Angiotensin II Mediates Early Changes in Diabetic Kidney

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，肾素血管紧张素系统的中断 (RAS)通过使用血管紧张素转换酶(ACE)抑制剂改善两种I型患者的肾脏结局 对于糖尿病和II型糖尿病，该系统对糖尿病肾病早期变化的影响还不是很清楚。 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 受体刺激降低肾血流动力学和肾小管功能，释放几种生长因子、细胞因子和 血管活性因子可增强糖尿病肾病中的许多病理变化。Ang II亚型-2(AT2) 最近在成年大鼠的肾小球、血管和小管上发现了受体。与AT1形成对比 AT2受体刺激可导致血管扩张、抑制细胞生长和细胞凋亡。我们的预赛 研究表明，糖尿病肾病早期，AT2受体表达和活性降低。 这项建议将评估这一假设，即在早期糖尿病肾病中，AT2受体的减少 表达和活性通过增加肾脏肿瘤的产生而促进肾脏疾病的发展。 肿瘤坏死因子-c_(TNFa)、转化生长因子-131(TGFI30)、内皮素-1(ET-1)、血栓素B_2。 建议的具体目标是： 目的：验证AT2受体抑制肾组织产生肿瘤坏死因子受体(TNFc)、血管内皮生长因子I31(TGFI31)、内毒素L(ET-L)和血栓素B_2(TXB_2)的假说。 目的II：验证AT2受体表达和活性降低互换增加AT1的假设。 受体活性在早期糖尿病肾病中增加肾脏产生TNFc_3、TGFI3b、ET-1和TXB2的作用 目的：验证早期糖尿病肾病改善AT2受体表达和AT2受体表达的假说。 活动减少肾脏TGFI3、TNFc、ET-1和TXB2的产生，这一过程可以防止这种进展 疾病。 拟议中的研究将有助于理解糖尿病的发病机制。 开发新的治疗方法以防止或减缓疾病的发展

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