Sodium intake and biological sex influence urinary endothelin-1 in salt-resistant adults: a pilot study

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: P < 0.001). Following increased dietary sodium, participants exhibited an increased urinary ET-1 excretion (diet: P = 0.038). Interestingly, post hoc testing revealed that only females displayed an increase in ET-1 excretion (recommended vs. high sodium, P = 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.NEW & NOTEWORTHY 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.