title: The epithelial sodium/proton exchanger, NHE3, is necessary for renal and intestinal calcium (re)absorption.
abstract: Passive paracellular proximal tubular (PT) and intestinal calcium (Ca(2+)) 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 Ca(2+) homeostasis remains unclear. We, therefore, set out to determine whether NHE3 is necessary for Ca(2+) (re)absorption from these epithelia by comparing Ca(2+) handling between wild-type and NHE3(-/-) mice. Serum Ca(2+) 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 Ca(2+) was also elevated in NHE3(-/-) mice. Paracellular Ca(2+) 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.( 45)Ca(2+) uptake after oral gavage and flux studies in Ussing chambers across duodenum of wild-type and NHE3(-/-) mice confirmed decreased Ca(2+) 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 Ca(2+) homeostasis in NHE3(-/-) mice and provide a molecular link between Na(+) and Ca(2+) (re)absorption.
authors.affiliation: Division of Nephrology, Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
authors.forename: Wanling
authors.initials: W
authors.lastname: Pan
authors.forename: Jelena
authors.initials: J
authors.lastname: Borovac
authors.forename: Zachary
authors.initials: Z
authors.lastname: Spicer
authors.forename: Joost G
authors.initials: JG
authors.lastname: Hoenderop
authors.forename: René J
authors.initials: RJ
authors.lastname: Bindels
authors.forename: Gary E
authors.initials: GE
authors.lastname: Shull
authors.forename: Michael R
authors.initials: MR
authors.lastname: Doschak
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Cordat
authors.forename: R Todd
authors.initials: RT
authors.lastname: Alexander
mesh_terms: D000818:Animals; D015519:Bone Density; D064026:Calbindins; D002117:Calcitriol / Q000097:blood; D002118:Calcium / Q000097:blood / Q000378:metabolism* / Q000652:urine; D002460:Cell Line; D057167:Claudins / Q000096:biosynthesis; D004386:Duodenum / Q000378:metabolism; D007408:Intestinal Absorption / Q000502:physiology*; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009893:Opossums; D010281:Parathyroid Hormone / Q000097:blood; D064030:S100 Calcium Binding Protein G; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*
chemical_list: D064026:Calbindins; D057167:Claudins; C113371:Cldn2 protein, mouse; D010281:Parathyroid Hormone; D064030:S100 Calcium Binding Protein G; C000613386:Slc9a3 protein, mouse; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; C459596:claudin 15; D002117:Calcitriol; D002118:Calcium