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

尽管有大量可用的治疗方法，但高血压仍然是全球公共卫生的主要挑战 选择。治疗不当和患者不依从是导致血液质量差的主要因素。 压力(BP)控制。确定特定患者队列中引起血压升高的机制 对于有效抗击高血压和相关疾病至关重要。过多的钠通过上皮细胞滞留 钠通道(ENaC)阻碍了肾脏对钠平衡的精确调节能力，是一种 高血压的常见致病决定因素。累积的证据表明，生物性行为是一种 影响人群高血压发展和病理生理学的关键协变量和 动物模型。我们的建议引入了一个新的概念，即调节肾脏和肾脏中的Na·重吸收 肾性血压控制依赖于调节醛固酮敏感末端ENaC活动的性别特异性机制 尼龙。我们和其他人之前已经证明了醛固酮与盐皮质激素受体的拮抗作用 (MR)抑制剂不足以降低过度的肾脏ENaC活性，也不能有效地降低男性的BP 患有血管紧张素II依赖性高血压的啮齿类动物。我们的初步实验表明，高血压 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，并表现出 与男性相比，更强的降压作用。MR BLOCKADE在减少肾脏方面也更有效 注射血管紧张素Ⅱ的雌性大鼠的ENAC活性高于雄性大鼠。我们的发现有力地表明，肾脏的敏感性 ENAC对醛固酮的作用是一种未知的性别特异性慢性血压调节机制。该提案是 建立在一个中心假设上，即ENaC对醛固酮的超敏反应是普遍存在的 与雄性相比，醛固酮对高血压雌性大鼠肾脏血压控制的贡献。我们建议 用两个互补的特定目标来检验假设，以解决与临床相关的适合性问题 在分子、细胞和综合水平上控制血压。目标1将测试 假设高血压雌性大鼠肾脏ENaC对醛固酮的敏感性大于雄性大鼠。我们的 假说预测，女性类固醇正向调节肾脏中MR依赖的信号，以 增强高血压女性ENaC对醛固酮的反应。目标2将检验这一假设 在雌性高血压大鼠中，醛固酮对肾脏血压的控制起主导作用，而在雄性大鼠中则不起作用。我们的假设预测 醛固酮-MR轴是女性高血压和肾脏损害的主要驱动因素，并与MR拮抗 在降低女性高血压患者的血压和肾脏损伤方面将比男性患者有效得多。 这一提议的成功完成将区分Na·的病理生理机制。 高血压男性和女性的保留，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应用。

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.