Sex differences in solute transport along the nephrons: effects of Na<sup>+</sup>transport inhibition
Rui Hu, Alicia A. McDonough, Anita T. Layton
Abstract
Each day, ~1.7 kg of NaCl and 180 liters of water are reabsorbed by nephron segments in humans, with urinary excretion fine tuned to meet homeostatic requirements. These tasks are coordinated by a spectrum of renal Na + transporters and channels. The goal of the present study was to investigate the extent to which inhibitors of transepithelial Na + transport (T Na ) along the nephron alter urinary solute excretion and how those effects may vary between male and female subjects. To accomplish that goal, we developed sex-specific multinephron models that represent detailed transcellular and paracellular transport processes along the nephrons of male and female rat kidneys. We simulated inhibition of Na + /H + exchanger 3 (NHE3), bumetanide-sensitive Na + -K + -2Cl − cotransporter (NKCC2), Na + -Cl − cotransporter (NCC), and amiloride-sensitive epithelial Na + channel (ENaC). NHE3 inhibition simulations predicted a substantially reduced proximal tubule T Na , and NKCC2 inhibition substantially reduced thick ascending limb T Na . Both gave rise to diuresis, natriuresis, and kaliuresis, with those effects stronger in female rats. While NCC inhibition was predicted to have only minor impact on renal T Na , it nonetheless had a notable effect of enhancing excretion of Na + , K + , and Cl − , particularly in female rats. Inhibition of ENaC was predicted to have opposite effects on the excretion of Na + (increased) and K + (decreased) and to have only a minor impact on whole kidney T Na . Unlike inhibition of other transporters, ENaC inhibition induced stronger natriuresis and diuresis in male rats than female rats. Overall, model predictions agreed well with measured changes in Na + and K + excretion in response to diuretics and Na + transporter mutations.