slc26a3 (dra)-deficient mice display chloride-losing diarrhea, enhanced colonic proliferation, and distinct up-regulation of ion transporters in the colon.
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.
Schweinfest
Clifford W
CW
Hollings Cancer Center and the Departments of Pathology and Laboratory Medicine and of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Spyropoulos
Demetri D
DD
Henderson
Kelly W
KW
Kim
Jae-Ho
JH
Chapman
Jeannie M
JM
Barone
Sharon
S
Worrell
Roger T
RT
Wang
Zhaohui
Z
Soleimani
Manoocher
M
D000818:Animals; D017920:Antiporters / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D001483:Base Sequence; D049109:Cell Proliferation; D002712:Chlorides / Q000378:metabolism*; D003106:Colon / Q000378:metabolism* / Q000473:pathology*; D017931:DNA Primers / Q000235:genetics; D005260:Female; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D017136:Ion Transport; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism; D000076988:Sulfate Transporters; D015854:Up-Regulation
D017920:Antiporters; D002712:Chlorides; D017931:DNA Primers; C000613385:SLC9A3 protein, human; C489860:Slc26a3 protein, mouse; C000613386:Slc9a3 protein, mouse; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D000076988:Sulfate Transporters; D017506:H(+)-K(+)-Exchanging ATPase