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.