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: 10298925
• 负责人: Mykola Mamenko
• 金额: $ 45.62万
• 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/10298925
• 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; Immunoblotting; 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; Woman; artery infusion; biological sex; 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; improved; inhibitor/antagonist; 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.

尽管可用的治疗抽象，但在全球范围内，高血压仍然是全球的主要公共卫生挑战 选项。不当治疗和患者不合规是血液不良的主要因素 压力（BP）控制。识别负责特定患者队列中BP升高的机制 对于有效打击高血压和相关疾病至关重要。通过上皮过多的钠保留 NA•通道（ENAC）阻碍了肾脏对钠平衡进行精确调整的能力，并且是 高血压的常见致病决定因素。累积证据表明生物性别是 关键协方差影响人口中高血压的发展和病理生理学，并 动物模型。我们的建议介绍了一个新颖的概念，该概念调节NA•肾脏中的重吸收和 肾脏BP控制依赖于对醛固酮敏感的ENAC活性的性别特异性机制 肾单位。我们和其他人先前已经表明醛固酮与矿物皮质激素接收器的拮抗作用 （MR）抑制剂不足以减少过量的肾脏ENAC活性，并且无法有效地减弱男性的BP 具有血管紧张素II（Angil）依赖性高血压的啮齿动物。我们的飞行员实验表明高血压 雌性对盐敏感和依赖Angil的高血压的雌性大鼠受益于MR拮抗作用，并表现出A 与男性相比，BP降低更强。 MR BLOCKADE在减少肾脏方面也具有更大的潜力 Ang II注入的雌性大鼠的ENAC活性比男性中的ENAC活性。我们的发现强烈表明肾脏的敏感性 醛固酮的ENAC是慢性BP调节的一种未识别的性别特异性机制。该提议是 建立围绕中心假设，即ENAC对醛固酮的超敏反应占了普遍性 与男性相比，醛固酮对高血压雌性大鼠的肾脏BP控制的贡献。我们建议 用两个完整的特定目的检验假设，以解决临床相关的问题 分子，细胞（AIM 1）和综合{AIM 2）水平的血压控制。 AIM 1将测试 假设肾脏对醛固酮的敏感性在高血压雌性大鼠中比男性更大。我们的 假设预测女性性别立体素会对肾脏中MR依赖性信号的正相依赖于 增强ENAC对高血压女性中醛固酮的反应。 AIM 2将检验以下假设 醛固酮主导了高血压女性的肾脏BP控制，但在雄性大鼠中不主导。我们的假设预测 该醛固酮MR轴是女性高血压和肾脏损伤的主要驱动力和MR拮抗作用 与男性相比，在减少高血压女性的BP和肾脏损伤方面，将更有效。 该提案的成功完成将区分有关NA的病理生理机制• 在高血压男性和女性中保留，并提供缺失的临床前证据以优化 在两性高血压患者中使用MR拮抗剂。