Renal Physiology


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 D3. 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. 45Ca2+ 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-D9K, 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.

  • calcium homeostasis
  • paracellular transport
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