Acclimation to a High‐Salt Diet Is Sex Dependent

BACKGROUND: Premenopausal women are less likely to develop hypertension and salt‐related complications than are men, yet the impact of sex on mechanisms regulating Na(+) homeostasis during dietary salt challenges is poorly defined. Here, we determined whether female rats have a more efficient capacity to acclimate to increased dietary salt intake challenge. METHODS AND RESULTS: Age‐matched male and female Sprague Dawley rats maintained on a normal‐salt (NS) diet (0.49% NaCl) were challenged with a 5‐day high‐salt diet (4.0% NaCl). We assessed serum, urinary, skin, and muscle electrolytes; total body water; and kidney Na(+) transporters during the NS and high‐salt diet phases. During the 5‐day high‐salt challenge, natriuresis increased more rapidly in females, whereas serum Na(+) and body water concentration increased only in males. To determine if females are primed to handle changes in dietary salt, we asked the question whether the renal endothelin‐1 natriuretic system is more active in female rats, compared with males. During the NS diet, female rats had a higher urinary endothelin‐1 excretion rate than males. Moreover, Ingenuity Pathway Analysis of RNA sequencing data identified the enrichment of endothelin signaling pathway transcripts in the inner medulla of kidneys from NS‐fed female rats compared with male counterparts. Notably, in human subjects who consumed an Na(+)‐controlled diet (3314–3668 mg/day) for 3 days, women had a higher urinary endothelin‐1 excretion rate than men, consistent with our findings in NS‐fed rats. CONCLUSIONS: These results suggest that female sex confers a greater ability to maintain Na(+) homeostasis during acclimation to dietary Na(+) challenges and indicate that the intrarenal endothelin‐1 natriuretic pathway is enhanced in women.