组蛋白脱乙酰基酶与肾间质纤维化的关系及药物干预研究

Histone deacetylase and tubulointerstitial fibrosis:correlation and drug intervention study

目的研究在幼年大鼠肾间质纤维化模型——单侧输尿管结扎(UUO)模型中组蛋白脱乙酰基酶(HDAC1,HDAC2)和转化生长因子-β1(TGF-β1)组织定位表达趋势、相关性及可能的病理意义,及应用HDAC抑制剂丙戊酸钠的干预效果。方法采用单侧输尿管结扎方法制备幼鼠肾间质纤维化模型,以第1、3、5、7、14天为观察点,采用苏木素-伊红(HE)和Masson染色评价各组各时间点肾小管受损的程度,用免疫组织化学法检测大鼠肾组织中HDAC1、HDAC2及TGF-β1蛋白定位,表达趋势及相关性研究。统计学方法采用单因素方差分析和Pearson相关分析。结果模型组HDAC1、HDAC2、TGF-β1与肾小管间质损伤程度均明显高于对照组(P<0.05);TGF-β1的随着时间的延长,表达强度增强,各时间点组内比较差异有统计学意义(P<0.05),HDAC1和HDAC2表达在第7天到达高峰,第14天时反而有所下降(P<0.05);丙戊酸组各时间点的表达明显低于模型组(P<0.05),但仍高于对照组(P<0.05);HDAC1、HDAC2与TGF-β1、肾小管间质损伤程度呈正相关。结论在幼年大鼠肾小管间质损伤过程中,HDAC1、HDAC2和TGF-β1的表达上调有重要的致病意义,而丙戊酸钠有明显的干预效应。

Objective To investigate the trend for tissue-specific expression and localization,relevance and the possible pathological significance of Histone deacetylase（HDAC1,HDAC2）and transforming growth factor-β1（TGF-β1） in juvenile rat models of tubulointerstitial fibrosis-unilateral ureteral obstruction（UUO）,and to explore the intervention effect of sodium valproate,an inhibitor of Histone deacetylase I.Methods Unilateral ureteral ligation was used to produce rat models of tubulointerstitial fibrosis.On days 1,3,5,7 and 14,the degree of tubulointerstitial injury was evaluated by using HE and Masson staining.The protein localization,expression trend and relevance of HDAC1,HDAC2 and TGF-β1 in rat kidneys were detected by immunohistochemistry.Results In the UUO group,expressions of HDAC1,HDAC2 and TGF-β1 and the degree of tubulointerstitial injury were found to be much greater than those in the control group（P0.05）.The expression level of TGF-β1 increased over time,which was statistically different at each time spot（P0.05）.The expressions of HDAC1 and HDAC2 peaked on day 7,but decreased on day 14（P0.05）.The sodium valproate group had a lower expression as compared with the UUO group at every time spot（P0.05）,but still much higher than that in the control group（P0.05）.The expressions of HDCA1,HDAC2 and TGF-β1 were positively correlated with the degree of tubulointerstitial injury.Conclusion The up-regulated expressions of HDAC1,HDAC2 and TGF-β1 were pathologically significant in the process of tubulointerstitial injury among juvenile rats.Evidenced intervention effect could be found after sodium valproate treatment.