糖尿病肾病已成为导致终末期肾病的首要原因。蛋白尿期是糖尿病肾病发生发展和治疗干预的重要阶段，但糖尿病时尿蛋白排泄调节机制尚未阐明。申请者前期研究和文献证据提示：血浆PEDF与足细胞膜上ATGL结合，激活胞内Rho/ROCK通路引起微丝重排，导致足突融合、足细胞与肾小球基底膜黏附力下降是糖尿病肾病中蛋白尿发生发展的关键分子机制和干预治疗环节。本课题拟构建糖尿病小鼠模型，结合ATGL基因敲除小鼠和足细胞系，利用功能磁共振、WB、病毒转染等研究方法，从动物和细胞水平，明确血浆PEDF在糖尿病肾病时的变化及其在蛋白尿发生发展中的作用，揭示PEDF增加尿蛋白排泄的作用靶点和环节，以及PEDF激活ATGL后导致足细胞损伤的分子机制，探讨抑制PEDF/ATGL对糖尿病肾病的保护作用。以期证实“PEDF/ATGL-Rho/ROCK-微丝重排-足细胞损伤”未知途径在糖尿病肾病蛋白尿调控中的作用和地位。

Diabetic kidney disease (DKD) is the most frequent cause of chronic kidney failure in both developed and developing countries. The microalbuminuria stage is the first clinically detectable sign of glomerular damage and is important for the DKD early treatment. However, the regulation of urinary albumin excretion has not been defined. The plasma pigment epithelium-derived factor (PEDF), an endogenous anti-angiogenic molecule, is significantly increased in DKD, but its role is still unclear. Our preliminary work demonstrated that intravenous infusion of exogenous PEDF led to increased urinary albumin to creatinine ratio (ACR), and this effect was inversed in the adipose triglyceride lipase (ATGL) knockout mouse, which suggested that PEDF may induce proteinuria development through its receptor ATGL in DKD. In addition, our previous work have proved that PEDF could induce the actin rearrangement through RhoA/ROCK pathway. So it is speculated that PEDF/ATGL may induce podocyte injury through RhoA/ROCK mediated actin rearrangement, which induces the proteinuria development. In order to clarify the role of PEDF and its mechanism in DKD, an STZ-induced mouse model of insensate diabetic neuropathy and the podocyte were chosen, and PEDF monoclonal antibody (PEDF-mAb) or recombinant lentivirus vectors targeting PEDF receptors ATGL will be applied to inhibit the PEDF. The ACR, kidney functional magnetic resonance imaging (fMRI) , actin arrangement, cell apoptosis, et al will be detected. All the studies were hoped to prove the key role of PEDF/ATGL in the urinary albumin excretion, and may offer a therapeutic targets for managing proteinuria development in DKD.