Angiotensin II Mediates Early Changes in Diabetic Kidney

描述(申请人提供)：糖尿病肾病与发病率和死亡率增加有关，主要由心血管疾病引起。尽管过去的临床研究提供了令人信服的证据表明，通过使用血管紧张素转换酶(ACE)抑制剂阻断肾素血管紧张素系统(RAS)可以改善I型和II型糖尿病患者的肾脏预后，但该系统对糖尿病肾病早期变化的影响尚不清楚。血管紧张素II(Ang II)亚型1(AT1)受体定位于肾血管、肾小球和肾小管。AT1受体的刺激降低了肾脏的血流动力学和肾小管功能，并释放了几种生长因子、细胞因子和血管活性因子，加强了糖尿病肾脏疾病中的许多病理变化。血管紧张素转换酶II亚型2(AT2)受体最近在成年大鼠肾小球、血管和小管中被检测到。与AT1受体不同，AT2受体刺激导致血管扩张、细胞生长抑制和细胞凋亡。我们的初步研究表明，在早期糖尿病肾病中，AT2受体的表达和活性降低。 这项建议将评估一种假说，即在早期糖尿病肾病中，AT2受体表达和活性的降低通过增加肾脏肿瘤坏死因子-α(TNFpha)、转化生长因子-β1(TGFbeta1)、内皮素-1(ET-1)和血栓素-B2的产生而促进肾脏疾病的发展。提出的具体目的是：目的I：验证AT2受体抑制肾脏产生肿瘤坏死因子α、转化生长因子β1、内皮素-L和血栓素B_2的假说。目的：验证早期糖尿病肾病AT2受体表达和活性降低，AT1受体活性增加，从而增加肾组织中肿瘤坏死因子α(TNFα)、转化生长因子β1(TGFbeta1)、内皮素-1(ET-1)和血栓素B2(TXB2)的产生。目的：验证在糖尿病肾病早期，AT2受体表达和活性增加可减少肾脏产生TGFbeta1、TNFα、ET-1和TXB2的假说，这一过程可阻止疾病的发展。 拟议的研究将有助于了解糖尿病肾病的机制，并可能导致开发新的治疗方式来预防或减缓这种疾病的发展。

DESCRIPTION (provided by applicant): Diabetic nephropathy is associated with increased morbidity and mortality, mainly from cardiovascular disease. Although past clinical studies have provided convincing evidence that interruption of the renin angiotensin system (RAS) through the use of angiotensin-converting enzyme (ACE) inhibitors improves the renal outcome in both type I and II diabetes mellitus, the effects of this system on early changes in diabetic nephropathy are not well known. Angiotensin II (Ang II) subtype-1 (AT1) receptors are localized in the renal blood vessels, glomeruli and tubules. AT1 receptor stimulation decreases renal hemodynamic and tubular functions and releases several growth, cytokine and vasoactive factors that enhances many pathologic changes seen in diabetic renal disease. Ang II subtype-2 (AT2) receptors have recently been detected in adult rat kidney glomeruli, blood vessels and tubules. In contrast to AT1 receptors, AT2 receptors stimulation lead to vasodilation, inhibition of cell growth and apoptosis. Our preliminary studies suggest that in early stage diabetic nephropathy, AT2 receptor expression and activity are decreased. This proposal will evaluate the hypothesis that in early stage diabetic nephropathy, the decrease in the AT2 receptor expression and activity contributes to development of this renal disease through increased renal production of tumor necrosis factor-alpha (TNFalpha), transforming growth factor-beta1 (TGFbeta1, endothelin-1 (ET-1) and thromboxan-B2. The proposed specific aims are: AIM I: To test the hypothesis that AT2 receptor inhibits renal production of TNFalpha, TGFbeta1, ET-l and TXB2. AIM II: To test the hypothesis that the decrease in AT2 receptor expression and activity reciprocally increases the AT1 receptor activity to increase renal production of TNFalpha, TGFbeta1, ET-1 and TXB2 in early stage diabetic nephropathy. AIM III: To test the hypothesis that in early stage diabetic nephropathy improving the AT2 receptor expression and activity reduces renal production of TGFbeta1, TNFalpha, ET-1 and TXB2, a process that can prevent the progression of this disease. The proposed studies will help understand the mechanisms that are involved in diabetic nephropathy and could lead to the development of new therapeutic modalities to prevent or slowdown the development of this disease.