Coupling of renal sodium and calcium transport: A modeling analysis of transporter inhibition and sex differences.

Abstract

Calcium (Ca2+) transport along the nephron occurs via specific transcellular and paracellular pathways, and is coupled to the transport of other electrolytes. Notably sodium (Na+) transport establishes an electrochemical gradient to drive Ca2+ reabsorption. Hence, alterations in renal Na+ handling, under pathophysiological conditions or pharmacological manipulations, can have major effects on Ca2+ transport. An important class of pharmacological agent is diuretics, which are commonly prescribed for the management of blood pressure and fluid balance. The pharmacological targets of diuretics generally directly facilitate Na+ transport, but also indirectly affect renal Ca2+ handling. To better understand the underlying mechanisms, we have developed a computational model of electrolyte transport along the superficial nephron in the kidney of a male and female rat. Sex differences in renal Ca2+ handling are represented. Model simulations predict in the female rat nephron lower Ca2+ reabsorption in the proximal tubule and thick ascending limb, but higher reabsorption in the late distal convoluted tubule and connecting tubule, compared to the male nephron. The male rat kidney model yields a higher urinary calcium excretion than female, consistent with animal experiments. Model results indicate that along the proximal tubule and thick ascending limb, Ca2+ and Na+ transport occurs in parallel, but those processes are dissociated in the distal convoluted tubule. Additionally, we conducted simulations of inhibition of channels and transporters that play a major role in Na+ and Ca2+ transport. Simulation results reveal alterations in transepithelial Ca2+ transport, with differential effects among nephron segments and between the sexes.