Basic Science Articles Chloride/Bicarbonate Exchanger SLC26A7 Is Localized in Endosomes in Medullary Collecting Duct Cells and Is Targeted to the Basolateral Membrane in Hypertonicity and Potassium Depletion Jie Xu,* Roger T. Worrell, † Hong C. Li,* Sharon L. Barone,* Snezana Petrovic,* Hassane Amlal,* and Manoocher Soleimani* ‡ Departments of *Medicine and † Surgery, University of Cincinnati, and ‡ Veterans Affairs Medical Center at Cincinnati, Cincinnati, Ohio SLC26A7 is a Cl  /HCO 3  exchanger that is expressed on the basolateral membrane and in the cytoplasm of two distinct acid-secreting epithelial cells: The A-intercalated cells in the kidney outer medullary collecting duct and the gastric parietal cells. The intracellular localization of SLC26A7 suggests the possibility of trafficking between cell membrane and intracellular compartments. For testing this hypothesis, full-length human SLC26A7 cDNA was fused with green fluorescence protein and transiently expressed in MDCK epithelial cells. In monolayer cells in isotonic medium, SLC26A7 showed punctate distribu- tion throughout the cytoplasm. However, in medium that was made hypertonic for 16 h, SLC26A7 was detected predominantly in the plasma membrane. The presence of mitogen-activated protein kinase inhibitors blocked the trafficking of SLC26A7 to the plasma membrane. Double-labeling studies demonstrated the localization of SLC26A7 to the transferrin receptor–positive endosomes. A chimera that was composed of the amino terminal fragment of SLC26A7 and the carboxyl terminal fragment of SLC26A1, and a C-terminal–truncated SLC26A7 were retained in the cytoplasm in hypertonicity. In separate studies, SLC26A7 showed predominant localization in plasma membrane in potassium-depleted isotonic medium (0.5 or 2 mEq/L KCl) versus cytoplasmic distribution in normal potassium isotonic medium (4 mEq/L). It is concluded that SLC26A7 is present in endosomes, and its targeting to the basolateral membrane is increased in hypertonicity and potassium depletion. The trafficking to the cell surface suggests novel functional upregulation of SLC26A7 in states that are associated with hypoka- lemia or increased medullary tonicity. Additional studies are needed to ascertain the role of SLC26A7 in enhanced bicarbonate absorption in outer medullary collecting duct in hypokalemia and in acid-base regulation in conditions that are associated with increased medullary tonicity. J Am Soc Nephrol 17: 956 –967, 2006. doi: 10.1681/ASN.2005111174 T he solute carrier families 4 and 26 (SLC4 and SLC26, respectively) encode two distinct groups of anion ex- changers. Several members of the SLC4 family, desig- nated as A1 (SLC4A1AE1), A2 (SLC4A2AE2), A3 (SLC4A3AE3), and A4 (SLC4A9AE4) are shown to mediate Cl - /HCO 3 - exchange (1,2). SLC26 is a new family of anion exchangers that is composed of 10 distinct genes (3). Members of the SLC26 family display very specific and limited tissue distribution. Functional studies demonstrate that a number of exchangers from this family, including SLC26A3 (DRA), SLC26A4 (pendrin), SLC26A6 (PAT1 or CFEX), SLC26A7, and SLC26A9 (4 –9) mediate Cl - /HCO 3 - exchange. SLC26A4, A6, and A7 are expressed in the kidney, whereas SLC26A3 and A9 are not. In the kidney, SLC26A4 (pendrin) is expressed on the apical membranes of B-intercalated and non-A non-B–interca- lated cells, whereas SLC26A6 (PAT1 or CFEX) is expressed on the brush border membranes of the proximal tubule. In the kidney, pendrin mediates bicarbonate secretion and chloride reabsorption in the connecting segment and cortical collecting duct (5,10 –12), whereas PAT1 is involved in transcellular chlo- ride reabsorption in the proximal tubule (6,13–16). SLC26A7 is a recently cloned member of the SLC26 family (17,18). Functional and molecular studies from our laboratory demonstrated that SLC26A7 is a chloride/bicarbonate ex- changer (7). In the stomach, SLC26A7 is expressed on the basolateral membrane of the acid-secreting gastric parietal cells (7), whereas in the kidney, it localizes on the basolateral mem- brane of acid-secreting A-intercalated (A-IC) cells of the outer medullary collecting duct (OMCD) (8,19). OMCD has the high- est rate of acid secretion among the collecting duct segments (20). Proton (acid) secretion across the apical membrane of A-IC cells in OMCD via vacuolar H + -ATPase (and to some extent via H + /K + ATPase) results in the generation of intracellular bicar- Received November 9, 2005. Accepted January 26, 2006. Published online ahead of print. Publication date available at www.jasn.org. Address correspondence to: Dr. Manoocher Soleimani, Division of Nephrology and Hypertension, Department of Medicine, University of Cincinnati, 231 Albert Sabin Way, MSB 259G, Cincinnati, OH 45267-0585. Phone: 513-558-5471; Fax: 513-558-4309; E-mail: manoocher.soleimani@uc.edu Copyright © 2006 by the American Society of Nephrology ISSN: 1046-6673/1704-0956