Sodium and its associated anions are the major determinant of extracellular fluid volume, and the reabsorption of Na+ by the kidney plays a crucial role in long-term blood pressure control. The goal of this study was to investigate the extent to which inhibitors of transepithelial Na+ transport (TNa) along the nephron alter urinary solute excretion and TNa efficiency and how those effects may vary along different nephron segments. To accomplish that goal, we used the multinephron model developed in the companion study (28). That model represents detailed transcellular and paracellular transport processes along the nephrons of a rat kidney. We simulated the inhibition of the Na+/H+ exchanger (NHE3), the bumetanide-sensitive Na+-K+-2Cl- transporter (NKCC2), the Na+-Cl- cotransporter (NCC), and the amiloride-sensitive Na+ channel (ENaC). Under baseline conditions, NHE3, NKCC2, NCC, and ENaC reabsorb 36, 22, 4, and 7%, respectively, of filtered Na+ The model predicted that inhibition of NHE3 substantially reduced proximal tubule TNa and oxygen consumption (QO2 ). Whole-kidney TNa efficiency, as reflected by the number of moles of Na+ reabsorbed per moles of O2 consumed (denoted by the ratio TNa/QO2 ), decreased by ∼20% with 80% inhibition of NHE3. NKCC2 inhibition simulations predicted a substantial reduction in thick ascending limb TNa and QO2 ; however, the effect on whole-kidney TNa/QO2 was minor. Tubular K+ transport was also substantially impaired, resulting in elevated urinary K+ excretion. The most notable effect of NCC inhibition was to increase the excretion of Na+, K+, and Cl-; its impact on whole-kidney TNa and its efficiency was minor. 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 TNa and TNa/QO2 Overall, model predictions agree well with measured changes in Na+ and K+ excretion in response to diuretics and Na+ transporter mutations.
Keywords: ENaC; NCC; NH3; NKCC2; oxygen consumption; sodium transport.
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