糖尿病肾病(DKD)是导致ESRD的主要原因，其发病机制尚不完全清楚。近期研究证明免疫炎症在DKD发病中起重要作用，其中巨噬细胞（MΦ）在DKD小管间质损伤中作用更加突出，但其机制尚待阐明。Epac1是cAMP激活小分子G蛋白酶Rap1的鸟嘌呤核苷酸交换因子，参与细胞粘附、分化、增殖与凋亡等，并在介导MΦ募集、活化、炎性因子分泌及吞噬中也起重要作用。申请人以往研究提示Epac/Rap1可保护高糖诱导的小管细胞线粒体损伤（Diabetes 2014），并初步发现Epac1可能调节DKD状态下MΦ介导的肾组织细胞炎症损伤。本项目继续以往研究，采用细胞分子生物学等技术，体内外研究Epac1在MΦ浸润、激活，分泌炎症因子、吞噬中的作用与机制，并探讨其与DKD小管及间质损伤关系，以确立Epac1在DKD免疫炎症损伤中的关键作用，阐明DKD免疫炎症损伤新机制，为DKD发病机制研究提供新思路与防治靶点。

Diabetic kidney disease (DKD) is the main cause of end stage renal disease. However, the pathogenesis of DKD is not fully clarified. Recent studies demonstrated that immune inflammation plays a key role in the pathogenesis and progression of DKD. Notably, the effect of macrophage on the tubulointerstitial injury in DKD was paid more attention, but the mechanism by which macrophage involved in this process remained unknown. Epac1 is a guanine nucleotide exchange factor of cAMP, which can activate small molecules G protease Rap1. It has been showed that Epac1 modulates cell adhesion, differentiation, proliferation and apoptosis. And it also plays an important role in the regulation of macrophage migration, activation, inflammatory cytokine secretion and phagocytosis as well. Previous study in our lab suggested that Epac/Rap1 can protect mitochondrial injury of tubular cells induced by high glucose (Diabetes, 2014) and found that Epac1 may regulate the immune inflammation damage of kidney cells modulated by macrophage under diabetic condition. On this basis, in this project, we will further investigate the effect of Epac1 on macrophage migration, activation, inflammatory cytokine secretion and phagocytosis under DKD condition, and observe the relationship between macrophage activation and tubulointerstitial damage in DKD. The aim of this subject is to illustrate a crucial role of Epac1 in the inmunne inflammation injury and its mechanism in DKD, and it will provide a new light about the pathogenesis and potential therapeutic target for DKD.