内质网应激IRE1－XBP1S通路在高糖引起肾脏及系膜细胞发生氧化应激及损伤中的机制研究

项目名称： 内质网应激IRE1－XBP1S通路在高糖引起肾脏及系膜细胞发生氧化应激及损伤中的机制研究

项目编号： No.81470951

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 陆利民

作者单位： 复旦大学

项目金额： 73万元

中文摘要： 氧化应激（oxidative stress）发生在糖尿病引起肾损害中起关键作用。其下游机制已被充分证实：氧化应激与肾局部RAS激活、系膜细胞功能异常、小管上皮细胞表型转变、炎症因子释放等均密切相关，然而，糖尿病导致氧化应激的上游机制却不清楚。我们在预实验中发现：1) 高糖导致肾脏及系膜细胞出现内质网应激（ERS），ERS中IRE1－XBP1S通路受到抑制；2) XBP1S能直接调控核转录因子CHOP(C/EBP homologous protein, CHOP)；3) NADPH氧化酶p47和gp91亚基Promoter区域有CHOP结合位点；4) 过表达XBP1S能抑制高糖引起的氧化应激。基于上述结果提出假说：高糖导致ERS，其中IRE1－XBP1S通路受到抑制，通过核转录因子CHOP调控NADPH亚单位表达升高，氧化酶活性增强，氧化应激发生和肾损伤。本课题拟在整体和离体上验证这一假说。

中文关键词： 糖尿病肾病；氧化应激；肾小球系膜细胞；内质网应激；XBP1S

英文摘要： Oxidative stress plays key role in diabetes-induced renal injury. The dowstream mechanism of oxidative stress in renal injury has been extansively investigated: overactivation of intrarenal RAS, renal glomerular endothelial cell damage, mesangial cell dysfunction and proinflammaroty factor releases are all related to the high glucose-induced oxidative stress. However, the upstream mechanism of oxidative stress is unclear. In our primary study, the data showed that: 1) supression in IRE1-XBP1S pathway was observed in both kidney of diabetic rats and high glucose-treated mesangial cells; 2) thanscriptional factor CHOP was directly regulated by XBP1S; 3) there is bingding site on the promoter regieon of p47phox and gp91phox; 4) overexpression of XBP1S reversed the high glucose-induced ROS generation and mesangial cell proliferation. Based on the preliminary data, we hypothesized that: hyperglycemia induced supression in IRE1-XBP1S pathway, then dereased the expression of CHOP, which inturn increase the expressions of p47phox and gp91phox, rsult in increase in NADPH oxidase activity and oxidative stress. The proposal plans to test the hypothesis on diabetic rats and isolated renal mesangial cell.

英文关键词： diabetic nephropathy;oxidative stress;glomerular mesangial cell;endoplasmic reticulum stress;XBP1S