Angiotensin II Mediates Early Changes in Diabetic Kidney

描述（由申请人提供）：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相关。 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（AT1）受体定位于肾血管、肾小球和肾小管中。AT1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，AT2受体的表达和活性降低。 本提案将评估以下假设：在早期糖尿病肾病中，AT 2受体表达和活性的降低通过增加肾脏产生肿瘤坏死因子-α（TNF α）、转化生长因子-β 1（TGF β 1）、内皮素-1（ET-1）和血栓素-B2而促成这种肾脏疾病的发展。 目的I：验证AT_2受体抑制肾脏TNF α、TGF β_1、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TNF α、TGF β 1、ET-1和TXB2的产生的假设。 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、TNF α、ET-1和TXB2的假设，这一过程可以防止这种疾病的进展。 拟议的研究将有助于了解参与糖尿病肾病的机制，并可能导致新的治疗方式的发展，以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.