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The objective of this study was to examine theoretically how Ca 2+ reabsorption in the proximal tubule (PT) is modulated by Na + and water fluxes, parathyroid hormone (PTH), Na + -glucose cotransporter (SGLT2) inhibitors, and acetazolamide. We expanded a previously published mathematical model of water and solute transport in the rat PT (Layton AT, Vallon V, Edwards A. Am J Physiol Renal Physiol 308: F1343-F1357, 2015) that did not include Ca 2+ . Our results indicate that Ca 2+ reabsorption in the PT is primarily driven by the transepithelial Ca 2+ concentration gradient that stems from water reabsorption, which is itself coupled to Na + reabsorption. Simulated variations in permeability or transporter activity elicit opposite changes in paracellular and transcellular Ca 2+ fluxes, whereas a simulated decrease in filtration rate lowers both fluxes. The model predicts that PTH-mediated inhibition of the apical Na + /H + exchanger NHE3 reduces Na + and Ca 2+ transport to a similar extent. It also suggests that acetazolamide- and SGLT2 inhibitor-induced calciuria at least partly stems from reduced Ca 2+ reabsorption in the PT. In addition, backleak of phosphate (PO 4 ) across tight junctions is predicted to reduce net PO 4 reabsorption by ~20% under normal conditions. When transcellular PO 4 transport is substantially reduced by PTH, paracellular PO 4 flux is reversed and contributes significantly to PO 4 reabsorption. Furthermore, PTH is predicted to exert an indirect impact on PO 4 reabsorption via its inhibitory action on NHE3. This model thus provides greater insight into the mechanisms that modulate Ca 2+ and PO 4 reabsorption in the PT.

A model of calcium transport and regulation in the proximal tubule