Angiotensin II Mediates Early Changes in Diabetic Kidney

超出所提供的空间。糖尿病肾病与主要由心血管疾病引起的发病率和死亡率增加有关。尽管过去的临床研究提供了令人信服的证据，通过使用血管紧张素转换酶（ACE）抑制剂中断肾素血管紧张素系统（RAS）改善I型和II型糖尿病的肾脏结局，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（AngII）亚型-1（AT 1）受体定位于肾血管、肾小球和肾小管中。AT 1受体刺激降低肾血流动力学和肾小管功能，并释放几种生长，细胞因子和血管活性因子，增强糖尿病肾病中观察到的许多病理变化。最近在成年大鼠肾小球、血管和肾小管中检测到血管紧张素Ⅱ亚型2（AT 2）受体。与AT 1受体相反，AT 2受体刺激导致血管舒张、细胞生长抑制和凋亡。我们的初步研究表明，在早期阶段的糖尿病肾病，AT 2受体的表达和活性降低。本研究旨在探讨早期糖尿病肾病患者肾组织中肿瘤坏死因子-c_（TNF α）、转化生长因子-131（TGF β_1）、内皮素-1（ET-1）和血栓素-B_2（TXB_2）的表达和活性降低与糖尿病肾病的关系。目的：1.验证AT_2受体抑制肾脏TNF_（Fc_2）、TGF_（F1）、ET-1和TXB_2的产生的假说。AIM II：为了验证早期糖尿病肾病中AT_2受体表达和活性的降低可增加AT_1受体活性，从而增加肾脏产生TNFc_2、TGF_（13）b、ET-1和TXB_2的假设。AIM III：为了验证在早期糖尿病肾病中改善AT 2受体表达和活性减少肾脏产生TGF β 1、TNFc、ET-1和TXB 2的假设，这一过程可以防止这种疾病的进展。拟定的研究将有助于了解糖尿病的相关机制，开发新的治疗方法以预防或减缓糖尿病的发展。性能站点==

EXCEED THE SPACE PROVIDED. 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-c_ (TNFa), transforming growth factor-131 ( TGFI30, 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 TNFc_, TGFI31, 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 TNFc_, TGFI3b 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 TGFI3_, TNFc¿, 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 the development of new therapeutic modalities to prevent or slowdown the development PERFORMANCE SITE ========================================Section End===========================================