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

摘要

Objective To investigate the trend for tissue-specific expression and localization, relevance and thepossible pathological significance of Histone deacetylase (HDAC1 ,HDAC2)and trans forming growth factor-β1(TGF-β1)in juvenile rat models of tubulointerstitial fibrosis-unilateral ureteral obstruction (UUO), and to explore the interven-tion effect of sodium valproate, an inhibitor of Histone deacetylase I. Methods Unilateral ureteral ligation was usedto produce rat models of tubulointerstitial fibrosis. On days 1, 3, 5, 7 and 14, the degree of tubulointerstitial injury wasevaluated by using HE and Masson staining. The protein localization, expression trend and relevance of HDACl,HDAC2 and TGF-β1 in rat kidneys were detected by immunohistochemistry. Results In the UUO group, expressionsof HDAC1, HDAC2 and TGF-β1 and the degree of tubulointerstitial injury were found to be much greater than those inthe control group (P＜0.05). The expression level of TGF-β1 increased over time, which was statistically different ateach time spot (P＜0.05). The expressions of HDAC1 and HDAC2 peaked on day 7, but decreased on day 14 (P＜0.05).The sodium valproate group had a lower expression as compared with the UUO group at every time spot (P＜0.05), butstill much higher than that in the control group (P＜0.05). The expressions of HDCA1, HDAC2 and TGF-β1 were posi-tively 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. Evi-denced interv ention effect could be found after sodium valproate treatment.%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.