Role of Down-Regulated in Adenoma Anion Exchanger in HCO3- Secretion across Murine Duodenum

Background & Aims The current model of duodenal HCO 3 − secretion proposes that basal secretion results from Cl − /HCO 3 − exchange, whereas cyclic adenosine monophosphate (cAMP)-stimulated secretion depends on a cystic fibrosis transmembrane conductance regulator channel (Cftr)-mediated HCO 3 − conductance. However, discrepancies in applying the model suggest that Cl − /HCO 3 − exchange also contributes to cAMP-stimulated secretion. Of 2 candidate Cl − /HCO 3 − exchangers, studies of putative anion transporter-1 knockout (KO) mice find little contribution of putative anion transporter-1 to basal or cAMP-stimulated secretion. Therefore, the role of down-regulated in adenoma (Dra) in duodenal HCO 3 − secretion was investigated using DraKO mice. Methods Duodenal HCO 3 − secretion was measured by pH stat in Ussing chambers. Apical membrane Cl − /HCO 3 − exchange was measured by microfluorometry of intracellular pH in intact villous epithelium. Dra expression was assessed by immunofluorescence. Results Basal HCO 3 − secretion was reduced ∼55%–60% in the DraKO duodenum. cAMP-stimulated HCO 3 − secretion was reduced ∼50%, but short-circuit current was unchanged, indicating normal Cftr activity. Microfluorimetry of villi demonstrated that Dra is the dominant Cl − /HCO 3 − exchanger in the lower villous epithelium. Dra expression increased from villous tip to crypt. DraKO and wild-type villi also demonstrated regulation of apical Na + /H + exchange by Cftr-dependent cell shrinkage during luminal Cl − substitution. Conclusions In murine duodenum, Dra Cl − /HCO 3 − exchange is concentrated in the lower crypt-villus axis where it is subject to Cftr regulation. Dra activity contributes most basal HCO 3 − secretion and ∼50% of cAMP-stimulated HCO 3 − secretion. Dra Cl − /HCO 3 − exchange should be considered in efforts to normalize HCO 3 − secretion in duodenal disorders such as ulcer disease and cystic fibrosis.