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）：高血压以及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% 的高血压患者血压未得到控制，女性比男性更容易血压未得到控制。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物之一，尽管现有数据表明 RAS 抑制并不能为女性和男性带来相同程度的心肾益处。本提案的目的是确定 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) 女性和男性在经典 RAS 激活方面的差异平衡有关，这会导致高血压和肾损伤，而非经典 RAS 则会导致高血压和肾损伤。促进心血管健康，(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 将检验以下假设：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) 和正常血压大鼠 (WKY) 的基线和 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 激活的增加是否解释了 (1) 女性 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，因为肾脏对于长期控制血压很重要。具体目标 2 将检验以下假设：与男性 SHR 相比，女性 SHR 在肾皮质中具有更高的 RAS 刺激一氧化氮 (NO) 生物利用度。 NO 是肾脏健康的重要调节剂。我们将确定 RAS 调节男性和女性 SHR 中 NO 生物利用度的能力。我们将测量血压以确定 RAS 介导的 NO 是否会导致 L-NAME 高血压的性别差异。具体目标 3 将检验这样的假设：AT1 激活导致男性和女性 SHR 的肾皮质中产生不同的信号分子，重点是超氧化物、转化生长因子 2 以及 Janus 激酶/信号转导器和转录激活剂。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，以及它们对 RAS 介导的高血压和肾损伤的贡献。这些研究可能提供基础科学框架，以开发更个性化和更有效的治疗方案，用于治疗男性和女性的高血压和预防慢性肾脏病。公众健康相关性：高血压以及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% 的高血压患者血压未得到控制，女性比男性更容易血压未得到控制。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法。治疗男性和女性高血压和预防慢性肾脏病的治疗选择。