Nasci Victoria L, Benjamin Jazmine I, Fetter Rebecca C, Stock Joseph M, Romberger Nathan T, Watso Joseph C, Babcock Matthew C, Wenner Megan M, Robinson Austin T, Gohar Eman Y
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States.
Department of Kinesiology, East Carolina University, Greenville, North Carolina, United States.
Am J Physiol Regul Integr Comp Physiol. 2025 Sep 1;329(3):R487-R494. doi: 10.1152/ajpregu.00119.2025. Epub 2025 Aug 19.
Hypertension is more prevalent in males than age-matched premenopausal females. Average sodium intake in the United States is higher than recommended and is a risk factor for developing hypertension. Sex differences in renal sodium homeostasis may underlie sex differences in hypertension prevalence. For example, renal endothelin-1 (ET-1) plays a key role in the maintenance of blood pressure and sodium homeostasis. Previous rodent studies demonstrate that females excrete higher urinary ET-1 compared with males, and increasing dietary sodium promotes urinary ET-1 excretion only in male rats. However, the impact of sex on sodium and renal ET-1 signaling in humans is unclear. Therefore, we aimed to determine whether the renal ET-1 system responds differently to salt loading in male and female human research participants. To test our hypothesis, normotensive salt-resistant male and female participants were administered a low (1 g/day), recommended (2.3 g/day), and high (7 g/day) sodium diet for 10 days each in random order. The 24-h urine samples were collected and assessed for sodium and ET-1. Following increased dietary sodium, both males and females increased urinary sodium excretion (diet: < 0.001). Following increased dietary sodium, participants exhibited an increased urinary ET-1 excretion (diet: = 0.038). Interestingly, post hoc testing revealed that only females displayed an increase in ET-1 excretion (recommended vs. high sodium, = 0.009). Overall, the current human study provides novel insights into potential sex-specific modulation of ET-1 and renal responses to dietary sodium. Further investigations are warranted to understand the underlying molecular mechanisms driving sex-related differences in renal ET-1 signaling and sodium handling. To our knowledge, this is the first human study detailing sex differences in the renal endothelin-1 (ET-1) system in response to increasing sodium diets. We found that increasing dietary sodium intake increases urinary ET-1 excretion, an effect that appeared to be specific to females, not males. These data highlight important sex differences in a key natriuretic mechanism, potentially modulating sex differences in the prevalence of hypertension. Further studies are needed to confirm our findings and provide mechanistic insight.
高血压在男性中比年龄匹配的绝经前女性更为普遍。美国的平均钠摄入量高于推荐水平，是患高血压的一个风险因素。肾钠稳态的性别差异可能是高血压患病率性别差异的潜在原因。例如，肾内皮素-1（ET-1）在维持血压和钠稳态中起关键作用。先前的啮齿动物研究表明，与雄性相比，雌性排泄的尿ET-1更高，并且增加饮食中的钠仅在雄性大鼠中促进尿ET-1排泄。然而，性别对人类钠和肾ET-1信号传导的影响尚不清楚。因此，我们旨在确定肾ET-1系统在男性和女性人类研究参与者中对盐负荷的反应是否不同。为了检验我们的假设，血压正常且耐盐的男性和女性参与者被随机给予低（1克/天）、推荐（2.3克/天）和高（7克/天）钠饮食，每种饮食持续10天。收集24小时尿液样本并评估其中的钠和ET-1。饮食中钠增加后，男性和女性的尿钠排泄均增加（饮食：<0.001）。饮食中钠增加后，参与者的尿ET-1排泄增加（饮食：=0.038）。有趣的是，事后检验显示只有女性的ET-1排泄增加（推荐钠饮食与高钠饮食相比，=0.009）。总体而言，当前的人体研究为ET-1的潜在性别特异性调节以及肾对饮食中钠的反应提供了新的见解。有必要进行进一步的研究以了解驱动肾ET-1信号传导和钠处理中性别相关差异的潜在分子机制。据我们所知，这是第一项详细描述肾内皮素-1（ET-1）系统在应对增加的钠饮食时性别差异的人体研究。我们发现增加饮食中的钠摄入量会增加尿ET-1排泄，这种效应似乎对女性而非男性具有特异性。这些数据突出了一种关键利钠机制中的重要性别差异，可能调节高血压患病率的性别差异。需要进一步的研究来证实我们的发现并提供机制性见解。
