Klotho抑制TRPC6诱导的足细胞损伤在糖尿病肾病中的作用及机制

Podocyte injury is the initial step of proteinuria and glomerulosclerosis in diabetic kidney disease (DKD). Klotho protein which is secrected from renal tubular epithelial cells can inhibit the progression of DKD, but the underlying mechanism remains poorly understood, and the level of Klotho protein in DKD was significantly decreased. Our preliminary study may suggest the role of Klotho may be related to inhibiting the podocyte injury. Studies have revealed that high glucose induced high expression of TRPC6 is a major cause of podocyte injury,and Klotho may inhibit high expression of TRPC6 in podocytes . We hypothesized that, the level of Klotho in serum is decreased significantly under high glucose condition, which weakened the inhibitory effect on TRPC6, leaded to podocyte injury agravated constantly and exacerbated DKD. Therefore, we plan to carry out a study on Klotho gene deficient mice and podocyte. Firstly, to determine whether Klotho through reduce podocyte injury suppress DKD; Secondly, to investigate the role and mechanism of Klotho in ameliorating podocyte injury by inhibition of high glucose induced high expression of TRPC6; Finally, to evaluate the prevention and treatment of podocyte injury and DKD with upregulation of Klotho protein levels. The purpose of this project is to reveal the internal mechanisms in the pathogenesis of DKD, and to provide effective prevention strategies and therapeutic target of DKD.

足细胞损伤是糖尿病肾病（DKD）蛋白尿发生和肾小球硬化的始动环节。肾小管上皮细胞分泌的Klotho蛋白可以抑制DKD进展，但机制亟待阐明，且DKD时其表达显著下调。我们前期研究提示Klotho的作用可能与抑制足细胞损伤有关。研究发现，高糖诱导TRPC6高表达是足细胞损伤的关键因素，而Klotho却具有抑制足细胞TRPC6高表达的可能。我们推测，高糖状态下循环中的Klotho水平明显降低，使其对足细胞TRPC6的抑制作用减弱，导致了足细胞损伤的发生和DKD持续进展。本项目拟以Klotho基因缺陷小鼠和足细胞株为研究对象，明确Klotho是否通过减轻足细胞损伤遏制了DKD进展；探讨Klotho抑制高糖诱导的TRPC6高表达在其减轻足细胞损伤中的关键作用和机制；并观察上调Klotho水平对足细胞损伤和DKD的抑制作用。本项目将深入揭示DKD内在发病机制，并为确立有效的防治措施提供理论与实验依据。