A Model of Calcium Transport and Regulation in the Proximal Tubule.
Edwards A, Bonny O.
The objective of this study was to examine theoretically how Ca2+ reabsorption in the proximal tubule (PT) is modulated by Na+ and water fluxes, parathyroid hormone (PTH), SGLT2 inhibitors, and acetazolamide. To do so, we expanded a previously published mathematical model of water and solute transport in the rat PT (Layton AT, Vallon V, and Edwards A. Am J Physiol Renal Physiol 308: F1343-F1357, 2015) that did not include Ca2+. Our results indicate that Ca2+ reabsorption in the PT is primarily driven by the transepithelial Ca2+ 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 Ca2+ 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 Ca2+ transport to a similar extent. It also suggests that acetazolamide- and SGLT2 inhibitor-induced calciuria at least partly stems from reduced Ca2+ reabsorption in the PT. In addition, the back-leak of phosphate (PO4) across tight junctions is predicted to reduce net PO4 reabsorption by about 20% under normal conditions. When transcellular PO4 transport is substantially reduced by PTH, the paracellular PO4 flux is reversed and contributes significantly to PO4 reabsorption. Furthermore, PTH is predicted to exert an indirect impact on PO4 reabsorption, via its inhibitory action on NHE3. This model thus provides greater insight into the mechanisms that modulate Ca2+ and PO4 reabsorption in the PT. Am J Physiol Renal Physiol. 2018 May 30. doi: 10.1152/ajprenal.00129.2018. [Epub ahead of print]
par Olivier Bonny