Signaling Pathways in Renovascular Hypertension

肾血管性高血压的信号通路

• 批准号: 7327508
• 负责人: JOSEPH PETER GRANDE
• 金额: $ 36.57万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7327508
• 关键词: Angiotensins; Atrophic; Blood Vessels; CDKN1A gene; Cardiovascular system; Cell Cycle; Cell Cycle Proteins; Clip; Contralateral; Cyclin-Dependent Kinase Inhibitor; Development; Elements; End stage renal failure; Essential Genes; Fibrosis; Human; Hyperplasia; Hypertension; Hypertrophy; Hypoxia; Inflammation; Injury; Interruption; Intervention; Kidney; Kidney Diseases; Knockout Mice; Lead; Lesion; MAP Kinase Gene; MAPK Signaling Pathway Pathway; Mediating; Modeling; Morbidity - disease rate; Mus; Nephrosclerosis; Oxidative Stress; Pathway interactions; Patients; Play; Renal Artery Stenosis; Renin-Angiotensin System; Renovascular Hypertension; Research Personnel; Role; Sclerosis; Signal Pathway; Signal Transduction; Stenosis; System; Testing; Tissues; Tubular formation; United States; base; hemodynamics; inhibitor/antagonist; interstitial; kidney hypertrophy; mortality; neutralizing antibody; novel therapeutics; oncoprotein p21; p27 Cell Cycle Protein; p27 Enzyme Inhibitor; programs; renal artery; response; therapeutic target

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.

肾血管高血压是美国发病率和死亡率的主要原因。最佳的 肾动脉狭窄患者（RAS）的管理是一个引起极大争议的主题 部分是因为心血管和肾脏疾病发展的基本信号传导机制 RA的设置尚不清楚。单侧RA已被用作人类的模型 肾血管高血压。这种病变会诱导血管肥大和硬化症，间质纤维化， 管状萎缩和狭窄肾脏的间质炎症和代偿性肥大 对侧肾脏。该计划项目应用程序的中心假设是形态学 单侧RAS后狭窄和对侧肾脏的改变是由血流动力学触发的 改变，狭窄肾脏中的组织缺氧，氧化。压力和肾素 - 血管紧张素的激活 系统。这些“启动因素”是项目1、2和4的主要重点。总体假设为 项目3中测试的是，这些“启动因子”负责诱导TGF-P，细胞周期 抑制剂p21和p27以及MAPK途径，在狭窄和 对侧肾脏。在特定目标1中，我们将测试以下假设：TGF-P，P21/P27和P-ERK是 狭窄的肾脏持续升高，导致间质纤维化和管状萎缩，并且是 在对侧肾脏中瞬时升高，导致代偿性肥大/增生。具体 AIM 2，通过使用TGF-P1中和抗体和小鼠，TGF-PL信号传导将中断 SMADS基因的纯合缺失是TGF-PL信号中必不可少的中间体，以测试 假设TGF-P在狭窄肾脏中肾脏萎缩的发展中起着核心作用 对侧肾脏中的代偿性肥大/增生。在特定目标3中，我们将使用P21和 p27敲除小鼠以检验p21和/或p27的删除将限制间隙程度的假设 狭窄肾脏中的纤维化，将促进增生而不是肥厚的反应 对侧肾脏。最后，我们将测试抑制ERK或其他MAPK途径的假设 限制狭窄肾脏和代偿性肥大中间质纤维化的发展和/或 对侧肾脏中的增生。拟议的研究将定义信号的关键要素 RA触发的途径，可能为针对的干预措施提供机械基础 阻止肾血管高血压患者的不可逆肾脏损伤发展。