以Cdk5为靶点探讨其在糖尿病肾病足细胞凋亡中的作用及机制

足细胞损伤与糖尿病肾病蛋白尿的发生和病情进展关系密切。细胞周期素依赖性蛋白激酶5（Cdk5）表达于肾小球的足细胞，对维持足细胞正常的形态结构和功能具有重要作用。我们前期研究发现，高糖状态下，足细胞内Cdk5表达与活性增高，并同细胞凋亡有关，但其诱导凋亡的具体机制尚不清楚。p38MAPK和JNK通路可被细胞外应激信号通过级联通路磷酸化激活，参与了凋亡的发生。高糖状态下，活化的Cdk5是否可以通过磷酸化激活此两条通路的上游分子MEKK1和（或）ASK1，进而活化p38MAPK和（或）JNK通路诱导足细胞凋亡是本课题研究的重点内容。本项目拟利用基因转染、shRNA干扰及特异性抑制剂，体外、体内深入探讨高糖状态下Cdk5诱导足细胞凋亡的细胞内信号机制。作为高糖和足细胞凋亡之间的重要中间介质Cdk5，我们的研究将进一步充实抑制其活性减少足细胞凋亡的理论依据，为糖尿病肾病的有效防治提供新的干预靶点。

The podocyte injury is closely related to the protein urine and the development and progression of diabetic nephropathy. Cyclin-dependent kinase 5 expresses in podocytes of glomeruli, and plays an important role in maintaining the podocyte normal morphology and function. Our early studies have demonstrated that the expression and activity of Cdk5 was significantly increased under the high glucose environments, and it was also associated with podocyte apoptosis. However, the specific mechnism of podocyte apoptosis is still unclear. The p38MAPK and JNK signaling pathways can be activated by phosphorylation of extracellular stress signal through a cascade, and involved in cell apoptosis. Our research focus on under the high glucose condition, whether the activated Cdk5 can phosphorylate and activate the pathway upstream molecules MEKK1 and (or) ASK1, followed by the activation of p38MAPK and (or) JNK pathway and podocyte apoptosis. The project intends to explore the signalling mechanism of podocyte apoptosis induced by Cdk5 under high glucose environment in vivo and in vitro, using the gene transfection, shRNA interference and specific inhibitors. Cdk5 is an important medium between high glucose and podocyte apoptosis. Our study will further enrich the theoretical basis that the inhibition of Cdk5 activity can reduce podocyte apoptosis, and provide a new target for the prevention and treatment of diabetic nephropathy.