新基因NDRG1通过STAT3/Snai1通路抑制糖尿病肾病上皮-间质转化发生

Diabetic nephropathy is one of the most severe diabetic complications. Recent researches showed that inhibiting renal epitheial-mesenchymal transition (EMT) could alleviate renal fibrosis effectively. N-myc downstream regulated gene (NDRG) is a new gene family that is discovered recently. Studies demonstrated that NDRG family could inhibit cell EMT process, and related to Snai1 and STAT3. But the relationship between NDGR, STAT3 and Snai1 is not studied until now. In this study, we hypothesize that NDRG1 inhibit EMT through STAT3/Snai1 pathway. So, in our project, we will test the expressions of EMT markers, STAT3 and Snai1 in renal epithelial cells, in condition that overexpression or knockout of NDGR1. And then we will study the function of STAT3 on Snai1 promoter region. On the same time, we will knock out renal NDRG1 gene in type 2 diabetic mice though conditional gene knock out technology. It is used to detect the function of NDRG1 and STAT3/Snai1 pathway on EMT. This is the first study on relationship of NDRG1 gene with EMT, and provide new target for diabetic nephropathy.

糖尿病肾病是糖尿病并发症中最严重的病症之一。近年研究发现阻断肾上皮细胞向间充质细胞转变（EMT）能有效减轻肾脏纤维化发生。N-myc下游调节基因(NDRG)是近年发现的新基因，该基因家族可抑制细胞EMT发生。现有研究显示NDRG家族抑制EMT与Snai1和STAT3相关,但NDRG1、STAT3和Snai1三者的相互关系未见系统报道。本研究假定肾上皮细胞过表达NDRG1后通过STAT3/Snai1通路抑制EMT发生。研究中将检测肾上皮细胞过表达及敲除NDRG1基因状态下，EMT标记物、STAT3和Snai1的变化，及STAT3对Snai1启动子区域的作用。并采用条件性敲除技术敲除2型糖尿病小鼠肾脏NDRG1基因，进一步探讨糖尿病肾脏纤维化中NDRG1是否通过STAT3/Snai1通路抑制EMT。这是首次在糖尿病肾病中探讨NDRG1与EMT关系，为糖尿病肾病治疗寻找新的靶点。

糖尿病肾病是糖尿病并发症中最严重的病症之一。近年研究发现阻断肾上皮细胞向间充质细胞转变（EMT）能有效减轻肾脏纤维化发生。N-myc下游调节基因(NDRG)是近年发现的新基因，该家族基因可抑制细胞EMT过程。现有研究显示NDRG家族参与EMT与Snai1及STAT3相关,但NDRG1、STAT3、Snai1的相互关系未见研究。本研究假定肾上皮细胞过表达NDRG1后通过STAT3/Snai1通路抑制EMT发生。研究中检测了肾上皮细胞过表达及敲除NDRG1基因状态下，EMT标记物、STAT3和Snai1的变化，及STAT3对Snai1启动子区域的作用。并应用动物模型进一步探讨了糖尿病肾脏纤维化中NDRG1是否通过STAT3/Snai1通路抑制EMT。经我们研究发现， NDRG1敲除后，STAT3/Snai1通路上调，肾脏细胞EMT发生增强，肾脏细胞上皮标记物的表达量上升，间质标记物的表达量下降。而NDRG1上调后，通过抑制STAT3/Snai1通路抑制肾脏细胞EMT发生，肾脏细胞上皮标记物的表达量下降，间质标记物的表达量上升。这是首次在糖尿病肾病中探讨NDRG1与EMT关系，为糖尿病肾病治疗寻找新的靶点。