Sex disparities in aldosterone-dependent renal Na+ transport and blood pressure control

醛固酮依赖性肾钠转运和血压控制的性别差异

• 批准号: 10461199
• 负责人: Mykola Mamenko
• 金额: $ 39.52万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-03 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10461199
• 关键词: Accounting; Address; Adult; Affect; Albuminuria; Aldosterone; Aldosterone Antagonists; Amiloride; Angiotensin II; Animal Model; Animals; Antihypertensive Agents; Area; Attenuated; Automobile Driving; Blood Pressure; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Chronic; Clinical; Data; Development; Disease; Distal; Dose; Equilibrium; Excretory function; Exhibits; Female; Functional disorder; Genomics; Gonadal Steroid Hormones; Human; Hypersensitivity; Hypertension; Inflammation; Infusion procedures; Injury to Kidney; Intervention; Investigation; Kidney; Kidney Diseases; Knowledge; Link; Measures; Mediating; Microscopy; Mineralocorticoid Receptor; Molecular; Mus; Natriuretic Peptides; Nephrons; Outcome; Pathogenicity; Pathology; Pathway interactions; Patient Noncompliance; Patients; Population; Production; Public Health; Quantitative Reverse Transcriptase PCR; Randomized; Rattus; Receptor Inhibition; Regulation; Risk; Rodent; Safety; Sex Differences; Signal Transduction; Sodium; Testing; Therapeutic; Treatment Efficacy; Western Blotting; Woman; antagonist; artery infusion; biological sex; blood pressure control; blood pressure elevation; blood pressure reduction; blood pressure regulation; cardiovascular risk factor; clinically relevant; cohort; combat; decubitus ulcer; epithelial Na+ channel; experimental study; female sex hormone; hypertension treatment; hypertensive; improved; inhibitor; male; men; modifiable risk; non-genomic; novel; pre-clinical; premature; receptor expression; renal artery; renal damage; renal epithelium; response; reuptake; salt sensitive; sex; sex disparity; treatment strategy

Hypertension remains a major public health challenge worldwide despite the abundance of available therapeutic options. Inappropriate therapy and patient non-compliance are the main factors accounting for poor blood pressure (BP) control. Identification of the mechanisms responsible for elevation of BP in specific patient cohorts is critical to effectively combat hypertension and related diseases. Excessive sodium retention via the Epithelial Na• Channel (ENaC) hampers the ability of the kidney to make precise adjustments to sodium balance and is a common pathogenic determinant of hypertension. Cumulative evidence suggests that biological sex is a pivotal covariate affecting the development and pathophysiology of hypertension in the human population and animal models. Our proposal introduces a novel concept that regulation of Na• reabsorption in the kidney and renal BP control rely on sex-specific mechanisms governing ENaC activity in the aldosterone-sensitive distal nephron. We and others have previously shown that aldosterone antagonism with mineralocorticoid receptor (MR) inhibitors is insufficient to reduce excessive renal ENaC activity and fails to effectively attenuate BP in male rodents with angiotensin II (Angil) dependent hypertension. Our pilot experiments reveal that hypertensive female rats with salt-sensitive and Angil-dependent hypertension benefit from MR antagonism and exhibit a stronger BP reduction, when compared to males. MR blockade is also much more potent at decreasing renal ENaC activity in Ang II-infused female rats than in males. Our findings strongly suggest that sensitivity of renal ENaC to aldosterone is an unrecognized sex-specific mechanism of chronic BP regulation. The proposal is built around the central hypothesis that hypersensitivity of ENaC to aldosterone accounts for a prevalent contribution of aldosterone to renal BP control in hypertensive female rats, when compared to males. We propose to test the hypothesis with two complementary specific aims addressing a clinically relevant problem of adequate blood pressure control at the molecular, cellular {Aim 1) and integrative {Aim 2) levels. Aim 1 will test the hypothesis that sensitivity of renal ENaC to aldosterone is greater in hypertensive female rats than in males. Our hypothesis predicts that female sex steroids positively modulate MR-dependent signaling in the kidney to augment the response of ENaC to aldosterone in hypertensive females. Aim 2 will test the hypothesis that aldosterone dominates renal BP control in hypertensive female, but not in male, rats. Our hypothesis predicts that aldosterone-MR axis is the primary driver of hypertension and renal damage in females and MR antagonism will be dramatically more effective at reducing BP and renal injury in hypertensive females than in males. Successful completion of this proposal will differentiate the pathophysiological mechanisms governing Na• retention in hypertensive males and females and provide the missing pre-clinical evidence to optimize the use of MR antagonists in hypertensive patients of both sexes.

尽管有丰富的可用治疗方法，高血压仍然是全世界主要的公共卫生挑战 选项。治疗不当和患者不依从是造成血液不良的主要原因 压力（BP）控制。确定特定患者群体血压升高的机制 对于有效对抗高血压及相关疾病至关重要。通过上皮细胞的钠潴留过多 Na• 通道 (ENaC) 会​​阻碍肾脏精确调节钠平衡的能力，并且是一种 高血压的常见致病决定因素。累积的证据表明，生物性别是 影响人群高血压发展和病理生理学的关键协变量 动物模型。我们的建议引入了一个新概念，即调节肾脏中的Na•重吸收和 肾血压控制依赖于控制醛固酮敏感远端 ENaC 活性的性别特异性机制 肾单位。我们和其他人之前已经证明醛固酮与盐皮质激素受体具有拮抗作用 (MR) 抑制剂不足以降低过度的肾 ENaC 活性，并且无法有效降低男性血压 患有血管紧张素 II (Angil) 依赖性高血压的啮齿动物。我们的试点实验表明，高血压 患有盐敏感性和Angil依赖性高血压的雌性大鼠受益于MR拮抗作用并表现出 与男性相比，血压降低幅度更大。 MR 阻滞剂在降低肾功能方面也更有效。 注入 Ang II 的雌性大鼠中的 ENaC 活性高于雄性大鼠。我们的研究结果强烈表明肾的敏感性 ENaC 转化为醛固酮是一种尚未认识到的慢性血压调节的性别特异性机制。该提案是 围绕以下中心假设建立：ENaC 对醛固酮的超敏反应是一种普遍存在的原因。 与雄性相比，醛固酮对雌性高血压大鼠肾脏血压控制的贡献。我们建议 通过两个互补的特定目标来检验假设，解决临床相关的足够问题 在分子、细胞（目标 1）和综合（目标 2）水平上控制血压。目标 1 将测试 假设高血压雌性大鼠肾 ENaC 对醛固酮的敏感性高于雄性。我们的 假设预测女性性类固醇会积极调节肾脏中 MR 依赖性信号传导，从而 增强 ENaC 对高血压女性醛固酮的反应。目标 2 将检验以下假设： 醛固酮在雌性高血压大鼠中主导肾脏血压控制，但在雄性大鼠中则不然。我们的假设预测 醛固酮-MR 轴是女性高血压和肾损伤以及 MR 拮抗作用的主要驱动因素 与男性相比，女性高血压患者在降低血压和肾损伤方面效果显着更有效。 该提案的成功完成将区分控制Na•的病理生理机制 保留在高血压男性和女性中，并提供缺失的临床前证据以优化 MR拮抗剂在男女高血压患者中的使用。