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Intrarenal Angiotensin II generation during Angiotensin II-induced hypertension

血管紧张素 II 诱导的高血压期间肾内血管紧张素 II 的生成

基本信息

批准号：
7918917
负责人：
Romer Andres Gonzalez-Villalobos
金额：
$ 9.5万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-21 至 2011-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this project is to delineate the precise mechanisms that control intrarenal angiotensin II generation and its impact on kidney function. It is known that Angiotensin (Ang II)-dependent hypertension is characterized by an increase in intrarenal Ang II levels that are associated with functional and morphological derangements in the kidney. Such augmentation involves an enhanced intrarenal Ang II synthesis by the local renin-angiotensin system (RAS) but, the exact contribution of intrarenal Ang II generation to the augmentation of Ang II in the kidney and the disturbances observed in this organ during Ang ll-dependent hypertension remains to be established. Previous studies by the applicant demonstrate that chronic Ang II infusions in mice cause increases in blood pressure that are associated with augmented angiotensinogen expression and the persistence of renin activity in the kidneys as well as high intrarenal Ang II content. Because is known that angiotensin-converting enzyme (ACE) is responsible for most of Ang I conversion to Ang II in the mouse kidney, this project will take advantage of recently generated tissue-specific ACE knockout mice to test the HYPOTHESIS that during Ang ll-induced hypertension, an increased angiotensinogen expression and persistent renin activity lead to an enhanced ACE-derived Ang II generation that in turn results in intrarenal Ang II augmentation, reductions on kidney function, water and sodium retention, the development of hypertension and renal injury. SPECIFIC AIMS: During the mentored phase: 1. To determine the impact of reduced intrarenal Ang II formation, as a consequence of the lack of ACE activity in the kidneys, on intrarenal Ang II content and blood pressure during chronic Ang II infusions. 2. To determine the effects of chronic infusions of the ACE substrate Ang I on intrarenal Ang II content and blood pressure when the activity of this enzyme is present only in kidneys. During the independent phase: 3. To determine the effects of reduced intrarenal Ang II formation (as in specific aim 1) on kidney function during chronic Ang II infusions and, to determine the effects of chronic Ang I infusions on kidney function when Ang II formation is restricted to the kidneys (as in specific aim 2). 4. To determine the effects of reduced intrarenal Ang II formation (as in specific aim 1) on the development and severity of kidney injury during chronic Ang II infusions and, to determine the effects of chronic Ang I infusions on the same parameters when Ang II formation is restricted to the kidneys (as in specific aim 2). PUBLIC HEALTH RELEVANCE: Angiotensin II is a hormone that plays a major role in renal function, hypertension and kidney damage. This proposal seeks to improve the current understanding of the mechanisms and consequences of Angiotensin II formation in the kidneys in order to provide a rational approach for developing better diagnostic and therapeutic strategies for hypertension and a variety of kidney diseases.

描述（由申请人提供）：该项目的长期目标是描述控制肾内血管紧张素II生成的精确机制及其对肾功能的影响。已知血管紧张素（Ang II）依赖性高血压的特征在于肾内Ang II水平的增加，其与肾脏中的功能和形态学紊乱相关。这种增强涉及通过局部肾素-血管紧张素系统（RAS）增强的肾内Ang II合成，但是，肾内Ang II生成对肾脏中Ang II增强的确切贡献以及在Ang II依赖性高血压期间在该器官中观察到的干扰仍有待确定。申请人先前的研究表明，小鼠中的慢性Ang II输注引起血压升高，这与血管紧张素原表达增加和肾中肾素活性的持续以及肾内高Ang II含量有关。由于已知血管紧张素转换酶（ACE）负责小鼠肾脏中大部分Ang I转化为Ang II，因此本项目将利用最近产生的组织特异性ACE敲除小鼠来测试假设，即在Ang II诱导的高血压期间，血管紧张素原表达的增加和持续的肾素活性导致ACE活性增强，衍生的Ang II生成，其反过来导致肾内Ang II增加、肾功能降低、水和钠潴留、高血压和肾损伤的发展。具体目标：在指导阶段：1。确定肾内血管紧张素II形成减少的影响，作为肾脏中缺乏ACE活性的结果，在慢性血管紧张素II输注过程中肾内血管紧张素II含量和血压。2.确定慢性输注ACE底物Ang I对肾内Ang II含量和血压的影响，当这种酶的活性仅存在于肾脏中时。独立阶段：3。确定慢性Ang II输注期间肾内Ang II形成减少（如具体目标1中所述）对肾功能的影响，并确定当Ang II形成仅限于肾脏时慢性Ang I输注对肾功能的影响（如具体目标2中所述）。4.确定肾内Ang II形成减少（如具体目标1）对慢性Ang II输注期间肾损伤的发展和严重程度的影响，并确定当Ang II形成仅限于肾脏时慢性Ang I输注对相同参数的影响（如具体目标2）。公共卫生相关性：血管紧张素II是一种激素，在肾功能、高血压和肾损伤中起主要作用。该提案旨在提高目前对肾脏中血管紧张素II形成的机制和后果的理解，以便为开发更好的高血压和各种肾脏疾病的诊断和治疗策略提供合理的方法。