同型半胱氨酸血癥與腎臟損傷

同型半胱氨酸血癥與腎臟損傷慢性腎臟病糖尿病腎小球腎炎高血壓感染遺傳腎衰竭藥、毒物慢性腎臟病是“全球公共健康問題”促進(jìn)慢性腎臟病進(jìn)展的危險(xiǎn)因素傳統(tǒng)危險(xiǎn)因素：高血壓、高脂血癥、糖尿病與腎功能減退有關(guān)的危險(xiǎn)因素：貧血、鈣磷代謝紊亂SchieppatiA,etal.KidneyInt2003

SarnakMJetal,circulation2003

Hcy是蛋氨酸循環(huán)的中間產(chǎn)物在肝臟、腎臟進(jìn)行FolicacidSAMSAHMethionieHomocysteinexxx同型半胱氨酸血癥背景知識同型半胱氨酸的正常血漿水平:5-15μM同型半胱氨酸血癥分級輕度16-30μM（FH、vitB）中度31-100μM(肝腎損傷，CKD患者常見)重度>100μM(MS、CBS、MTHFR等基因突變)61.營養(yǎng)因素：中國人葉酸缺乏率高達(dá)65%，高于歐美國家（0.6%）2.遺傳因素：MTHFR基因TT型的比例（25%）也高于歐美人群（2-3%），導(dǎo)致同型半胱氨酸代謝障礙我國人群同型半胱氨酸血癥發(fā)生率高循環(huán)Hcy水平與eGFR呈負(fù)相關(guān)KidneyInternational(1999)55,1028–1035CKD患者普遍存在同型半胱氨酸血癥同型半胱氨酸人群CKD發(fā)病率高Age-adjusted5-yearcumulativeincidenceratesofCKDAmJKidney

Dis(2004)44:437-445HHcys是CKD的獨(dú)立危險(xiǎn)因素AmJKidney

Dis(2004)44:437-445HHcys是非糖尿病人群發(fā)生蛋白尿的危險(xiǎn)因素TheHoornstudyArteriosclerThrombVascBiol.2001;21:74-81HHcys是否直接導(dǎo)致腎損傷？Hhcys引起足細(xì)胞損傷AmJNephrol2007;27:262–268Hhcys誘導(dǎo)系膜細(xì)胞凋亡KidneyInternational(2007)71,304–311.HHcys加重缺血再灌注引起的腎損傷**HHcys加重順鉑誘導(dǎo)的急性腎損傷ConHHcyCisplatin***Hhcys不影響順鉑誘導(dǎo)的炎癥反應(yīng)HHcys加重順鉑誘導(dǎo)的細(xì)胞凋亡ConHHcyCisplatinVehicleCleavedCaspase3GAPDHConHcyCPHcy+CPHHcys是否促進(jìn)腎臟纖維化？Hhcys上調(diào)TGF-

表達(dá)TGF-b/GADPH**conTSAHCYKidneyLungLiverHeartRelativemRNALevelofTGF-

(RelativetoControl)******#**#**#NormalHighLow/CBS+/-High/CBS+/-ConHMConHMKidneyβ-actinLungLiverHeartCBS+/+CBS+/-TGF-βIBHhcys上調(diào)collagenI表達(dá)（invitro）Con1050100200(μM)β-actinHCY(48h)ColICon12244872(h)ColIβ-actinHCY(100μM)Con12244872(h)***RelativeCol1

1mRNAlevel(RatiotoCon)Con1050100200(μM)***RelativeCol1

1mRNAlevel(RatiotoCon)Hhcys上調(diào)collagenI表達(dá)（invivo）RelativeCol1

1mRNAlevel(RatiotoCon)*ConHMColIβ-actinConHMProteinColI

Level(relativetoβ-actin)*ConHM背景知識ATGCollagenIREST……TTCAGCACCNNGGACAGNNNC……21-23bpRESTRESFG9aH3K9MeHP1DNMTsG9a是H3K9，H3K27的

一二甲基酶CollagenIHcys抑制G9a表達(dá)+++++-+-----ConsiNCsiG9aConVectorG9aHCYHCYβ-actinG9aColIRelativeLuciferaseActivity(%untreated)+++-+---+*RelativeLuciferaseActivity(%untreated)***1μg3μg6μgpCol-GL3pCDNAFlagg-G9apCol-GL3pCDNAFlagg-G9a甲基轉(zhuǎn)移酶G9a調(diào)控collagenI基因表達(dá)β-actinG9aColIA0bp-1000bpNRSE-789bp-768bp-723bp-1017bpCol1

1FGCTGGGAAGGAGGGTCTCTARTGAGAGATGGAGTGGGGAGGHumana0bp-1000bpNRSE-263bp-238bp-51bp-428bpCol1

1FCATGGCCAGGAGGACCTTTTRTTGATGGAGAGCTGGGAGGAMousebG9aCHIPBinding(RelativetoInput)G9aCHIPBinding(RelativetoInput)G9aCHIPBinding(RelativetoInput)Con4872(h)HCY(100μM)Con50100200(μM)HCY(48

h)ConHM***G9a結(jié)合在collagenI啟動(dòng)子區(qū)域**Hcy抑制H3K9me2與I型膠原啟動(dòng)子的結(jié)合H3K9me2CHIPBinding(RelativetoInput)H3K9me2CHIPBinding(RelativetoInput)Con4872(h)HCY(100μM)Con50100200(μM)HCY(48

h)*****ConHM*H3K9me2CHIPBinding(RelativetoInput)RESTRESFG9aK9HP1DNMTsCollagenIHCYTGF-、I