糖尿病肾病（DKD）是糖尿病严重的慢性微血管并发症之一，是全球终末期肾病的最主要原因。大量研究显示正常的线粒体功能对防止DKD的发生发展至关重要。线粒体相关内质网膜（MAM）结构及功能的协调稳定是维持细胞正常生理功能的基础。课题组前期RNA-Seq分析发现PACS-2在db/db组肾组织中表达明显下降，并通过Western blot进行了验证。体外实验也证实，PACS-2过表达可减少高糖诱导的细胞凋亡和线粒体功能降低。我们提出假说：2型糖尿病时，内质网锚定蛋白PACS-2表达下降是导致肾脏线粒体功能障碍、内质网应激的重要分子机制之一，参与DKD发生。本课题以肾小球系膜细胞、足细胞和肾小管上皮细胞及糖尿病肾病的动物模型为研究对象，检测PACS-2过表达或基因缺陷对MAM结构和功能的影响，验证MAM中关键蛋白PACS-2在糖尿病肾病肾脏纤维化中的调控作用，为其防治提供理论依据和新的治疗靶点。

Diabetic nephropathy (DKD) is one of the serious chronic microvascular complications of diabetes mellitus and the main cause of end-stage renal disease worldwide. Numerous studies have shown that normal mitochondrial function is essential to prevent the occurrence and development of DKD. Coordination and stability of mitochondrial-associated endoplasmic reticulum (MAM) structure and function is the basis of maintaining normal physiological function of cells. Previous RNA-Seq analysis showed that the expression of PACS-2 in kidney tissue of db/db group decreased significantly, which was verified by Western blot. We also confirmed that PACS-2 overexpression can reduce apoptosis and mitochondrial dysfunction induced by high glucose in vitro. We hypothesize that in type 2 diabetes mellitus, the decreased expression of endoplasmic reticulum anchoring protein PACS-2 is one of the important molecular mechanisms leading to renal mitochondrial dysfunction and endoplasmic reticulum stress, and is involved in the occurrence of DKD. In this study, glomerular mesangial cells, podocytes, tubular epithelial cells and the animal models of diabetic nephropathy were studied. We examined the effects of PACS-2 overexpression or gene defect on the structure and function of MAM. We validate the regulatory role of PACS-2, a key protein in MAM, in renal fibrosis of diabetic nephropathy, and provide theoretical basis and new therapeutic targets for its prevention and treatment.