Title: Colonic anion secretory defects and metabolic acidosis in mice lacking the NBC1 Na+/HCO3- cotransporter.
Authors: Gawenis, Lara R; Bradford, Emily M; Prasad, Vikram; Lorenz, John N; Simpson, Janet E; Clarke, Lane L; Woo, Alison L; Grisham, Christina; Sanford, L Philip; Doetschman, Thomas; Miller, Marian L; Shull, Gary E
Published In J Biol Chem, (2007 Mar 23)
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.
PubMed ID: 17192275
MeSH Terms: Acidosis/genetics*; Aldosterone/metabolism; Animals; Anions; Colon/metabolism*; Cyclic AMP/metabolism; Intestinal Mucosa/metabolism; Kidney/metabolism; Mice; Mice, Mutant Strains; Mice, Transgenic; Phenotype; Phosphorylation; Sodium-Bicarbonate Symporters/genetics*; Sodium-Bicarbonate Symporters/physiology; Sodium/metabolism