Sexual dimorphisms in mechanisms of pressure natriuresis

Aim: 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 impact of sex on pressure- natriuresis mechanisms. Methods: In anesthetized 8-10 week 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 (IHC) were determined. A subset received 1-aminobenzotriazole (ABT) to inhibit cytochrome P450-derived arachidonic acid metabolites. Results. At baseline, females (vs. males) exhibited lower baseline 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 NHE3 and NaPi2 out of microvilli, and, by immunoblot, greater abundance of cortical NHE3p in both sexes (indicating less PT reabsorption), less medullary NHE3 and NKCC2 in females, and less distal NCC in males. ABT provoked leftward-shift in renal function curve in both sexes, and 2-fold higher natriuresis in males. Conclusion: 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.