Colonic anion secretory defects and metabolic acidosis in mice lacking the NBC1 Na +/HCO 3 - cotransporter

Lara R. Gawenis, Emily M. Bradford, Vikram Prasad, John N. Lorenz, Janet E. Simpson, Lane L. Clarke, Alison L. Woo, Christina Grisham, L. Philip Sanford, Thomas C Doetschman, Marian L. Miller, Gary E. Shull

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112 Scopus citations

Abstract

The NBC1 Na +/HCO 3 - 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 HCO 3 - 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 HCO 3 - 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 +, hyperaldosteronism, 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 pHi 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 HCO 3-, the magnitude ofcAMP-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 HCO 3 - revealed a sharp decrease in both cAMP-stimulated HCO 3 - secretion and SITS-sensitive current in NBC1 -/- proximal colon. These results are consistent with the known function of NBC1 in HCO 3 - absorption in the kidney and demonstrate that NBC1 activity is a component of the basolateral mechanisms for HCO 3 - uptake during cAMP-stimulated anion secretion in the proximal colon.

Original languageEnglish (US)
Pages (from-to)9042-9052
Number of pages11
JournalJournal of Biological Chemistry
Volume282
Issue number12
DOIs
Publication statusPublished - Mar 23 2007
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Gawenis, L. R., Bradford, E. M., Prasad, V., Lorenz, J. N., Simpson, J. E., Clarke, L. L., ... Shull, G. E. (2007). Colonic anion secretory defects and metabolic acidosis in mice lacking the NBC1 Na +/HCO 3 - cotransporter. Journal of Biological Chemistry, 282(12), 9042-9052. https://doi.org/10.1074/jbc.M607041200