Angiotensin II Mediates Early Changes in Diabetic Kidney

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， (RAS)通过使用血管紧张素转换酶（ACE）抑制剂，改善了I型和II型糖尿病患者的肾脏结局。 和II型糖尿病，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。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。血管紧张素Ⅱ亚型2（AT 2） 最近在成年大鼠肾小球、血管和肾小管中检测到受体。与AT 1相比 受体，AT 2受体刺激导致血管舒张，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，AT 2受体表达和活性降低。 该建议将评估以下假设：在早期糖尿病肾病中，AT 2受体的减少 表达和活性通过增加肿瘤的肾产生而促进这种肾病的发展。 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。 拟议的具体目标是： 目的一：验证AT_2受体抑制肾脏TNF_（Fc_2）、TGF_（FI_（31））、ET-1和TXB_2的产生的假说。 目的II：验证AT 2受体表达和活性的降低会增加AT 1受体表达和活性的假说。 受体活性增加早期糖尿病肾病中肾脏产生TNFc_1、TGFI 3b、ET-1和TXB_2。 目的III：验证在早期糖尿病肾病中改善AT 2受体表达， 活动减少肾脏产生的TGFI 3_，TNFc_，ET-1和TXB 2，这一过程可以防止这种进展。 疾病 这些研究将有助于了解糖尿病患者的发病机制。 开发新的治疗方式，以防止或减缓发展

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