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.

尽管有大量可用的治疗方法，高血压仍然是世界范围内的一个主要公共卫生挑战