Role of the renin-angiotensin system in sexual dimorphisms in the development of

肾素-血管紧张素系统在性二态性发育中的作用

• 批准号: 7851391
• 负责人: Jennifer C Sullivan
• 金额: $ 36.75万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7851391
• 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; Role; 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; public health relevance; receptor; receptor expression; research study; response; sex; sexual dimorphism; 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; Role; 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; public health relevance; 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）：在联合国各州，高血压以及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血压，女性比男性更有可能无法控制的血压。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的最常见的药物之一，尽管可用的数据表明RAS抑制作用并未赋予男性和男性的心脏肾脏益处。该提案的目的是确定分子机制，通过这些机制激活和抑制RAS调节女性和男性的高血压和肾脏损伤。我们假设对RAS激活和抑制功能反应的性别差异与（1）女性和雄性在激活中的差异平衡有关，经典RAS激活，从而诱导高血压和肾脏损伤，与非经典性RAS相关，而非经典性RA，该RAS促进了心血管健康，以及（2）性别差异。三个具体目标将检验我们的假设。具体的目标1将检验以下假设：与男性相比，女性具有更大的表达和激活，这会减弱Ras介导的高血压和肾脏损伤。我们将在基线时测量经典和非经典RAS成分的表达水平，并在男性和女性自发性高血压大鼠（SHR）以及正常的大鼠（WKY）中的RAS刺激后进行测量。我们将测量血压，以确定女性SHR中的非经典RAS激活是否增加了（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对RAS刺激的肾脏的敏感性，因为肾脏对长期控制血压很重要。具体目标2将检验以下假设：与雄性SHR相比，肾皮质中雌性SHR具有更大的RAS刺激的一氧化氮（NO）生物利用度。否是肾脏健康的重要调节者。我们将确定RAS在男性和女性SHR中不调节无生物利用度的能力。我们将测量血压，以确定RAS介导的是否没有促进L-NAME高血压的性别差异。具体目标3将检验以下假设：AT1激活会导致男性和雌性SHR肾脏皮层中不同信号分子的产生，重点是超氧化物，转化生长因子2，以及Janus激酶/信号转录器和转录的激活剂。我们将确定RAS激活对男性和女性SHR肾皮质中这些因素水平的影响，以及它们对RAS介导的高血压和肾脏损伤的贡献。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选择，以治疗男性和女性的高血压和预防慢性肾脏疾病。公共卫生相关性：在联合国各州，高血压以及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血压，女性比男性更有可能无法控制的血压。肾素 - 血管紧张素系统（RAS）是控制血压的关键系统。该研究项目将获取有关男性和女性疾病进展的分子机制的新信息，有可能解释为什么传统治疗在女性中可能不如男性有效，并且（2）有助于发展为高血压治疗的更有效的治疗选择，以治疗高血压和预防男性和女性慢性肾脏疾病。