Intrarenal Angiotensin II generation during Angiotensin II-induced hypertension

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产生的精确机制及其对肾功能的影响。已知血管紧张素(Ang II)依赖型高血压的特征是肾内Ang II水平升高，这与肾脏的功能和形态紊乱有关。这种增强包括局部肾素-血管紧张素系统(RAS)对肾内Ang II合成的增强，但肾内Ang II生成对肾脏Ang II增强的确切贡献以及在Ang II依赖型高血压期间观察到的该器官的紊乱仍有待确定。 申请人之前的研究表明，在小鼠体内长期输注血管紧张素II会导致血压升高，这与血管紧张素原表达增强、肾脏肾素活性持续存在以及肾内血管紧张素II含量高有关。由于已知血管紧张素转换酶(ACE)负责在小鼠肾脏中将Ang I转化为Ang II的大部分过程，该项目将利用最近产生的组织特异性ACE基因敲除小鼠来验证以下假设：在AngⅡ诱导的高血压期间，血管紧张素原表达增加和肾素持续活性会导致ACE衍生的Ang II生成增加，进而导致肾内Ang II增加，肾功能、水和钠滞留减少，高血压和肾脏损伤的发展。具体目标：在指导阶段：1.确定由于肾脏缺乏血管紧张素转换酶活性而导致的肾内血管紧张素转换酶II生成减少对肾内血管紧张素转换酶II含量和慢性血管紧张素转换酶II输注期间血压的影响。2.研究血管紧张素转换酶底物血管紧张素转换酶(ACE)底物Ang I长期输注对肾脏Ang II含量及血压的影响。在独立期：3.确定慢性Ang II输注过程中肾内Ang II生成减少(如特定目标1)对肾功能的影响，以及当Ang II仅限于肾脏形成(如特定目标2)时，慢性Ang I输注对肾功能的影响。4.确定肾内Ang II生成减少(如特定目标1)对慢性Ang II输注过程中肾脏损伤的发展和严重程度的影响，以及当Ang II形成仅限于肾脏时(如特定目标2)，确定慢性Ang I输注对相同参数的影响。 与公众健康相关：血管紧张素II是一种荷尔蒙，在肾功能、高血压和肾脏损害中发挥重要作用。这一建议旨在提高目前对肾脏血管紧张素II形成机制和后果的理解，以便为制定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。

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.