糖尿病肾病是糖尿病重要的微血管病变并发症，是引起糖尿病患者终末肾疾病甚至死亡的主要原因。糖尿病时肾脏细胞内质网应激反应和天然免疫系统相关的炎症反应近来被认为参与糖尿病肾病的病理生理过程，但肾素-血管紧张素系统（RAS）过度激活或抑制在此过程中的作用仍不清楚。与ACEi或ARB相比，肾素直接抑制剂能够更完整的抑制RAS系统，减少由于应用ACEi或ARB所带来的负反馈作用，延缓糖尿病肾病的发展。本课题拟在初步发现肾素抑制剂或血管紧张素1-7（Ang1-7）缓解肾细胞内质网应激反应和抑制天然免疫相关的炎症反应的基础上，采用生理学，免疫学和分子生物学技术，在细胞，器官和动物整体水平上，深入研究肾素抑制剂和/或Ang1-7在糖尿病肾病时对肾脏功能和肾脏细胞的保护作用，特别着重于对内质网应激反应和天然免疫诱导的炎症反应的抑制作用的研究，并阐明其分子细胞机制，为治疗糖尿病肾病提供新的思路和理论依据。

Diabetes mellitus is becoming the leading cause of cardiovascular and renal diseases in China and most of the world. The pathogenesis of diabetic complications are multifactorial, recent evidences showed that endoplasmic reticulum stress (ER stress) and innate immune response (e.g.TLR, NLR families) played important roles in development of diabetic nephropathy. The benefits of blockade of the renin-angiotensin-aldosterone system (RAAS) in diabetes (mainly by inhibiting effects of angiotensin II in the kidney), namely angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II type 1 receptor blockers (ARB) are well established. However, ACEi or ARB treatment does not prevent development of diabetic nephropathy which is at least, in part, attributed to feedback effects arising from the blockade of the RAAS. Recently a renin direct inhibitor aliskiren was developed which may cause more complete inhibition of the RAAS. It reduces angiotensin II levels and plasma renin activity (PRA) without stimulating compensatory increases in PRA or angiotensin II that is seen in ACEi and ARBs treatments. Use of aliskiren in combination with other agents that antagonize the RAAS is considered as a treatment stratagy. Angiotensin 1-7 (Ang 1-7) has been shown to increase insulin sensitivity，mice with genetic ablation of the Ang 1-7 Mas receptor develop features of metabolic syndrome. Therefore aiming at amplifying effects of Ang 1-7-Mas axis should be investigated in the prevention and treatment of diabetes and its complications. Our hypothesis is that aliskiren treatment with Ang 1-7 could have synergistic effects in preventing diabetic nephropathy and its complications, by inhibiting ER stress and innate immunity response in the diabetic kidneys. Expression and regulation of markers of ER stress and innate immunity response as well as their signaling pathways in cultured human podocytes, in cultured proximal tubular cells (HK2), and in the kidneys of diabetic mice, will be investigated. Specific Aim 1: To determine protection and molecular mechanism of aliskiren and /or Ang 1-7 on cultured human podocytes and tubular cells in response to palmitic acid-induced ER stress or high glucose-induced inflammation (TLR and NLR). Specific Aim 2: To determine and compare effects and molecular mechanisms of renal protection of aliskiren and/or Ang 1-7, in streptozotocin(STZ)-induced type I diabetic DBA/2J mice, in STZ-induced type I diabetic AT1R knockout mice, and in type II KKAy/KKaa mice. The proposed studies will therefore establish physiological, cellular, and molecular effects of renin inhibitor and ANG1-7 in the prevention of diabetic nephropathy and will add novel therapies for treatment of diabetes complications.