肾小球内皮细胞表达的swiprosin-1在早期糖尿病肾病发病中的作用及机制研究

项目名称： 肾小球内皮细胞表达的swiprosin-1在早期糖尿病肾病发病中的作用及机制研究

项目编号： No.81473258

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 李玲

作者单位： 中国人民解放军第二军医大学

项目金额： 60万元

中文摘要： 糖尿病肾病（DN）的确切发病机制至今尚未完全阐明，近年研究发现肾脏内皮细胞功能障碍在DN的发生发展中起重要作用。我们前期研究发现一种新型蛋白swiprosin-1（SWP）在肾小球内皮细胞高表达；糖尿病大鼠模型4w后肾皮质组织增加SWP表达；人肾小球内皮细胞（HRGEC）在高糖诱导后增加SWP表达；过表达SWP基因后HRGEC的通透性增加，表明SWP可能是影响早期DN发病的重要蛋白。 本项目拟进一步观察SWP基因敲除小鼠DN的发病情况及高糖诱导干扰SWP基因表达的HRGEC通透性，明确SWP在DN早期中的重要作用；抑制或干扰蛋白激酶C对DN小鼠早期肾脏和HRGEC表达SWP的影响及过表达SWP对细胞骨架蛋白的影响，从而明确SWP影响早期DN的信号通路及调节细胞通透性机制。本项目将有助完善阐明DN早期发病机制，发现调控DN新分子靶点，为设计延缓DN新型药物提供一定的理论基础。

中文关键词： 糖尿病肾病；分子药理学；信号通路；作用机制；swiprosin-1

英文摘要： The pathogenesis of diabetic nephropathy remain unclear. It was demonstrated that the glomerular endothelial cells dysfunction played a vital role in diabetic nephropathy and caused mesangial cells lesions and glomerular sclerosis. Our previous studies found that swiprosin-1, a novel calcium-binding protein, was highly expressed in renal glomerular endothelial cell of mice. Swiprosin-1 expression increased in renal cortical tissue of rat after streptozotocin-induced diabetes mellitus 4 weeks. Over-expression of swiprosin-1 in human renal glomerular endothelial cell significantly increased cell permeability. These results suggested that swiprosin-1 might play an important role in pathogenesis of diabetic nephropathy. However the mechanisms of swiprosin-1 involved in the early stage of diabetic nephropathy are still unclear. To further demonstrate that swiprosin-1 involves in the early stage of diabetic nephropathy, the streptozotocin-induced diabetic nephropathy is planned to investigate in swiprosin-1 knockout mice and wild type mice. The cell permeability is intended to observe after RNA interfering swiprosin-1 in human renal glomerular endothelial cells. To explore the signal transduction pathway of swiprosin-1 in diabetic nephropathy, the swiprosin-1 expression is observed in diabetic nephropathy mice and human renal glomerular endothelial cells after inhibition or RNA interference of protein kinase C-beta. To explore the mechanisms of swiprosin-1 in regulation of human renal glomerular endothelial cells permeability, the expression and function of cytoskeleton protein, F-actin, is intended to examine when over-expression of swiprosin-1 in human renal glomerular endothelial cell. Our studies will contribute to clarigy the mechanisms of early diabetic nephropathy, to find the potential target for therapeutic intervention diabetic nephropathy, and provide a theoretical basis for design a novel drug for prevent of diabetic nephropathy.

英文关键词： diabetic nephropathy;molecular pharmacology;signal pathway;effect mechanism;swiprosin-1