Nampt在糖尿病肾病炎症-纤维化过程中的分子机制

项目名称： Nampt在糖尿病肾病炎症-纤维化过程中的分子机制

项目编号： No.81460164

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 冯乐平

作者单位： 桂林医学院

项目金额： 48万元

中文摘要： 糖尿病肾病(DN)肾脏纤维化导致终末肾病阶段(ESRD)严重威胁人类健康。然而，其发病原因迄今远未清楚。因此，揭示DN肾脏纤维化的发病机理已经成为防治DN重点。目前研究证实，在DN纤维化形成过程中，肾组织炎症先于纤维化，即炎症通路是纤维化共有途径。我们前期结果发现：Nampt在DN肾脏中呈异常高表达，且明确与炎性细胞侵润并存，而此时组织中NAD减少，NAD/NADH比值倒置。提示：DN肾组织炎症-纤维化与Nampt过度表达密切相关。由此我们推测：通过Nampt调节SIRT1和NF-κB平衡对肾病炎症-纤维化的形成意义重大，可能成为DN治疗靶点。本研究应用qRT-PCR微阵列、实时定量PCR方法，通过整体实验检测组织中各相关因子的mRNA表达，应用免疫组化、免疫印迹和激光共聚焦结合代谢分析方法，对OLETF大鼠DN模型和细胞株进行研究，进一步证实Nampt在调节SIRT1和NF-κB作用过程中，影响DN纤维化形成的作用机制，揭示DN肾脏炎性-纤维化过程中各炎性因子变化及相互作用规律，为DN防治提供新的理论依据。

中文关键词： 2型糖尿病；糖尿病肾病；炎症因子；肾纤维化；Nampt

英文摘要： Renal fibrosis of Diabetic nephropathy (DN) leads to end stage of kidney disease (ESRD),a serious threat to human health,but it is hitherto unknown of pathogenesis of diabetic renal fibrosis. So, it is a key point for prevention and treatment of diabetic nephropathy(DN) by revealing renal fibrosis pathogenesis. Pathological studies confirm that renal tissue inflammatory reaction happened ahead of preceded the process of renal fibrosis formation and inflammatory pathways is a common way of kidney fibrosis formation procedures. Our previous study found: Nicotinamide phosphoribosyl transferase (Nampt) abnormally elevated expression in diabetic kidney tissues, and coexist accompanied by renal inflammatory cells invasion within the tissue.Meanwhile,poly-ADP-ribose polymerase (PARP) level increased, but Nicotinamide Adenine Dinucleotide (NAD) + decreased and NAD/NADH ratio inversion. It is suggested that Nampt maybe play an important roles during the inflammation and fibrosis formation procedures by means of silent information regulator 1 (SIRT1) and nuclear factor kappa B (NK-kappa B) balance, It could become a pivotal target of the fibrosis formation of diabetic nephropathy therapeutic method. In this study,we will use qRT-PCR micro array,immunohistochemistry,western blot and laser confocal combining with biochemical metabolism technology to explore mechanism of Nampt act on SIRT1 and NF-kappa B balance in renal fibrosis procedure formation with OLETF rat diabetic nephropathy model and cell line in vivo and in vitro. The purpose of our study is to reveal the principle of cells conversion and inflammatory cytokines infiltration in process of inflammatory-fibrosis in diabetic nephropathy which provides new ideas for prevention and treatment of diabetic nephropathy.

英文关键词： type 2 diabetes mellitus;diabetic nephropathy;inflammatory factor;renal fibrosis;Nicotinamide phosphoribosyl transferase