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

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 isoform 3 (NHE3) to the base of the microvilli, reducing activated forms of the distal NaCl cotransporter (NCC) and epithelial Na+ channel (ENaC). Males (M) and females (F) on normal-salt (NS) diet present sex-specific profiles of "transporters" (cotransporters, channels, pumps, and claudins) along the nephron, e.g., F exhibit 40% lower NHE3 and 200% higher NCC abundance than M. We tested the hypothesis that adaptations to HS diet along the nephron will, likewise, exhibit sexual dimorphisms. C57BL/6J mice were fed for 15 days with 4% NaCl diet (HS) versus 0.26% NaCl diet (NS). On HS, M and F exhibited normal plasma [Na+] and [K+], 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.