Renal and intestinal transport defects in Slc26a6-null mice

Departments of 1 Internal Medicine and 4 Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio; Departments of 2 Cellular and Molecular Physiology and 5 Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; 3 Department of Gastroenterology, Hepatology, and Endocrinology, Hanover Medical School, Hanover, Germany; and 6 Veterans Affairs Medical Center, Cincinnati, Ohio Submitted 14 October 2004 ; accepted in final form 23 November 2004 ABSTRACT SLC26A6 (PAT1, CFEX) is an anion exchanger that is expressed on the apical membrane of the kidney proximal tubule and the small intestine. Modes of transport mediated by SLC26A6 include Cl – /formate exchange, Cl – /HCO 3 – exchange, and Cl – /oxalate exchange. To study its role in kidney and intestinal physiology, gene targeting was used to prepare mice lacking Slc26a6. Homozygous mutant Slc26a6 –/– mice appeared healthy and exhibited a normal blood pressure, kidney function, and plasma electrolyte profile. In proximal tubules microperfused with a low-HCO 3 – /high-Cl – solution, the baseline rate of fluid absorption ( J v ), an index of NaCl transport under these conditions, was the same in wild-type and null mice. However, the stimulation of J v by oxalate observed in wild-type mice was completely abolished in Slc26a6-null mice ( P < 0.05). Formate stimulation of J v was partially reduced in null mice, but the difference from the response in wild-type mice did not reach statistical significance. Apical membrane Cl – /base exchange activity, assayed with the pH-sensitive dye BCPCF in microperfused proximal tubules, was decreased by 58% in Slc26a6 –/– animals ( P < 0.001 vs. wild types). In the duodenum, the baseline rate of HCO 3 – secretion measured in mucosal tissue mounted in Ussing chambers was decreased by 30% ( P < 0.03), whereas the forskolin-stimulated component of HCO 3 – secretion was the same in wild-type and Slc26a6 –/– mice. We conclude that Slc26a6 mediates oxalate-stimulated NaCl absorption, contributes to apical membrane Cl – /base exchange in the kidney proximal tubule, and also plays an important role in HCO 3 – secretion in the duodenum. chloride absorption; bicarbonate secretion; proximal tubule; duodenum; apical anion exchange Address for reprint requests and other correspondence: M. Soleimani, Division of Nephrology and Hypertension, Dept. of Internal Medicine, Univ. of Cincinnati, 231 Albert Sabin Way, MSB 259G, Cincinnati OH 45267-0585 (E-mail: