title: Calcium reabsorption in the distal tubule: regulation by sodium, pH, and flow.
abstract: We developed a mathematical model of Ca(2+) transport along the late distal convoluted tubule (DCT2) and the connecting tubule (CNT) to investigate the mechanisms that regulate Ca(2+) reabsorption in the DCT2-CNT. The model accounts for apical Ca(2+) influx across transient receptor potential vanilloid 5 (TRPV5) channels and basolateral Ca(2+) efflux via plasma membrane Ca(2+)-ATPase pumps and type 1 Na(+)/Ca(2+) exchangers (NCX1). Model simulations reproduce experimentally observed variations in Ca(2+) uptake as a function of extracellular pH, Na(+), and Mg(2+) concentration. Our results indicate that amiloride enhances Ca(2+) reabsorption in the DCT2-CNT predominantly by increasing the driving force across NCX1, thereby stimulating Ca(2+) efflux. They also suggest that because aldosterone upregulates both apical and basolateral Na(+) transport pathways, it has a lesser impact on Ca(2+) reabsorption than amiloride. Conversely, the model predicts that full NCX1 inhibition and parathyroidectomy each augment the Ca(2+) load delivered to the collecting duct severalfold. In addition, our results suggest that regulation of TRPV5 activity by luminal pH has a small impact, per se, on transepithelial Ca(2+) fluxes; the reduction in Ca(2+) reabsorption induced by metabolic acidosis likely stems from decreases in TRPV5 expression. In contrast, elevations in luminal Ca(2+) are predicted to significantly decrease TRPV5 activity via the Ca(2+)-sensing receptor. Nevertheless, following the administration of furosemide, the calcium-sensing receptor-mediated increase in Ca(2+) reabsorption in the DCT2-CNT is calculated to be insufficient to prevent hypercalciuria. Altogether, our model predicts complex interactions between calcium and sodium reabsorption in the DCT2-CNT.
authors.affiliation: Department of Toxicology and Pharmacology, University of Lausanne, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bonny
authors.forename: Aurélie
authors.initials: A
authors.lastname: Edwards
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D017136:Ion Transport; D007686:Kidney Tubules, Distal / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*
chemical_list: D044169:Receptors, Calcium-Sensing; D019831:Sodium-Calcium Exchanger; D000584:Amiloride; D012964:Sodium; D002118:Calcium