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.

高血压仍然是一个主要的公共卫生挑战，尽管有丰富的可用的治疗方法， 选项.治疗不当和患者不依从是导致血液不良的主要因素 压力（BP）控制。确定特定患者队列中血压升高的机制 对有效防治高血压和相关疾病至关重要。通过上皮细胞的过度钠潴留 钠通道（ENaC）阻碍肾脏对钠平衡进行精确调节的能力，是一种代谢性疾病。 高血压的常见致病决定因素。累积的证据表明，生物性别是一个 影响人群中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的概念，即肾脏钠重吸收的调节， 肾血压控制依赖于性别特异性机制，在醛固酮敏感性远端ENaC活性 肾单位我们和其他人先前已经表明醛固酮拮抗盐皮质激素受体 (MR)抑制剂不足以降低过度的肾脏ENaC活性，并且不能有效地降低男性的BP 啮齿类动物血管紧张素II（血管紧张素II）依赖性高血压。我们的初步实验表明，高血压 患有盐敏感性和血管紧张素依赖性高血压的雌性大鼠受益于MR拮抗作用， 与男性相比，BP降低更强。MR阻滞在降低肾功能方面也更有效。 ENaC活性在血管紧张素II输注雌性大鼠比雄性。我们的研究结果强烈表明，肾敏感性 ENaC对醛固酮是一种未被认识的慢性血压调节的性别特异性机制。该提案 建立在ENaC对醛固酮的超敏反应是ENaC与醛固酮结合的主要原因这一中心假设的基础上。 与雄性大鼠相比，醛固酮对高血压雌性大鼠肾脏血压控制的作用。我们提出 用两个互补的具体目标来检验假设，以解决临床相关问题， 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脏ENaC对醛固酮的敏感性高于雄性大鼠。我们 一种假说预测，女性性类固醇积极调节肾脏中的MR依赖性信号传导， 增强女性高血压患者ENaC对醛固酮的反应。目标2将检验以下假设： 在雌性高血压大鼠中，醛固酮主导肾血压控制，但在雄性大鼠中不主导肾血压控制。我们的假设预测 醛固酮-MR轴是女性高血压和肾损害的主要驱动因素， 在降低女性高血压患者的血压和肾损伤方面比男性更有效。 成功地完成这项建议将区分的病理生理机制，管理钠· 保留在高血压男性和女性，并提供缺失的临床前证据，以优化 MR拮抗剂在两性高血压患者中的应用。