糖尿病腎病與小管間質(zhì)損傷-從基礎(chǔ)到臨床

糖尿病腎病與小管間質(zhì)損傷

-從基礎(chǔ)到臨床

Tubulointerstitialinjuryindiabetickidneydisease

FromBench

to

ClinicalWork中國-糖尿病發(fā)病率國際首位12%患有糖尿病，而前驅(qū)糖尿病的患病率大約為50%,占世界1/32023/11/12糖尿病心心皮膚眼腎NatureNature1.pdfDiabetes:Thegoodinfat.2014;516:49-50.nature2.pdfDiabetesrecoverybyage-dependentconversionofpancreaticδ-cellsintoinsulinproducers.2014;514:503-7.nature3.pdfMetabolismofstromalandimmunecellsinhealthanddisease.2014;511:167-76.nature4.pdfAnti-diabeticactivityofinsulin-degradingenzymeinhibitorsmediatedbymultiplehormones.2014;511:94-8.nature5.pdfAsmall-moleculeAdipoRagonistfortype2diabetesandshortlifeinobesity.2013;503:493-9.Nature6.pdfCooperationbetweenbrainandisletinglucosehomeostasisanddiabetes.2013;503:59-66.nature7.pdfGutmetagenomeinEuropeanwomenwithnormal,impairedanddiabeticglucosecontrol.2013;498:99-103.Nature8.pdfMechanisticstudiesofanunprecedentedenzyme-catalysed1,2phosphono-migrationreaction.2013;496:114-8.

NatureNewlightsNEnglJMedNEngl1.pdfFibrosis—ACommonPathwaytoOrganInjuryandFailure.2015;372:1138-49.NEngl2.pdfAcid-baseproblemsindiabeticketoacidosis.2015;372:546-54.NEngl3.pdfGlycemiccontrolandexcessmortalityintype1diabetes.2014;371:1972-82.NEngl4.pdfTheTargetofMetformininType2Diabetes.2014;371:1547-8.NEngl5.pdfFollow-upofblood-pressureloweringandglucosecontrolintype2diabetes.2014;371:1392-406.NEngl6.pdfCombinedAngiotensinInhibitionfortheTreatmentofDiabeticNephropathy.2013;369:1892-903.NEngl7.pdfCardiovasculareffectsofintensivelifestyleinterventionintype2diabetes.2013;369:145-54.

Cell.pdfHepaticAcetylCoALinksAdiposeTissueInflammationtoHepaticInsulinResistanceandType2Diabetes.2015;160:745-58.

Cell.

NEnglJMedLancetLancet1.pdfType2diabetesandincidenceofawiderangeofcardiovasculardiseases:acohortstudyin1·9millionpeople.2015;305–113.Lancet2.pdfStatinsandtype2diabetes:geneticstudiesontarget.2015;385:310-2.Lancet3.pdfCardiovascularoutcometrialsofglucose-loweringstrategiesintype2diabetes.2014;384:1095.lancet4.pdfTheglobalimplicationsofdiabetesandcancer.2014;383:1947-8.Lancet5.pdfApainfulswollenthighinadiabeticpatient:diabeticmyonecrosis.2014;383:1860.lancet6.pdfSexdisparityintheriskofdiabetes-associatedstroke.2014;383:1948-50.lancet7.pdfType2diabetesasaredoxdisease.2014;383:841-3Controlled-releasemitochondrialprotonophorereversesdiabetesandsteatohepatitisinrats.2015;347:1253-6.science.pdfFFAROutNewTargetsforDiabetes.2015;21:353-4.

CellMetab..pdf

CellMetab.

