硫化氢通过STAT1途径对小鼠酒精性肾间质纤维化的影响

Hydrogen sulfide alleviates alcoholic renal interstitial fibrosis in mice via down-regulating the expression of STAT1

目的观察气体信号分子硫化氢(H_2S)对小鼠酒精性肾间质纤维化以及基质金属蛋白酶-24(MMP-24)、金属蛋白酶组织抑制因子-1(TIMP-1)及信号转导和转录激活因子-1(STAT1)表达的影响。方法将40只雄性昆明小鼠适应性喂养1周后,随机分为4组:对照组、酒精干预组、酒精加H_2S组、酒精加炔丙基甘氨酸(PAG)组,每组10只。在标准饲料喂养的基础上,除对照组外,小鼠经由每天饮用4%(Vol/Vol)的乙醇水溶液12周制作慢性酒精中毒模型,对照组则每天自由饮用等量清水。另外,酒精加H_2S组小鼠每天腹腔注射H_2S供体硫氢化钠(NaHS)(50μmol/kg),酒精加PAG组小鼠每天腹腔注射PAG(40mg/kg),对照组和酒精干预组每天腹腔注射1次PBS。90 d后处死小鼠,取出肾脏组织,PAS染色观察小鼠肾组织结构变化以及Masson染色观察肾间质纤维化,Western blot检测MMP-24、TIMP-1以及STAT1蛋白表达的变化。结果与对照组相比,酒精干预组肾脏肾小球肥大,肾小管间质炎性改变以及肾间质出现明显纤维化,同时MMP-24、TIMP-1以及STAT1蛋白表达水平明显升高(P<0.05);与酒精干预组相比,酒精加H_2S组肾小球和肾小管间质炎性及肾间质纤维化明显改善,而肾组织中MMP-24、TIMP-1和STAT1蛋白表达水平也显著降低(P<0.05);酒精加PAG组与酒精干预组相比,小鼠肾组织肾间质纤维化加重,且TIMP-1和STAT1蛋白表达水平均明显上升(P<0.05)。结论 H_2S可改善小鼠酒精性肾间质纤维化,其机制可能通过下调STAT1改善MMP-24/TIMP-1失调有关。

Objective To explore the effects of hydrogen sulfide （H2 S） on the alcoholic renal interstitial fibrosis in mice and the expression of signal transducer and activator of transcription 1 （ STAT1 ） , metalloproteinase - 1 （ TIMP - 1 ） and matrix metalloproteinase - 24 （ MMP - 24）. Methods Totally 40 male Kunming mice were randomly divided in- to four groups （n = 10）, control group, alcoholic group, H2S group , PAG group. Based on standard rat forage in control group, the rats in treatment groups received 4% ethanol water every day for 12 weeks, while normal water was given in control as placebo. NAHS and PAG treatment were given in H2S group and PAG group, respectively. After 90 days, the pathological changes of kidney tissues were analyzed by PAS staining, and renal interstitial fibrosis were analyzed by Mas- son staining. The expression of MMP - 24, TIMP - 1 and STAT1 was analyzed by Western blot. Results Compared with the control group, significant glomerular hypertrophy, tubulointerstitial inflammation and renal interstitial fibrosis were ob- served in alcoholic group ; and the expression levels of MMP - 24, TIMP - 1 and STAT1 were also significantly increased （ P 〈 0. 05 ）. Compared with the alcoholic group, significant alleviation in tubulointerstitial inflammation and renal intersti- tial fibrosis were revealed H2 S group ; with significant down - regulation in MMP - 24, TIMP - 1 and STAT1 （ P 〈 0. 05 ）. Compared with alcoholic group, significantly severer renal interstitial fibrosis was observed in PAG group, with significant- ly up - regulation of STAT1 and TIMP - 1 （ P 〈 0. 05 ）. Conclusion H2 S can improve the alcoholic renal interstitial fi- brosis in mice, may be related to down - regulating the expression of STAT1 and improve the imbalance of MMP24/ TIMP1.