A model of calcium transport and regulation in the proximal tubule.

The objective of this study was to examine theoretically how Ca 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. Our results indicate that Ca reabsorption in the PT is primarily driven by the transepithelial Ca 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 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 transport to a similar extent. It also suggests that acetazolamide- and SGLT2 inhibitor-induced calciuria at least partly stems from reduced Ca reabsorption in the PT. In addition, backleak of phosphate (PO) across tight junctions is predicted to reduce net PO reabsorption by ~20% under normal conditions. When transcellular PO transport is substantially reduced by PTH, paracellular PO flux is reversed and contributes significantly to PO reabsorption. Furthermore, PTH is predicted to exert an indirect impact on PO reabsorption via its inhibitory action on NHE3. This model thus provides greater insight into the mechanisms that modulate Ca and PO reabsorption in the PT.