Lancet

Science

糖尿病腎病小管及間質(zhì)損傷

2023/11/12糖尿病性腎小球腎?。╠iabeticglomerulopathy）：腎臟活檢證實(shí)的由糖尿病引起的腎小球病變糖尿病腎臟疾病(diabetickidneydisease,DKD）：是指由糖尿病引起CKD，GFR<60ml·min-1·1.73m2

orACR>30mg/g,持續(xù)超過3個月

主要依據(jù):腎小球系膜增生、基底膜增厚和K-W（Kimmelstiel-Wilson）結(jié)節(jié)等輔助指標(biāo):腎小管間質(zhì)、腎微血管病變，如腎間質(zhì)纖維化、腎小管萎縮、出球動脈透明變性或腎微血管硬化等-2014ADA&NKF2023/11/12a.正常腎小球，b.增厚的腎小球基底膜，c.K-w氏結(jié)節(jié)，d.腎血管及間質(zhì)纖維化病變

。

KanwarYS/SunL,Annu.Rev.Pathol.Mech.Dis.2011.6:395-423

DKD小管細(xì)胞凋亡、萎縮

SunL/KanwarYSProcNatlAcadSciUSA.2005,102(50):17952-7AB

TubularcellapoptosisandatrophyinDKDAwadAS,YouH,Gao1Tetal.KidneyInternationalininprintSunL/KanwarYSKidneyInternational*commentaryinprint

糖尿病腎病小管及間質(zhì)損傷

基礎(chǔ)研究新亮點(diǎn)-聚焦線粒體2023/11/121.線粒體與糖尿病腎病小管損傷2.線粒體動力學(xué)變化的調(diào)節(jié)機(jī)制3.靶向線粒體ROS治療糖尿病腎病線粒體及其動力學(xué)ZhanM,LiuFY/SunL.

KidneyInt.2013;83(4):568-81ThemitochondrialdynamicschangemPTP阿爾伯特·馮·科立克1857.瑞士卡爾·本達(dá)1898年.德國線粒體動力學(xué)當(dāng)代細(xì)胞生物學(xué)研究熱點(diǎn)MitochondrialdynamicsHot線粒體動力學(xué)與細(xì)胞凋亡2012，337:1052內(nèi)質(zhì)網(wǎng)小管與線粒體分化2012，334:358線粒體融合與心肌細(xì)胞分化2013，342；734新的線粒體動力學(xué)調(diào)節(jié)蛋白2014，344；1514ThefragmentationofmitochondriaintubularcellsofDKDpatients

糖尿病患者小管細(xì)胞線粒體變化XiaoL，LiuFY/SunL.Diabetes.2014,63(4):1366-80

2.DaneshFetal

.AmJKidneyDis.2014;63(2)(suppl2):S63-S83HG誘導(dǎo)小管上皮細(xì)胞線粒體片段化Highglucoseinducedmitochondriafragmentationintubularepithelialcells1.ZhanM,LiuFY/SunL.

KidneyInt.2013;83(4):568-81DKD小管細(xì)胞線粒體Drp1/Mfn1表達(dá)變化AlteredexpressionofmitochondrialdynamicsproteinintubularcellsofDKDpatients詹明/孫林.2012中南大學(xué)臨床醫(yī)學(xué)專業(yè)博士研究生畢業(yè)論文（unpublished）HG通過Drp1誘導(dǎo)線粒體片段化與ROS產(chǎn)生HGinducedmitochondrialfragmentationandROSproductionbyDrp1詹明/孫林，2012中南大學(xué)臨床醫(yī)學(xué)專業(yè)博士研究生畢業(yè)論文（unpublished）

糖尿病腎病小管及間質(zhì)損傷

基礎(chǔ)研究新亮點(diǎn)-聚焦線粒體2023/11/121.線粒體與糖尿病腎病小管損傷2.線粒體動力學(xué)變化的調(diào)節(jié)機(jī)制3.靶向線粒體ROS治療糖尿病腎病

Publicatio(s)KidneyInt2002PNAS.2002JBC2002JBC2002ExpNephrol.2002JASN2008AnnRevPathol.2011AmJPathol.2011KindeyInt2012AJPrenal2013PLOSONE2013AdvNephrol,2013KidneyInt2013AJPRenal2013CMC2014AJPrenal2014Diabetes2014OMC2014

Rap1調(diào)節(jié)小管細(xì)胞線粒體形態(tài)與功能Rap1regulatethetubularcellsmitochondrialmorphology&function

SunL,LiuFY/KanwarYS.

