气体信号分子硫化氢下调CTGF途径在改善小鼠酒精性肾间质纤维化中的应用

Hydrogen sulfide alleviates renal fibrosis in alcoholic rats through CTGF signaling pathway

目的:观察气体信号分子硫化氢(Hydrogen sulfide,H2S)对乙醇所诱导的小鼠肾间质纤维化及结缔组织生长因子(CTGF)与基质金属蛋白酶(MMP)-8/基质金属蛋白酶组织抑制因子(TIMP)-1蛋白表达水平的影响。方法:将40只雄性小鼠随机分为对照组(Control组)、酒精性肾损伤组(ARD组)、硫化氢干预组(H2S组)及乙醇加炔丙基甘氨酸组(PAG组)。除Control组外,其他三组小鼠每天饮用4%(Vol/Vol)的乙醇水溶液12周以构建酒精性肾损伤模型;Control组每天饮用清水,H2S组每天腹腔注射硫氢化钠(H2S供体)溶液(50μmol/kg),PAG组每天腹腔注射硫化氢抑制剂PAG(40 mg/kg)。12周后,处死小鼠取肾脏标本,PAS染色观察小鼠肾组织形态学变化和Masson染色观察小鼠肾脏组织间质纤维化改变,Western blot法检测CTGF、MMP-8和TIMP-1蛋白表达的变化。结果:与Control组相比,ARD组可见明显肾小管间质纤维化,肾小球和肾小管肿胀,同时CTGF、MMP8和TIMP1蛋白表达水平显著增高(P<0.05);与ARD组相比,H2S组肾损害程度减轻,肾小管间质纤维化明显改善,MMP-8、TIMP-1和CTGF蛋白表达水平也明显下调,差异有统计学意义(P<0.05),而PAG组差异无统计学意义(P>0.05)。结论:硫化氢可改善乙醇所诱导小鼠肾小管间质纤维化,其机制可能与下调CTGF信号通路及其调控的MMP-8/TIMP-1有关。

Objective To explore the effects of hydrogen sulfide(Hydrogen sulfide,H2 S)on renal interstitial fibrosis and the expression of MMP-8、TIMP-1 and CTGF in mice of alcoholic renal damage and discuss the potential mechanism and therapy.Method Forty adult male mice were randomly divided into control group,alcoholic renal damage group(ARD group),alcoholic renal damage with H2 S treatment group(H2 S group),and alcoholic renal damage with PAG treatment group(PAG group).Alcoholic renal damage was induced by the drinking of 4%ethanol-water solution for twelve weeks.The mice in the control group received by the drinking of water daily,those in H2 S group were given Na HS(50μmol/kg)injections,and those in PAG group were given PAG(40 mg/kg)injections.Twelve weeks later,the pathological changes of kidney tissues were examined by PAS staining,and renal interstitial fibrosis were examined by Masson staining,and the expressions of MMP-8/TIMP-1 and CTGF were analyzed with Western blot.Results Compared with the control group,the mice of ARD group showed obvious renal tubule-interstitial fibrosis and glomerular and renal tubular hypertrophy with significantly increased expression levels of MMP-8/TIMP-1 and CTGF(P<0.05),while changes in H2 S group were markedly reversed(P<0.05).There were no significant differences in the degree of renal tubule-interstitial fibrosis and glomerular and renal tubular hypertrophy between the PAG group and the ARD group,so was the expression levels of MMP-8/TIMP-1 and CTGF(P>0.05).Conclusion Hydrogen sulfide can alleviate renal tubule-interstitial fibrosis in mice of alcoholic renal damage,and the mechanism may involve the inhibition of MMP-8/TIMP-1 and CTGF signaling pathway.