Progranulin在糖尿病肾病足细胞损伤中的保护作用及分子机制

项目名称： Progranulin在糖尿病肾病足细胞损伤中的保护作用及分子机制

项目编号： No.81470958

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： 易凡

作者单位： 山东大学

项目金额： 73万元

中文摘要： 糖尿病肾病发病机制的研究越来越关注于免疫平衡和细胞稳态的调控，而与之相关的炎性反应和自噬成为该领域的研究热点。Progranulin（PGRN）是一种多功能自分泌生长因子，在多种生理和疾病进程中发挥关键作用，但在糖尿病肾病中的作用机制尚不清楚。我们前期工作中首次证实PGRN在糖尿病肾病病人和糖尿病小鼠的肾脏中表达显著降低，同时发现PGRN在高糖条件下的表达变化具有细胞特异性并与足细胞自噬和炎性反应相关。为此，本课题将以PGRN为中心，运用细胞生物学、cre-loxp条件基因敲除技术构建特异性足细胞PGRN基因敲除小鼠等手段深入探讨PGRN在糖尿病肾病中的作用及探讨PGRN-自噬-NLRP3 炎性体在足细胞中的分子调控机制；并进一步以重组蛋白PGRN作为糖尿病肾病治疗手段的初步药效学研究。此研究将拓展对PGRN生物学功能的新认识，为糖尿病肾病的防治提供新靶点和思路，具有重要的理论价值。

中文关键词： 糖尿病肾病；足细胞损伤；细胞自噬；炎症反应

英文摘要： Although the pathogenesis of diabetic nephropathy (DN) is multifactorial, an increasing number of clinical and animal studies have implicated that the regulation of cellular homeostasis and the activation of innate immune system are of importance in the pathogenesis of DN. Therefore, inflammatory response and autophagy take center stage in the study of DN. Progranulin（PGRN）, a pleiotrophic growth factor, is known to play an important role in the maintenance and regulation of the homeostatic dynamics of normal tissue development, proliferation, regeneration, and the host-defense response. In addition, PGRN has also emerged as a multifaceted immune-regulatory molecule through regulating the signaling pathways known to be critical for immunology. However, it is unknown whether PGRN contributes to the regulation of renal functions. Our preliminary studies showed that PGRN was down-regulated in the kidney from streptozotocin-induced diabetic mice and kidney biopsies from diabetic patients. Exacerbation of inflammation and further reduced autophagy were detected in PGRN-/- diabetic mice. We further found that podocytes treated with high glucose selectively reduced PGRN expression. Recombinant PGRN can recover high glucose-reduced autophay and ameliorated inflammation. Therefore, the present study is designed to explore the protective role of PGRN in DN and investigate PGRN-autophagy-NLRP3 inflammasome activation signaling pathways in podocytes both in vitro and in vivo animal studies using podocyte-specific deletion of PGRN mice. We then evaluated the possibility of recombinant PGRN as a therapeutic drug for the treatment of DN. In this study, we postulate that PGRN-induced autophagy is a major protective mechanism against podocyte injury, representing a putative target to ameliorate human glomerular disease.

英文关键词： diabetic nephropathy;podocyte injury;autophagy;inflammation