Annu.Rev.Pathol.Mech.Dis.2011.6:395-423Rap1Rap1ROCK1P66ShcRap1Rap1陽石坤/劉伏友/孫林中華腎臟病雜志2012;28:498-502

SunL/KanwarYSetal.JBiolChem2002,277(44):41725-41735.DaneshFSunL/KanwarYSPNAS2002,99(12):8301-05YangSK,LiuFY/SunL.AmJPhysiolRenalPhysiol.2013,304(7):F831-9MitochondrialdynamicsLinS/KanwarYS.KidneyInt.2001,60(6):2129-41.XiaP,SunL/KanwarYS.AmJPhysiolRenalPhysiol.2014,306(11):F1260-74MIOX資料來源：2008中國衛(wèi)生年鑒SunL,LiuFY/KanwarYS.JAmSocNephrol.2008;19(12).2293-301Rap1保護(hù)高糖誘導(dǎo)的小管細(xì)胞線粒體細(xì)胞凋亡Rap1inhibitedHGinducedmitochondrialcellsdeathpathwayintubularcells資料來源：2008中國衛(wèi)生年鑒SunL,LiuFY/KanwarYS.

JAmSocNephrol.2008;19(12).2293-301

5mM30mM30mM+Rap1b(Glu.)Rap1抑制高糖誘導(dǎo)的線粒體損傷Rap1regulationofmitochondrialstructureandmembranepotentialdamageinducedbyHGRap1inhibitedHGinducedphosphorylationofDrp1anditsmitochondrialtranslocation

Rap1抑制HG誘導(dǎo)Drp1磷酸化及線粒體片段化XiaoL,LiuFY/SunL.Diabetes.2014;63(4):1366-80Rap1調(diào)節(jié)小管上皮細(xì)胞線粒體mPTP,MMP,H2O2Rap1regulatedmPTP,MMPandH2O2productionintubularcells(invivo)XiaoL,LiuFY/SunL.Diabetes.2014;63(4):1366-80

資料來源：2008中國衛(wèi)生年鑒PKCb介導(dǎo)HG誘導(dǎo)的小管細(xì)胞p66Shc線粒體轉(zhuǎn)位SunL,XiaoL/LiuFY,etal.AmJPhysiolRenalPhysiol.2010;299(5):F1014-25PKCbmediatedthemitochondrialtranslocationofp66ShcinHK2cellinducedbyHG肌醇加氧酶(MIOX)

糖尿病腎病狀態(tài)下（體內(nèi)或體外）小管細(xì)胞線粒體片段化

同時伴有肌醇加氧酶(MIOX)的表達(dá)最高

體內(nèi)外用MIOXsiRNA或其抑制劑葡萄糖二酸鹽(glucarate)提高線粒體質(zhì)量

其機(jī)制提供調(diào)節(jié)PTNE、線粒體自噬（mitophagy等途徑)ROCK1介導(dǎo)DKD腎臟細(xì)胞線粒體片段化ROCK1knockoutpreventedthefragmentationofmitochondriainDKDmodelWangWJ/DaneshF.CellMotabolism201215,186-200

糖尿病腎病小管及間質(zhì)損傷

基礎(chǔ)研究新亮點(diǎn)-聚焦線粒體2023/11/121.線粒體與糖尿病腎病小管損傷2.線粒體動力學(xué)變化的調(diào)節(jié)機(jī)制3.靶向線粒體ROS治療糖尿病腎病資料來源：2008中國衛(wèi)生年鑒ROS過度表達(dá)是DKD發(fā)病機(jī)制的中心環(huán)節(jié)YangSK,LiuFY/SunL.RenFail.2014,36(2).313-20ExcessiveROSisacentraleventinthepathogenesisofdiabeticnephropathySunL,LiuFY/KanwarYS,.

