Endothelin mediates sex-differences in acclimation to high salt diet in rats

Abstract

Introduction Current understanding of sodium (Na+) handling is based on studies done primarily in males. Contrary to the gradual increase in high salt (HS) induced natriuresis over 3–5 days in males, female Sprague Dawley (SD) rats have a robust natriuresis after 1 day of HS. Renal endothelin-1 (ET-1) signaling, through ET receptor A and B, is an important natriuretic pathway and was implicated in our previous dietary salt acclimation studies, however, the contribution of ET receptors to sex-differences in acclimation to dietary Na+ challenges has yet to be clarified. We hypothesized that ET receptors mediate the augmented natriuretic capacity of female rats in response to a HS diet. Methods To test our hypothesis, male and female SD rats were implanted with telemeters and randomly assigned to treatment with A-182086, a dual ETA and ETB receptor antagonist, or control. 24-h urine samples were collected and assessed for electrolytes and ET-1. Studies were performed on a normal salt (NS, 0.3% NaCl) diet and after challenging rats with HS (4% NaCl) diet for 1 day. Results We found that A-182086 increased blood pressure in male and female SD rats fed either diet. Importantly, A-182086 eliminated sex-differences in natriuresis on NS and HS. In particular, A-182086 promotes HS-induced natriuresis in male rats rather than attenuating the natriuretic capacity of females. Further, the sex-difference in urinary ET-1 excretion in NS-fed rats was eliminated by A-182086. Conclusion In conclusion, ET receptors are crucial for mediating sex-difference in the natriuretic capacity primarily through their actions in male rats.

Comprehensive analysis of the endothelin system in the kidneys of mice, rats, and humans

“…However, qualitatively, female mice had a greater intensity of epithelial ET-1 immunoreactivity and this agrees with previously published studies which demonstrated that kidney ET-1 production is enhanced in female rats and women [ 51 ]. It is hypothesized that in female/women greater kidney ET-1 promotes efficient return to sodium balance and buffers blood pressure in response to high dietary salt intake [ 51 , 60 , 61 ].…”

The Role of Human and Animal Monocytes and Macrophages in Homeostasis and Disease

“…These findings are highly significant as mosquito-borne arboviruses represent a significant threat to humans worldwide; they are also surprising because endothelins are vasoconstrictors, and thus regulate blood flow [11]. However, peptide endothelin signaling may have many other functions, such as the recently discovered regulation of sex differences in salt balance management and the kidney response to high salt intake [12]. In this Special Issue, Makjaroen et al describe how lipopolysaccharide (LPS) tolerance might increase susceptibility to secondary infection and/or viral reactivation, and that, in cases of LPS tolerance, macrophages have reduced glycolysis and mitochondrial activities, decreased anti-viral responses, and a down-regulation of anti-viral genes, such as Mx1 and Isg15.…”