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

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.