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

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.

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。

近年来我国糖尿病发病率呈现快速增长，由糖尿病导致的肾脏损害已成为慢性肾损伤的主要因素。肾素-血管紧张素系统（renin-angiotensin system，RAS）异常激活在糖尿病导致的肾损伤中起到关键作用，但对RAS异常激活的发生机制并未揭示。本课题研究结果证实，转激活因子SNDp102在RAS异常激活作用起重要作用，高糖环境导致的活性氧水平升高刺激SNDp102表达水平升高，SNDp102可上调RAS多个成员，包括AT1受体的表达水平，进而引起肾损伤发生。RAS激活通过刺激TGF-合成和激活导致肾损伤发生，重编程因子c-Myc参与了TGF-的激活过程，c-Myc通过直接调控intergrin av的表达增加，使潜伏状态下的TGF-被释放，此外，c-Myc还参与小管上皮细胞凋亡的调控。C-Myc通过负性调控FAS受体介导的细胞死亡受体通路中关键的负性调控因子c-FLIP，导致FAS受体介导的细胞死亡通路激活，使小管上皮细胞凋亡增加，肾损伤肾损伤加剧。炎症反应介导了TGF-引起的肾损伤。过度的炎症反应导致肾组织过度修复形成纤维疤痕，Caspase家族新成员Caspase-11参与炎性因子激活过程，Caspase-11通过非经典炎性小体依赖通路，直接激活Caspase-1，进而激活IL-1和IL-18等炎性因子。在糖尿病及其他病理因素导致蛋白尿发生后，蛋白尿通过抑制NIX受体介导的线粒体自噬，促进肾小管上皮细胞的凋亡，加剧肾损伤。本课题的研究成果有助于认识糖尿病肾病发生机制及其他病因导致的慢性肾病发生机制。