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

高血压和肾损伤中肾素-血管紧张素系统的性别二态性

• 批准号: 8307938
• 负责人: Jennifer C Sullivan
• 金额: $ 36.88万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307938
• 关键词: AGTR2 gene; Accounting; Address; Albuminuria; Animal Model; Attenuated; Automobile Driving; Basic Science; Biological Availability; Blood Pressure; Cardiovascular system; Chronic Kidney Failure; Data; Development; Disease Progression; Drug Prescriptions; Effectiveness; Equilibrium; Estrogens; Female; Gonadal structure; Health; Hypertension; Inbred SHR Rats; Inbred WKY Rats; Individual; Infusion procedures; Injury; Janus kinase; Janus kinase 2; Kidney; Kidney Diseases; Measures; Mediating; Molecular; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Patients; Phosphorylation; Production; Receptor Activation; Relative (related person); Renal Hypertension; Renin-Angiotensin System; Reporting; Research Project Grants; STAT protein; STAT1 gene; STAT5A gene; Sex Characteristics; Signal Transduction; Signaling Molecule; Superoxides; System; Testing; Therapeutic; Transcriptional Activation; Transforming Growth Factors; United States; Woman; blood pressure regulation; conventional therapy; hemodynamics; hypertension prevention; hypertension treatment; improved; inhibitor/antagonist; kidney cortex; male; men; normotensive; receptor; receptor expression; research study; response; sex; sexual dimorphism

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.

描述（由申请人提供）：高血压及其相关的肾脏和心血管并发症是美国严重的健康问题。大约65%的高血压患者没有控制血压，女性比男性更容易出现血压失控。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，RAS抑制剂对女性和男性的心脏和肾脏的益处程度不同。本研究的目的是确定RAS的激活和抑制调节女性和男性高血压和肾损伤的分子机制。我们假设对RAS激活和抑制的功能反应的性别差异与(1)女性和男性在诱导高血压和肾损伤的经典RAS与促进心血管健康的非经典RAS激活方面的差异平衡以及(2)RAS信号分子激活的性别差异有关。三个具体目标将检验我们的假设。特异性目的1将验证与男性相比，女性具有更高的非经典RAS表达和激活，从而减轻RAS介导的高血压和肾损伤。我们将测量雄性和雌性自发性高血压大鼠（SHR）和正常大鼠（WKY）在基线和RAS刺激后经典和非经典RAS成分的表达水平。我们将测量血压，以确定女性SHR中非经典RAS激活的增加是否可以解释(1)女性对RAS激活和血压的不平衡以及(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中很重要。特异性目的2将验证与男性SHR相比，女性SHR在肾皮质具有更高的ras刺激的一氧化氮（NO）生物利用度的假设。一氧化氮是肾脏健康的重要调节因子。我们将确定RAS在男性和女性SHR中调节NO生物利用度的能力。我们将测量血压，以确定ras介导的NO是否导致L-NAME高血压的性别差异。特异性Aim 3将验证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、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介导的高血压和肾损伤中的作用。这些研究可能为开发更个性化和更有效的治疗方案提供基础科学框架，用于治疗高血压和预防男性和女性慢性肾脏疾病。公共卫生相关性：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血压，女性比男性更容易出现血压失控。肾素-血管紧张素系统（RAS）是控制血压的关键系统。该研究项目将获得有关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。