Signaling Pathways in Renovascular Hypertension

肾血管性高血压是美国发病率和死亡率的主要原因。最优 肾动脉狭窄（RAS）患者的管理是一个相当有争议的问题， 部分原因是心血管和肾脏疾病发展的基本信号机制， RAS的设置还不太清楚。单侧RAS已被用作人类的模型 肾血管性高血压这种病变诱导血管肥大和硬化，间质纤维化， 肾小管萎缩和间质性炎症，在狭窄的肾脏和代偿性肥大， 对侧肾该项目申请的中心假设是， 单侧RAS后狭窄肾和对侧肾的改变由血流动力学触发， 改变，狭窄肾脏组织缺氧，氧化。应激和激活的肾素-血管紧张素 系统这些“启动因素”是项目1、2和4的主要重点。总的假设是 在项目3中测试的是，这些“起始因子”负责诱导TGF-β，即细胞周期 抑制剂p21和p27，以及MAPK途径，它们在狭窄和狭窄中受到不同的调节。 对侧肾在具体目标1中，我们将检验TGF-β、p21/p27和p-ERK是 在狭窄的肾脏中持续升高，导致间质纤维化和肾小管萎缩， 在对侧肾脏中一过性升高，导致代偿性肥大/增生。在特定 目的2、利用TGF-β 1中和抗体阻断TGF-β 1信号通路， 携带SmadS基因（TGF-β 1信号传导中的必需中间体）的纯合缺失，以测试 TGF-β在狭窄肾的肾萎缩发展中起核心作用的假说， 对侧肾脏代偿性肥大/增生。在具体目标3中，我们将使用p21， p27敲除小鼠来检验p21和/或p27的缺失将限制间质性 在狭窄的肾脏纤维化，并将促进增生，而不是肥大反应， 对侧肾最后，我们将检验抑制ERK或其他MAPK通路将 限制狭窄肾间质纤维化和代偿性肥大的发展和/或 对侧肾脏增生拟议的研究将定义信号的关键要素 RAS触发的通路，并可能为针对RAS的干预提供机制基础。 阻止肾血管性高血压患者发生不可逆性肾损伤。

Renovascular hypertension is a major cause of morbidity and mortality in the United States. Optimal management of patients with renal artery stenosis (RAS) is a subject of considerable controversy, in large part because basic signaling mechanisms underlying the development of cardiovascular and renal disease in the setting of RAS are not well understood. Unilateral RAS has been employed as a model of human renovascular hypertension. This lesion induces vascular hypertrophy and sclerosis, interstitial fibrosis, tubular atrophy, and interstitial inflammation in the stenotic kidney and compensatory hypertrophy in the contralateral kidney. The central hypothesis of this Program Project application is that the morphologic alterations in the stenotic and contralateral kidneys following unilateral RAS are triggered by hemodynamic alterations, tissue hypoxia in the stenotic kidney, oxidative. stress, and activation of the renin-angiotensin system. These "initiating factors" are the primary focus of Projects 1, 2, and 4. The overall hypothesis to be tested in Project 3 is that these "initiating factors" are responsible for induction of TGF-p, the cell cycle inhibitors p21 and p27, and the MAPK pathways, which are differentially regulated in the stenotic and contralateral kidney. In Specific Aim 1, we will test the hypothesis that TGF-p, p21/p27, and p-ERK are persistently elevated in the stenotic kidney, leading to interstitial fibrosis and tubular atrophy, and are transiently elevated in the contralateral kidney, leading to compensatory hypertrophy/hyperplasia. In Specific Aim 2, TGF-pl signaling will be interrupted through the use of TGF-p1 neutralizing antibodies and mice bearing homozygous deletion of the SmadS gene, an essential intermediate in TGF-pl signaling, to test the hypothesis that TGF-p plays a central role in the development of renal atrophy in the stenotic kidney and compensatory hypertrophy/hyperplasia in the contralateral kidney. In Specific Aim 3, we will employ p21 and p27 knockout mice to test the hypothesis that deletion of p21 and/or p27 will limit the extent of interstitial fibrosis in the stenotic kidney and will promote a hyperplastic rather than hypertrophic response in the contralateral kidney. Finally, we will test the hypothesis that inhibition of ERK or other MAPK pathways will limit the development of interstitial fibrosis in the stenotic kidney and compensatory hypertrophy and/or hyperplasia in the contralateral kidney. The proposed studies will define critical elements of signaling pathways triggered by RAS and may provide the mechanistic basis for interventions directed towards arresting the development of irreversible renal injury in patients with renovascular hypertension.