胰岛素功能缺乏在引起肾小球系膜细胞功能改变及糖尿病肾病发病中的作用及机制研究

项目名称： 胰岛素功能缺乏在引起肾小球系膜细胞功能改变及糖尿病肾病发病中的作用及机制研究

项目编号： No.81670664

项目类型： 面上项目

立项/批准年度： 2017

项目学科： 医药、卫生

项目作者： 陆利民

作者单位： 复旦大学

项目金额： 25万元

中文摘要： 糖尿病肾病（DN）是多种因素共同作用的结果。肾素-血管紧张素系统过度激活、高血糖、氧化应激等均与DN有关。然而，基于上述研究成果的干预并不能从根本上解决DN的治疗。糖尿病发病的根本原因是胰岛素功能性缺乏（ID），但对ID与肾损害发生的关系并未阐明。预实验观察到，ID可使系膜细胞增殖水平升高、细胞外基质蛋白（ECM）合成增加；ID时胰岛素样生长因子（IGF-1）及受体受体上调，阻断IGF-1能逆转ID引起的上述反应；给予IGF-1产生与ID相似的作用，并使调控ECM合成的核转录因子MRTF-A升高；糖尿病大鼠肾组织中IGF-1及其受体水平也明显升高。基此，我们提出假说：ID是肾损害发生的直接原因，ID使IGF-1及受体上调，刺激MRTF-A表达，进而促进系膜细胞功能改变，加速合成ECM可能是其机制之一。课题拟通过离体研究结合整体观察，验证该假说，从新视角探寻糖尿病时肾脏损害发生机制。

中文关键词： 系膜细胞；糖尿病肾病；细胞外基质；胰岛素缺乏；胰岛素样生长因子

英文摘要： China has been the country with the largest population of diabetes. Diabetic nephropathy (DN) is a serious complication of diabetes. DN is a consequence of mutifactors. Available evidence suggested that overactivation of intrarenal renin-angiotensin system, oxidative stress, accumulation of advanced glycation end products are all involved in the development of DN. However, the manipulation strategy based on those theories does not completely eliminate the progress of DN in clinic. The primary cause of diabetes is the functional deficiency of insulin (ID). The role of ID in functional deterioration has not been elucidated. In our preliminary observation, the result showed that DI increased the renal mesangial cell proliferation and extracellular matrix production. The blockade on insulin-like growth factor-1 (IGF-1) receptor eliminated the effect of ID while application of IGF-1 evoked similar effects of ID. IGF-1 and its receptor were up-regulated in ID-treated renal mesangial cells as well as renal tissues of diabetic rats. Treatment of the mesangial cells with IGF-1 elevated the expression of MRTF-A, which is a transcriptional factor related to ECM synthesis. Based on those observations, we hypothesized that DI is directly related to functional deterioration of kidney. Up-regulating IGF-1 and its receptor, then elevating the expression of MRTF-A, stimulating proliferation of renal mesangial cell and ECM synthesis might be one of the effect of ID. We will test the hypothesis on both in vivo and in vitro studies in the proposal.

英文关键词： renal mesangial cell ;diabetic nephropathy;extracellular matrix;insulin deficiency;insulin-like growth factor