Sexual dimorphisms in mechanisms of pressure natriuresis.

The renal pressure-natriuresis response defines the blood pressure set-point and maintains circulating volume. In male rats, the mechanisms involve trafficking and inactivation of renal proximal sodium transporters. Mechanisms may differ in females due to sex differences in transporters along the nephron: lower proximal and higher distal nephron salt reabsorption. We aimed to determine the impact of sex on pressure-natriuresis mechanisms. In anesthetized 8- to 10-wk-old male and female Sprague-Dawley rats, hypertension was induced by vasoconstriction (25 min), and mean arterial pressure, urine excretion, glomerular filtration rate, renal transporters' abundance (immunoblot), and subcellular location [immunohistochemistry (IHC)] were determined. A subset received 1-aminobenzotriazole (ABT) to inhibit cytochrome P450-derived arachidonic acid metabolites. At baseline, females (vs. males) exhibited lower baseline mean arterial pressure (MAP) and, during hypertension, greater sodium excretion at any given pressure, and 1.7-fold higher sodium clearance (P = 0.01). With hypertension, immunofluorescence revealed sex- and transporter-specific redistribution of Na/H exchanger isoform 3 (NHE3) and Na-phosphate cotransporter 2A (NaPi2) out of microvilli, and, by immunoblot, greater abundance of cortical NHE3 phosphorylated at S552 (NHE3p) in both sexes [indicating less proximal tubule (PT) reabsorption], less medullary NHE3 and Na-K-2Cl cotransporter isoform 2 (NKCC2) in females, and less distal Na-Cl cotransporter (NCC) in males. ABT provoked a leftward shift in the renal function curve in both sexes, and twofold higher natriuresis in males. Female Sprague-Dawley rats exhibit a more robust acute pressure-natriuretic response than males, facilitated by baseline sex differences in renal transporter patterns and reduced medullary NHE3 and NKCC2. These female-specific responses augment the pressure-natriuresis response, which may contribute to their lower baseline blood pressure.NEW & NOTEWORTHY Three discoveries contribute to understanding sex differences in blood pressure set-point: 1) females exhibit a greater natriuresis to acute hypertension (aHTN) than males; 2) aHTN provokes sex-specific molecular adaptations along the nephron: proximal NHE3 and NaPi2 redistribute in both sexes; medullary NHE3 and NKCC2 abundance are reduced in females, distal NCC abundance is reduced in males; 3) inhibition of arachidonic acid metabolites shifts renal function curves leftward in both sexes, and augments natriuresis in males.