Sex-specific adaptations to high-salt diet preserve electrolyte homeostasis with distinct sodium transporter profiles

Abstract

Kidneys continuously filter an enormous amount of sodium and adapt kidney Na+ reabsorption to match Na+ intake to maintain circulatory volume and electrolyte homeostasis. Males (M) respond to high salt (HS) diet by translocating proximal tubule Na+/H+ exchanger 3 (NHE3) to the base of the microvilli, reducing activated forms of the distal NaCl cotransporter (NCC) and epithelial Na+ channel (ENaC). Males and females (M, F) on normal salt (NS) diets present sex-specific profiles of "transporters" (co-transporters, channels, pumps and claudins) along the nephron, e.g., F exhibit 40% lower NHE3 and 200% higher NCC abundance vs. M. We tested the hypothesis that adaptations to HS diet along the nephron will, likewise, exhibit sexual dimorphisms. C57BL/6J mice were fed 15 d with 4% NaCl diet (HS) vs. 0.26% NaCl diet (NS). On HS, M and F exhibited normal plasma [Na+] and [K+], and similar urine volume, Na+, K+, and osmolal excretion rates normalized to body weight. In F, like M, HS lowered abundance of distal NCC, phosphorylated NCC, and cleaved (activated) forms of ENaC. The adaptations associated with achieving electrolyte homeostasis exhibit sex-dependent and independent mechanisms: Sex differences in baseline "transporters" abundance persist during HS diet, yet the fold changes during HS diet (normalized to NS) are similar along the distal nephron and collecting duct. Sex dependent differences observed along the proximal tubule during HS show that female kidneys adapt differently from patterns reported in males yet achieve and maintain fluid and electrolyte homeostasis.

Dietary sodium enhances the expression of SLC4 family transporters, IRBIT, L-IRBIT, and PP1 in rat kidney: Insights into the molecular mechanism for renal sodium handling

“…Consistently, knocking-out I-1 substantially decreases the phoshorylation level of NCC in mouse kidney ( Picard et al, 2014 ; Penton et al, 2019 ). In the present study, we show that the renal abundance of pNCC (phosphorylated NCC) is decreased under high sodium intake, an observation consistent with previous studies ( Shao et al, 2021 ; Torres-Pinzon et al, 2021 ). This decrease in pNCC is likely attributable to the increased expression of PP1.…”

“…Moreover, the relative abundance of pNCC in rat kidney was significantly negatively correlated with dietary sodium level by regression analysis (r 2 = 0.353, p = 0.0003). Our data are consistent with the previous study on mice (Torres-Pinzon et al, 2021).…”

“…Phosphorylation increases the activity of NCC ( Glover et al, 2010 ). Others have shown that high-salt diet decreases the abundance of phosphorylated NCC (pNCC) in mouse kidney ( Torres-Pinzon et al, 2021 ). Shown in Figure 5F are representative Western blots for the expression of pNCC in rat kidney.…”

Hypertension and human immunodeficiency virus: A paradigm for epithelial sodium channels?

“…High dietary sodium consumption may contribute to gut dysbiosis by altering the gut microbial composition, and inducing an inflammatory response which alters the gut anatomy ( 197 ), and is associated with increased immunogenic IsoLG-adduct formation responsible for salt-sensitivity and upregulation of ENaC ( 61 , 198 ), and women have been reported to be more sensitive to salt ( 188 , 189 ). The group by McDonough et al reported that in mice, sodium channels in the kidney demonstrate a sex-specific adaptation to high-salt diet that ultimately preserve electrolyte homeostasis ( 199 ). Several sodium transporters along the nephron (Na+/H+exchanger 3 (NHE3), bumetanide-sensitive Na + -K + -2Cl cotransporter (NKCC2), Na + -Cl – cotransporter (NCC), and the ENaC) play specific roles in the ultimate maintenance of electrolyte homeostasis and changes in the activity of one may affect the expression and activity of the other transporters ( 200 – 202 ).…”

Circadian Gene Expression in Mouse Renal Proximal Tubule

“…Aside from the experimental variable of interest, there are many potential confounding variables that could influence the interpretation of results. For example, the sex of the animal can have an important influence on certain physiological functions and gene expression (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Other important variables include the age of the animals under study, diet, and the time of day when the observations are made.…”