Annu.Rev.Pathol.Mech.Dis.2011,6:395-423資料來源：2008中國衛(wèi)生年鑒線粒體呼吸鏈功能異常是細(xì)胞ROS的主要來源

SunLetal.MolCellBiol.2008,28.1007-17.DysfunctionofthemitochondrialrespiratorychainisthemainsourceofcellularROSSunL,LiuFY/KanwarYS.

Annu.Rev.Pathol.Mech.Dis.2011.6:395-423TheEffectandmechanismofMitoQonDNtubularinjuryviamitochondria/NLRP3/IL-1βbiologicalaxisBiochemicalparametersandUrinaryalbuminand8-OHdG*P＜0.05,comparedwithcontrol；#P＜0.05,comparedwithdb/dbMitoQattenuatesrenalpathologicallesionsMitoQattenuatesoxidativestressinjuryMitoQattenuatesROSproductionofmitochondriaMitoQdecreasedFNandCollagneIinHK-2cellsinducedbyhighglucose

資料來源：2008中國衛(wèi)生年鑒ChackoB,etal.BiochemJ.2010,15;432(1):9-19MitoQ防治糖尿病足細(xì)胞損傷MitoQpreventedrenalcelldamageofDKDSchematicSketch糖尿病腎病與小管損傷

臨床研究新進(jìn)展1.糖尿病腎病小管損傷與臨床2.糖尿病腎病小管損傷的早期診斷3.糖尿病腎病小管與間質(zhì)損傷的防治僅1/3的糖尿病微量白蛋白尿患者具有典型的腎小球結(jié)構(gòu)損傷1/3患者無或很輕微腎小球損傷，但腎小管損傷嚴(yán)重，表現(xiàn)為腎小管基底膜增厚、小管炎性病變，腎小管萎縮、細(xì)胞凋亡增加，間質(zhì)纖維化、管周毛細(xì)血管稀疏等糖尿病腎小管病變1/3的患者腎臟結(jié)構(gòu)正常DKD腎組織小管損傷的臨床特點(diǎn)DallaVestraMetal.DiabetesMetab.200026Suppl4:8-14.朱雪婧，劉伏友、孫林等中南大學(xué)學(xué)報(bào)（醫(yī)學(xué)版），2012,37(2),185-18932例DN中，1~3分的輕型小管間質(zhì)病變者12例(37.5%)，4~6分中度病變者15例(46.9%)，7分以上病變較重者5例(15.6%)Clinicalfeatures&renaltubulardamageinDKD2023/11/12IFTAscoreAll(43)0(3)1(11)2(18)3(11)Male(%)72.1%(n=31)66.7%(n=2)63.6%(n=7)88.9%(n=16)54.5%(n=6)Age(year)47.1±12.560.7±6.449.3±9.146.1±14.742.9±10.8bWeight(Kg)61.4±12.06057.9±10.761.2±14.164.6±10.0U-Pro(g/day)4.9±4.51.3±0.54.4±4.74.4±4.67.3±3.9

