Sexual dimorphisms of renin-angiotensin system in hypertension and renal injury

描述(申请人提供)：高血压及其相关的肾脏和心血管并发症在美国是一个严重的健康问题。大约65%的高血压患者没有控制他们的血压，女性比男性更有可能血压不受控制。肾素-血管紧张素系统(RAS)是控制血压的关键系统。RAS抑制剂是治疗高血压和肾脏疾病最常用的处方药之一，尽管现有数据表明，抑制RAS对女性和男性的心脏和肾脏益处程度并不相同。本研究的目的是确定激活和抑制RAS调节女性和男性高血压和肾脏损伤的分子机制。我们假设，对RAS激活和抑制的功能反应的性别差异与(1)导致高血压和肾脏损伤的经典RAS的激活与促进心血管健康的非经典RAS的性别平衡有关，(2)RAS信号分子激活的性别差异。三个具体目标将检验我们的假设。具体目标1将检验这样一种假设，即女性比男性有更多的非经典RAS表达和激活，这种非经典RAS可以减轻RAS介导的高血压和肾脏损伤。我们将在正常血压大鼠(WKY)和雄性自发性高血压大鼠(SHR)中检测经典和非经典RAS组分在基线和RAS刺激后的表达水平。我们将测量血压，以确定女性SHR中非经典RAS激活增加是否导致(1)女性对RAS激活和血压的失衡，以及(2)经典RAS抑制剂有效性的性别差异。我们将评估男性和女性肾脏对RAS刺激的敏感性，因为肾脏在长期控制血压方面非常重要。特定目标2将验证这样的假设，即与男性SHR相比，女性SHR在肾皮质中具有更大的RAS刺激的一氧化氮(NO)生物利用度。NO是肾脏健康的重要调节因子。我们将确定RAS调节NO在男性和女性SHR中的生物利用度的能力。我们将测量血压，以确定RAS介导的NO是否有助于L名字高血压的性别差异。具体目标3将测试AT1激活导致雄性和雌性SHR肾皮质产生不同信号分子的假设，重点是超氧化物歧化、转化生长因子-2和Janus激酶/信号转导和转录激活因子。我们将确定RAS激活对男性和女性SHR肾皮质中这些因子水平的影响，以及它们在RAS介导的高血压和肾脏损伤中的作用。这些研究可能提供基本的科学框架，以开发更个性化和更有效的治疗方案，治疗高血压和预防男性和女性的慢性肾脏疾病。公共卫生相关性：在美国，高血压及其相关的肾脏和心血管并发症是一个严重的健康问题。大约65%的高血压患者没有控制他们的血压，女性比男性更有可能血压不受控制。肾素-血管紧张素系统(RAS)是控制血压的关键系统。这项研究项目将获得关于导致男性和女性疾病进展的分子机制的新信息，有可能(1)解释为什么传统治疗方法对女性可能不如男性有效，(2)有助于开发更有效的治疗方案，用于治疗高血压和预防男性和女性的慢性肾脏疾病。

DESCRIPTION (provided by applicant): Hypertension and the associated renal and cardiovascular complications are a serious health problem in the Unites States. Approximately 65% of hypertensive patients do not have their blood pressure controlled and women are more likely than men to have uncontrolled blood pressure. The renin-angiotensin system (RAS) is a key system in controlling blood pressure. RAS inhibitors are among the most commonly prescribed drugs for the treatment of hypertension and renal disease, although available data suggests that RAS inhibition does not confer the same degree of cardio-renal benefit in women and men. The objective of this proposal is to determine the molecular mechanisms by which activation and inhibition of the RAS regulate hypertension and renal injury in females and males. We hypothesize that sex differences in functional responses to RAS activation and inhibition are related to (1) a differential balance in females and males in the activation of the classical RAS, which induces hypertension and renal injury, vs. the non-classical RAS, which promotes cardiovascular health, and (2) sex differences in RAS activation of signaling molecules. Three Specific Aims will test our hypotheses. Specific Aim 1 will test the hypothesis that females have greater expression and activation of the non-classical RAS which attenuates RAS-mediated hypertension and renal injury compared to males. We will measure expression levels of the classical and non-classical RAS components at baseline and following RAS stimulation in male and female spontaneously hypertensive rats (SHR) and in normotensive rats (WKY). We will measure blood pressure to determine if increased non-classical RAS activation in female SHR accounts for (1) the imbalance in females to RAS activation and blood pressure and (2) sex differences in the effectiveness of classical RAS inhibitors. We will assess the sensitivity of kidneys in males and females to RAS stimulation, as the kidney is important in the long-term control of blood pressure. Specific Aim 2 will test the hypothesis that female SHR have greater RAS-stimulated nitric oxide (NO) bioavailability in the renal cortex compared to male SHR. NO is an important regulator of renal health. We will determine the ability of the RAS to regulate NO bioavailability in male and female SHR. We will measure blood pressure to determine if RAS-mediated NO contributes to sex differences in L-NAME hypertension. Specific Aim 3 will test the hypothesis that AT1 activation results in the production of different signaling molecules in the renal cortex of male and female SHR, focusing on superoxide, transforming growth factor-2, and Janus kinase/signal transducers and activators of transcription. We will determine the effects of RAS activation on the levels of these factors in the renal cortex of male and female SHR, and their contribution to RAS mediated hypertension and renal injury. These studies may provide the basic science framework to develop more personalized and more effective therapeutic options for the treatment of hypertension and the prevention of chronic kidney disease in men and women. PUBLIC HEALTH RELEVANCE: Hypertension and the associated renal and cardiovascular complications are a serious health problem in the Unites States. Approximately 65% of hypertensive patients do not have their blood pressure controlled and women are more likely than men to have uncontrolled blood pressure. The renin-angiotensin system (RAS) is a key system in controlling blood pressure. This research project will obtain new information on the molecular mechanisms responsible for disease progression in both males and females has the potential to (1) explain why conventional treatments may not be as effective in women as men and (2) contribute to development of more effective therapeutic options for the treatment of hypertension and the prevention of chronic kidney disease in men and women.