MG132通过上调Nrf2/ARE信号通路治疗糖尿病肾病的实验研究

项目名称： MG132通过上调Nrf2/ARE信号通路治疗糖尿病肾病的实验研究

项目编号： No.81200525

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学二处

项目作者： 崔文鹏

作者单位： 吉林大学

项目金额： 23万元

中文摘要： 目前糖尿病肾病（DN）的治疗尚缺乏有效手段，因此探索治疗DN的新方法势在必行。氧化应激可通过产生过量的活性氧簇（ROS）导致肾组织损伤，而内源性抗氧化剂转录因子NE-F2相关因子2（Nrf2）可以减少ROS产生，具有潜在的抗氧化活性。证据表明，蛋白酶体抑制剂MG132可以通过抑制Nrf2的降解而上调其表达。因此，我们推测MG132可能通过上调Nrf2/ARE信号通路，提高机体抗氧化能力，从而治疗DN。本项目拟采用OVE26小鼠建立更接近人的DN模型，并首次应用小剂量MG132治疗已出现显性蛋白尿的DN小鼠，通过观察肾脏损伤指标的变化评价其治疗效果；然后分别上调和下调人肾小球系膜细胞的Nrf2表达，在细胞水平探讨可能机制；最后通过体内敲除Nrf2基因，验证Nrf2/ARE信号通路在MG132治疗DN中的核心作用。本课题的完成将为DN的治疗开辟新途径，具有重要的理论意义和社会价值。

中文关键词： 糖尿病肾病；MG132；转录因子NE-F2相关因子2；氧化应激；

英文摘要： Treatment of diabetic nephropathy (DN) has been the focus of clinical research；however，there is no effective approach available so far. Therefore, it is an urgent need to explore a new way to treat DN. Oxidative stress can cause renal tissue damage because reactive oxygen species (ROS) can disrupt the balance between antioxidants and ROS generation. As one of the most critical endogenous anti-oxidative mechanisms, NF-E2-related factor 2 (Nrf2) has potent antioxidative activity to prevent ROS-induced damage. In addition, accumulating evidence demonstrates that MG132, an inhibitor of proteasome, can upregulate the expression of Nrf2 indirectly via protecting Nrf2 from degenerating by proteasome. Therefore, we hypothesize that MG132 may have the therapeutical effect on DN trough activating Nrf2/ARE pathway to increase antioxidative compounents that scavenge ROS accumulation and consequent oxiative damage. In our project we will use OVE26 mice to set up DN model. This model can mimic the pathogenic progress of human DN very well. To our knowledge, this is the first time to use MG132 to treat DN mice with obvious proteinuria. The efficacy will be evaluated by detecting renal damage markers. Then we will explore the mechanism by using Nrf2 activator and Nrf2-siRNA to upregulate and downregulate Nrf2 expression in huma

英文关键词： diabetic nephropathy；MG132；Nrf2；oxidative stress；