bsBP(mmHg)145.6±19.5149.3±37.9150.6±21.8141.3±17.1146.5±16.6dBP(mmHg)85.3±11.185.0±7.885.6±13.786.2±12.083.5±8.4Type1DM(%)14.0%(n=6)0%(n=0)18.2%(n=2)11.1%(n=2)18.2%(n=2)DurationofDM(year)3.9±4.46.7±2.93.1±3.23.7±4.54.3±5.9AcuteonsetofDN46.5%(n=20)66.7%(n=2)45.5%(n=5)50%(n=9)36.4%(n=4)eGFR(ml/min/1.73m2)61.1±31.863.4±13.391.7±35.456.3±24.1d37.9±17.6cfRBCinurinarysediment(%)55.8(n=24)33.3%(n=1)36.4%(n=4)55.6%(n=10)90.9%(n=10)acRetinopathy(%)44.2%(n=19)0%(n=0)36.4%(n=4)50%(n=9)54.5%(n=6)FBG(mmol/l)8.1±3.68.9±2.38.8±3.17.0±2.18.8±5.5HbA1c(%)7.6±2.16.7±2.77.9±2.08.2±2.26.6±1.3s-Cr(umol/l)159.4±127.8101.6±5.685.7±37.9170.8±90.9bc230.1±201.0acBUN(mmol/l)8.7±3.26.9±1.27.4±2.08.6±3.010.6±4.0s-Alb(g/dl)27.5±5.729.0±2.625.5±5.629.6±5.925.7±5.3Hb(g/dl)114.3±23.7130±33.4115.8±23.2116.6±22.9104.6±22.7TC(mmol/l)6.4±2.95.4±0.48.3±4.65.3±1.46.5±2.2TG(mmol/l)2.3±1.32.9±1.73.0±1.72.0±0.8d1.9±1.1dLDL-c(mmol/l)4.2±2.33.4±0.55.7±3.53.3±1.04.1±1.5ACE-IorARB(%)74.4%(n=32)100%(n=3)90.9%(n=10)83.3%(n=15)36.4%(n=4)Antihypertensivetherapy(%)81.4%(n=35)33.3%(n=1)72.7%(n=8)83.3%(n=15)100%(n=11)ESA(%)18.6%(n=8)0%(n=0)9.1%(n=1)11.11%(n=2)45.5%(n=5)OHAtherapy(%)30.2%(n=13)100%(n=3)54.5%(n=6)16.7%(n=3)

9.1%(n=1)Insulinetherapy(%)88.4%(n=38)66.7%(n=2)90.9%(n=10)94.4%(n=17)81.8%(n=9)Numberofglomeruli14.4±7.510.7±3.816.1±8.012.8±6.516.5±9.2Interstitialinflammationscore1.58±0.661±0.45b2ae1.91±0.30aeArteriolarhyalinosis1.2±0.80.3±0.61.5±0.7b1.3±0.81.1±0.9Arteriosclerisisscore0.86±0.520.67±0.580.73±0.471±0.490.82±0.60WBC(*109)7.2±3.16.4±2.68.1±4.07.4±3.36.3±1.0GRA(*109)4.6±2.64.1±2.35.6±3.54.4±2.84.1±0.6LYM(*109)1.8±0.71.8±0.71.9±0.92.0±0.71.5±0.6MON(*109)0.4±0.10.3±0.10.4±0.10.4±0.20.4±0.1GRA%64.5±9.561.1±11.866.5±10.160.8±8.369.3±8.7fap<0.01:versusscore0.bp<0.05:versusscore0.Cp<0.01:versusscore1.dp<0.05:versusscore1ep<0.01:versusscore2.fp<0.05:versusscore2.

XongX/SunL,etal.unpublished44小管與間質(zhì)損傷預(yù)后差XiaoL/SunL,etal.Diabetes.2014.63(4):1366-80糖尿病腎病小管損傷與臨床預(yù)后糖尿病腎病與小管損傷

臨床研究新進(jìn)展1.糖尿病腎病小管損傷與臨床2.糖尿病腎病小管損傷的生物標(biāo)記物3.糖尿病腎病小管與間質(zhì)損傷的防治資料來源：2008中國衛(wèi)生年鑒中性粒細(xì)胞明膠酶相關(guān)載脂蛋白-NGAL宋盼愛/孫林.中華腎臟病雜志2012.28(2):155-158Neutrophilgelatinase-associatedlipocalin(NGAL))DN患者血、尿NGAL水平較正常對照者明顯增高，尿NGAL含量與尿蛋白水平、腎功能損傷程度呈正相關(guān)。血NGAL改變較早且變化較大，對DN早期監(jiān)測較為理想，而尿NGAL對DN腎功能的評估具有重要意義

YangYH,etal.Endocrine.2009;36(1):45-51.Group1:normo-albuminuriagroupGroup2:micro-albuminuriagroupGroup3:macro-albuminuriagroup

DKD患者血NGAL含量變化ChangesofserumNGALlevelsinDKDpatientsLanHY.,etal.

Diabetes.2011;60(7):1832-7.miRNA與糖尿病腎病SunL.,