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: 8484865
• 负责人: Jennifer C Sullivan
• 金额: $ 35.11万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8484865
• 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.

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。

项目成果

Hemodynamic responses to acute angiotensin II infusion are exacerbated in male versus female spontaneously hypertensive rats.

与雌性自发性高血压大鼠相比，雄性自发性高血压大鼠对急性血管紧张素 II 输注的血流动力学反应加剧。

• 发表时间: 2016-01
• 影响因子: 2.5
• 作者: Elmarakby, Ahmed A;Bhatia, Kanchan;Crislip, Ryan;Sullivan, Jennifer C
• 通讯作者: Sullivan, Jennifer C

Female sex hormones protect against salt-sensitive hypertension but not essential hypertension.

女性性激素可以预防盐敏感性高血压，但不能预防原发性高血压。

• DOI: 10.1152/ajpregu.00061.2014
• 发表时间: 2014-07-15
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Krystal N. Brinson;O. Rafikova;J. Sullivan
• 通讯作者: J. Sullivan

Use of ultrasound to assess renal reperfusion and P-selectin expression following unilateral renal ischemia.

使用超声评估单侧肾缺血后的肾再灌注和 P-选择素表达。

• DOI: 10.1152/ajprenal.00406.2012
• 发表时间: 2012-11-01
• 期刊: American journal of physiology. Renal physiology
• 作者: Erika I Boesen;G. Crislip;Jennifer C Sullivan
• 通讯作者: Jennifer C Sullivan

Sex differences in angiotensin-converting enzyme modulation of Ang (1-7) levels in normotensive WKY rats.

正常血压 WKY 大鼠中血管紧张素转换酶调节 Ang (1-7) 水平的性别差异。

• 发表时间: 2013-05
• 影响因子: 3.2
• 作者: Bhatia, Kanchan;Zimmerman, Margaret A;Sullivan, Jennifer C
• 通讯作者: Sullivan, Jennifer C

Sex differences in blood pressure control: are T lymphocytes the missing link?

血压控制的性别差异：T 淋巴细胞是缺失的一环吗？

• 发表时间: 2014-08
• 作者: Tipton, Ashlee J;Sullivan, Jennifer C
• 通讯作者: Sullivan, Jennifer C