The epithelial sodium/proton exchanger, NHE3, is necessary for renal and intestinal calcium (re)absorption

Pan W, Borovac J, Spicer Z, Hoenderop JG, Bindels RJ, Shull GE, Doschak MR, Cordat E, Alexander RT. The epithelial sodium/proton exchanger, NHE3, is necessary for renal and intestinal calcium (re) absorption. Am J Physiol Renal Physiol 302: F943-F956, 2012. First published September 21, 2011; doi:10.1152/ajprenal.00504.2010.-Passive paracellular proximal tubular (PT) and intestinal calcium (Ca2+) fluxes have been linked to active sodium (re) absorption. Although the epithelial sodium/proton exchanger, NHE3, mediates apical sodium entry at both these sites, its role in Ca2+ homeostasis remains unclear. We, therefore, set out to determine whether NHE3 is necessary for Ca2+ (re) absorption from these epithelia by comparing Ca2+ handling between wild-type and NHE3(-/-) mice. Serum Ca2+ and plasma parathyroid hormone levels were not different between groups. However, NHE3(-/-) mice had increased serum 1,25-dihydroxyvitamin D-3. The fractional excretion of Ca2+ was also elevated in NHE3(-/-) mice. Paracellular Ca2+ flux across confluent monolayers of a PT cell culture model was increased by an osmotic gradient equivalent to that generated by NHE3 across the PT in vivo and by overexpression of NHE3. Ca-45(2+) uptake after oral gavage and flux studies in Ussing chambers across duodenum of wild-type and NHE3(-/-) mice confirmed decreased Ca2+ absorption in NHE3(-/-) mice compared with wild-type mice. Consistent with this, intestinal calbindin-D-9K, claudin-2, and claudin-15 mRNA expression was decreased. Microcomputed tomography analysis revealed a perturbation in bone mineralization. NHE3(-/-) mice had both decreased cortical bone mineral density and trabecular bone mass. Our results demonstrate significant alterations of Ca2+ homeostasis in NHE3(-/-) mice and provide a molecular link between Na+ and Ca2+ (re)absorption.