title: Colonic anion secretory defects and metabolic acidosis in mice lacking the NBC1 Na+/HCO3- cotransporter.
abstract: The NBC1 Na+/HCO3- cotransporter is expressed in many tissues, including kidney and intestinal epithelia. NBC1 mutations cause proximal renal tubular acidosis in humans, consistent with its role in HCO3- absorption in the kidney. In intestinal and colonic epithelia, NBC1 localizes to basolateral membranes and is thought to function in anion secretion. To test the hypothesis that NBC1 plays a role in transepithelial HCO3- secretion in the intestinal tract, null mutant (NBC1-/-) mice were prepared by targeted disruption of its gene (Slc4a4). NBC1-/- mice exhibited severe metabolic acidosis, growth retardation, reduced plasma Na+, hyperal-dosteronism, splenomegaly, abnormal dentition, intestinal obstructions, and death before weaning. Intracellular pH (pH(i)) was not altered in cAMP-stimulated epithelial cells of NBC1-/- cecum, but pH(i) regulation during sodium removal and readdition was impaired. Bioelectric measurements of NBC1-/- colons revealed increased amiloride-sensitive Na+ absorption. In Ringer solution containing both Cl- and HCO3-, the magnitude of cAMP-stimulated anion secretion was normal in NBC1-/- distal colon but increased in proximal colon, with the increase largely supported by enhanced activity of the basolateral NKCC1 Na+-K+-2Cl- cotransporter. Anion substitution studies in which carbonic anhydrase was inhibited and transepithelial anion conductance was limited to HCO3- revealed a sharp decrease in both cAMP-stimulated HCO3- secretion and SITS-sensitive current in NBC1-/- proximal colon. These results are consistent with the known function of NBC1 in HCO3- absorption in the kidney and demonstrate that NBC1 activity is a component of the basolateral mechanisms for HCO3- uptake during cAMP-stimulated anion secretion in the proximal colon.
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Lara R
authors.initials: LR
authors.lastname: Gawenis
authors.forename: Emily M
authors.initials: EM
authors.lastname: Bradford
authors.forename: Vikram
authors.initials: V
authors.lastname: Prasad
authors.forename: John N
authors.initials: JN
authors.lastname: Lorenz
authors.forename: Janet E
authors.initials: JE
authors.lastname: Simpson
authors.forename: Lane L
authors.initials: LL
authors.lastname: Clarke
authors.forename: Alison L
authors.initials: AL
authors.lastname: Woo
authors.forename: Christina
authors.initials: C
authors.lastname: Grisham
authors.forename: L Philip
authors.initials: LP
authors.lastname: Sanford
authors.forename: Thomas
authors.initials: T
authors.lastname: Doetschman
authors.forename: Marian L
authors.initials: ML
authors.lastname: Miller
authors.forename: Gary E
authors.initials: GE
authors.lastname: Shull
mesh_terms: D000138:Acidosis / Q000235:genetics*; D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D000838:Anions; D003106:Colon / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D010641:Phenotype; D010766:Phosphorylation; D012964:Sodium / Q000378:metabolism; D027982:Sodium-Bicarbonate Symporters / Q000235:genetics* / Q000502:physiology
chemical_list: D000838:Anions; C498899:Slc4a4 protein, mouse; D027982:Sodium-Bicarbonate Symporters; D000450:Aldosterone; D012964:Sodium; D000242:Cyclic AMP