AOPPandanti-TGF-β1oranti-AngⅡ2021/4/2738AOPP表達(dá)水平與腎組織細(xì)胞炎癥程度相關(guān)XuJ,HouFF,etal.PapersubmittedDependentvariablesIndependentvariablesβP腎小球AOPP染色積分

(R2=0.256)腎小球巨噬細(xì)胞數(shù)目0.3290.003系膜細(xì)胞增殖程度0.2530.023腎小管間質(zhì)AOPP染色積分

(R2=0.410)間質(zhì)巨噬細(xì)胞數(shù)目0.395＜0.001血漿AOPP水平0.409＜0.00198例eGFR＞80ml/min/1.73m2的IgAN患者，與腎臟AOPP表達(dá)相關(guān)的因素（多變量線性回歸）2021/4/2739XuJ,HouFF,etal.Papersubmitted28例接受重復(fù)腎活檢的IgAN患者（重復(fù)腎活檢的間隔時(shí)間平均3.5年），首次活檢的AOPP染色積分與重復(fù)腎活檢時(shí)腎纖維化指數(shù)增加與eGFR下降相關(guān)腎AOPP表達(dá)水平預(yù)示IgAN腎纖維化進(jìn)展2021/4/2740XuJ,HouFF,etal.Papersubmitted首次腎活檢AOPP表達(dá)水平＞中位數(shù)者在重復(fù)腎活檢時(shí)腎小管間質(zhì)纖維化和腎小球硬化指數(shù)明顯增加腎AOPP表達(dá)水平預(yù)示IgAN腎纖維化進(jìn)展2021/4/2741XuJ,HouFF,etal.Papersubmitted多因素回歸分析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腎AOPP表達(dá)水平預(yù)示IgAN腎纖維化進(jìn)展2021/4/2742血漿AOPP水平預(yù)示IgA腎病的腎臟存活率Descamps-LatschaB,etal.KidneyInt.2004;66:1606基線血漿AOPP水平＜40μmol/L(N=84)或≥40μmol/L(N=36)患者腎臟存活率的比較PlasmaAOPPsProteinuria2021/4/2743血漿AOPP是內(nèi)皮功能障礙的標(biāo)志物UAC<30mg/d的新診斷的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是促進(jìn)血透患者CVD的獨(dú)立危險(xiǎn)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,