Angiotensin II Mediates Early Changes in Diabetic Kidney

描述（由申请人提供）：糖尿病肾病与发病率和死亡率增加相关，主要来自心血管疾病。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、肾小球和小管。AT1受体刺激降低肾脏血流动力学和肾小管功能，释放多种生长因子、细胞因子和血管活性因子，增强糖尿病肾病的许多病理改变。近年来在成年大鼠肾小球、血管和小管中检测到Ang II亚型-2 （AT2）受体。与AT1受体相比，AT2受体的刺激可导致血管舒张，抑制细胞生长和凋亡。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。

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.