糖尿病肾病（DKD）是糖尿病最常见的并发症之一，是导致终末期肾衰的重要原因。足细胞损伤在DKD的发生中起重要作用, 但其分子机制尚不清楚。P53是一种重要肿瘤抑制蛋白。在细胞应激（cell stress）受损时, P53被激活进而诱导凋亡相关基因的表达，或通过转位到线粒体，激活内源性凋亡途径，诱发凋亡。 在肾脏病中，本课题国内合作者董政的研究阐明了p53在急性肾损伤中对肾小管上皮细胞凋亡的重要调控作用，最近又进一步揭示糖尿病肾病中p53的激活。 其他研究提示p53可能参与足细胞凋亡。但是，p53在DKD足细胞损伤的作用尚不明确。申请人和董政已合作三年并发表4篇论文，而且建立了足细胞特异性P53敲除的小鼠模型，本课题将利用这一模型，并结合培养足细胞，研究p53对DKD中足细胞凋亡的调控，进一步阐明DKD足细胞损伤的分子机制，为临床DKD防治提供新的靶点。

Diabetic kidney disease (DKD) is one of the most common complications of diabetes, and a leading cause of end-stage renal failure. Podocyte injury plays key roles in the pathogenesis of DKD, but the underlying mechanisms of which remain largely unclear. P53 is an important tumor suppressor. In response to cellular stress, p53 is activated to induce apoptosis through regulating expression of apoptotic genes, or through mitochondrial translocation to active caspase cascade. In kidney diseases, the project collaborator in China Dr. Dong has demonstrated the critical role of p53 in apoptosis of renal tubular epithelial cells during acute kidney injury, and more recently revealed p53 activation in DKD. Other research has implicated p53 in podocyte apoptosis. However, the role of p53 in podocyte injury in DKD remains unknown. The applicant has been collaborating with Dr. Dong for 3 years, published 4 collaborative papers, and established the mouse model with specific P53 deletion in podocytes. Using this conditional P53-knockout model and cultured podocytes, this project will explore the role of p53 in podocyte apoptosis in DKD to further the understanding of molecular mechanisms of podocyte injury in DKD, and identify novel therapeutic targets .

糖尿病肾病（DKD）是糖尿病最常见的并发症之一，是导致终末期肾衰的重要原因。足细胞是一种终末分化细胞，不仅是肾小球滤过的关键屏障，还参与维持毛细血管襻正常结构、基底膜（GBM） 更新和修复。足细胞损伤在DKD的发生中起重要作用,但其分子机制尚不清楚。P53 是一种重要肿瘤抑制蛋白。在细胞应激（cell stress）受损时, P53 被激活进而诱导凋亡相关基因的表达，或通过转位到线粒体，激活内源性凋亡途径，诱发凋亡。本项目总的研究目标是明确p53在糖尿病肾病足细胞损伤中的作用。通过体外研究p53 在高糖诱导的足细胞凋亡中的作用，体内研究p53 抑制剂pifithrin-a 对DKD 足细胞损伤的影响以及研究足细胞p53 基因缺失对DKD 足细胞损伤的影响，本课题基本达到了预定的研究目标。延伸研究还发现细胞自噬在足细胞凋亡中起重要作用。受本项目资助共发表SCI论文6篇，其中第一标注的6篇.