Abstract
The anion exchanger slc26a3 (DRA), which is mutated in congenital chloride-losing diarrhea, is expressed in the apical membrane of the cecum and middle-distal colon but not in the proximal colon of rodent large intestines. To elucidate the functional roles of DRA, we measured unidirectional 36Cl− and 22Na+ fluxes and HCO3− secretion in vitro in each of these segments using DRA-KO mice. Robust Cl− absorption, which was largely abolished after DRA deficiency, was present in the cecum and middle-distal colon but absent in the proximal colon. Na+ absorption was present in all three segments in both the control and DRA-KO mice. The luminal-Cl−-dependent HCO3− secretions in the cecum and middle-distal colon were abolished in the DRA-KO mice. In conclusion, DRA mediates Cl− absorption and HCO3− secretion in the mouse cecum and middle-distal colon, and may have roles in H2O absorption and luminal acid/base regulation in these segments.
Highlights
Intestinal fluid absorption is mediated by epithelial NaCl absorption involving parallel operation of N a+/H+ and Cl−/HCO3− exchangers in the apical membrane and water followed by osmotic forces, which was first proposed based on in vivo perfusion experiments in humans [1]
This model indicated that congenital chloride-losing diarrhea (CCD), a disorder characterized by massive loss of chloride in acidic watery stools [2,3,4], is caused by a defect in the C l−/HCO3− exchanger [5, 6]
In most of the following experiments, we grouped the slc26a3(+/+) and slc26a3(+/−) mice together as the control, and the data obtained from the control mice were compared with those from the scl26a3(−/−) (DRA-KO) mice. [the results obtained from the slc26a3(+/−) mice were not markedly different from those obtained from the slc26a3(+/+) mice as shown in “additional information” of the figure and table legends.]
Summary
Intestinal fluid absorption is mediated by epithelial NaCl absorption involving parallel operation of N a+/H+ and Cl−/HCO3− exchangers in the apical membrane and water followed by osmotic forces, which was first proposed based on in vivo perfusion experiments in humans [1]. We determined (1) unidirectional 36Cl− and 22Na+ fluxes, (2) the Cl-dependent HCO3− secretion rate, and (3) the following characteristics in the feces: H2O content, Na+, K+, and Cl− concentrations, and pH These experiments and measurements were repeated using DRA-KO (slc26a3(−/−)) mice, and the results were compared with those obtained from nonDRA-KO control mice [slc26a3(+/+) and slc26a3(+/−)] to elucidate the functions of DRA
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