Acclimation to a High‐Salt Diet Is Sex Dependent

Abstract

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.

G protein-coupled estrogen receptor 1 regulates renal endothelin-1 signaling system in a sex-specific manner

“…Our results revealed sex and genotypic differences in urinary ET-1 excretion ( Figure 3 ). Among WT mice, females excreted significantly more ET-1 compared to males ( Figure 3 ), which is consistent with recent reports in rats and humans ( Gohar et al, 2022 ). Interestingly, female GPER1 KO mice excreted significantly lower levels of urinary ET-1 compared to female WT littermates ( Figure 3 ), suggesting that GPER1 contributes to the sex difference in urinary ET-1 excretion.…”

“…In outer and inner medullary tissues, female mice regardless of their genotype have increased ET-1 peptide content than males. These results support previous evidence (Nakano and Pollock, 2009;Jin et al, 2013;Johnston et al, 2016;Gohar et al, 2020;Gohar et al, 2022) that females have greater ET-1 activity than males. Furthermore, our results reveal that GPER1 deletion increases outer medullary ET-1 mRNA expression and ET-1 protein content in females but not males.…”

“…Male-female differences in renal ET-1 signaling have been observed in a wide range of studies ( Nakano and Pollock, 2009 ; Jin et al, 2013 ; Johnston et al, 2016 ; Gohar et al, 2020 ; Gohar et al, 2022 ). Ovary-intact female, but not male or OVX female, rats have been shown to utilize ET A receptors to induce natriuresis while being fed a high salt diet ( Nakano and Pollock, 2009 ).…”

Sex Differences in Diurnal Sodium Handling During Diet-Induced Obesity in Rats

“…Prior studies in both rats and humans have demonstrated that females are more efficiently and rapidly able to excrete an acute salt load. 35,36 Gohar et al 36 recently reported that female rats can acclimate to HS diets more rapidly than males along with evidence for additional mechanisms for achieving salt balance compared with males.…”

Uncovering the Complexities of Salt Sensitivity

“…Furthermore, other models of salt sensitivity show that males have a more severe phenotype to high salt diets and so this highlights the complexity and wider array of mechanisms that contribute to the mechanisms of sodium homeostasis. 9 , 10 …”