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

Ca transport along the nephron occurs via specific transcellular and paracellular pathways and is coupled to the transport of other electrolytes. Notably, Na transport establishes an electrochemical gradient to drive Ca reabsorption. Hence, alterations in renal Na handling, under pathophysiological conditions or pharmacological manipulations, can have major effects on Ca 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 Ca handling. To better understand the underlying mechanisms, we developed a computational model of electrolyte transport along the superficial nephron in the kidney of a male and female rat. Sex differences in renal Ca handling are represented. Model simulations predicted in the female rat nephron lower Ca reabsorption in the proximal tubule and thick ascending limb, but higher reabsorption in the late distal convoluted tubule and connecting tubule, compared with the male nephron. The male rat kidney model yielded a higher urinary Ca excretion than the female model, consistent with animal experiments. Model results indicated that along the proximal tubule and thick ascending limb, Ca and Na transport occurred in parallel, but those processes were dissociated in the distal convoluted tubule. Additionally, we conducted simulations of inhibition of channels and transporters that play a major role in Na and Ca transport. Simulation results revealed alterations in transepithelial Ca transport, with differential effects among nephron segments and between the sexes. The kidney plays an important role in the maintenance of whole body Ca balance by regulating Ca reabsorption and excretion. This computational modeling study provides insights into how Ca transport along the nephron is coupled to Na. Model results indicated that along the proximal tubule and thick ascending limb, Ca and Na transport occur in parallel, but those processes were dissociated in the distal convoluted tubule. Simulations also revealed sex-specific responses to different pharmacological manipulations.