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J. Biol. Chem., Vol. 281, Issue 49, 37962-37971, December 8, 2006

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slc26a3 (dra)-deficient Mice Display Chloride-losing Diarrhea, Enhanced Colonic Proliferation, and Distinct Up-regulation of Ion Transporters in the Colon^*

Clifford W. Schweinfest¹, Demetri D. Spyropoulos^¶, Kelly W. Henderson, Jae-Ho Kim², Jeannie M. Chapman³, Sharon Barone^||, Roger T. Worrell^||, Zhaohui Wang^||, and Manoocher Soleimani^||**4

From the Hollings Cancer Center and the Departments of ^¶Pathology and Laboratory Medicine and of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, the ^||Department of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0585, and the ^**Veterans Affairs Medical Center, Cincinnati, Ohio 45220

Mutations in the SLC26A3 (DRA (down-regulated in adenoma)) gene constitute the molecular etiology of congenital chloride-losing diarrhea in humans. To ascertain its role in intestinal physiology, gene targeting was used to prepare mice lacking slc26a3. slc26a3-deficient animals displayed postpartum lethality at low penetrance. Surviving dra-deficient mice exhibited high chloride content diarrhea, volume depletion, and growth retardation. In addition, the large intestinal loops were distended, with colonic mucosa exhibiting an aberrant growth pattern and the colonic crypt proliferative zone being greatly expanded in slc26a3-null mice. Apical membrane chloride/base exchange activity was sharply reduced, and luminal content was more acidic in slc26a3-null mouse colon. The epithelial cells in the colon displayed unique adaptive regulation of ion transporters; NHE3 expression was enhanced in the proximal and distal colon, whereas colonic H,K-ATPase and the epithelial sodium channel showed massive up-regulation in the distal colon. Plasma aldosterone was increased in slc26a3-null mice. We conclude that slc26a3 is the major apical chloride/base exchanger and is essential for the absorption of chloride in the colon. In addition, slc26a3 regulates colonic crypt proliferation. Deletion of slc26a3 results in chloride-rich diarrhea and is associated with compensatory adaptive up-regulation of ion-absorbing transporters.

Received for publication, August 7, 2006 , and in revised form, September 22, 2006.

^* This work was supported by National Institutes of Health Grants R01 CA095172 (to C. W. S.) and R01 DK62809 (to M. S.), United States Department of Defense Grant N00014-96-1-1298 (to C. W. S.), the Department of Veterans Affairs (to M. S.), and the Medical University of South Carolina University Research Committee (to C. W. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Present address: Dept. of Math and Science, Rogers State University, Claremont, OK 74017.

³ Present address: Div. of Natural Sciences and Engineering, University of South Carolina Upstate, Spartanburg, SC 29303.

¹ To whom correspondence may be addressed: Hollings Cancer Center, Rm. 321-A, Medical University of South Carolina, 86 Jonathan Lucas St., Charleston, SC 29425. Tel.: 843-792-3971; Fax: 843-792-8143; E-mail: schweicw{at}musc.edu.

⁴ To whom correspondence may be addressed: Div. of Nephrology and Hypertension, Dept. of Internal Medicine, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0585, P. O. Box 670585, Cincinnati, OH 45267-0585. Tel.: 513-558-5471; Fax: 513-558-4309; E-mail: Manoocher.Soleimani{at}uc.edu.

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