Loss of Cystic Fibrosis Transmembrane Regulator Impairs Intestinal Oxalate Secretion.
Patients with cystic fibrosis have an increased incidence of hyperoxaluria and calcium oxalate nephrolithiasis. Net intestinal absorption of dietary oxalate results from passive paracellular oxalate absorption as modified by oxalate back secretion mediated by the SLC26A6 oxalate transporter. We used mice deficient in the cystic fibrosis transmembrane conductance regulator gene (Cftr) to test the hypothesis that SLC26A6-mediated oxalate secretion is defective in cystic fibrosis. We mounted isolated intestinal tissue from C57BL/6 (wild-type) and Cftr-/-mice in Ussing chambers and measured transcellular secretion of [14C]oxalate. Intestinal tissue isolated from Cftr-/-mice exhibited significantly less transcellular oxalate secretion than intestinal tissue of wild-type mice. However, glucose absorption, another representative intestinal transport process, did not differ in Cftr-/-tissue. Compared with wild-type mice, Cftr-/-mice showed reduced expression of SLC26A6 in duodenum by immunofluorescence and Western blot analysis. Furthermore, coexpression of CFTR stimulated SLC26A6-mediated Cl--oxalate exchange in Xenopus oocytes. In association with the profound defect in intestinal oxalate secretion, Cftr-/-mice had serum and urine oxalate levels 2.5-fold greater than those of wild-type mice. We conclude that defective intestinal oxalate secretion mediated by SLC26A6 may contribute to the hyperoxaluria observed in this mouse model of cystic fibrosis. Future studies are needed to address whether similar mechanisms contribute to the increased risk for calcium oxalate stone formation observed in patients with cystic fibrosis.
Departments of Internal Medicine, Felix.Knauf@uk-erlangen.de Peter.Aronson@yale.edu.|Department of Nephrology and Hypertension, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
Felix
F
Knauf
Departments of Internal Medicine.
Robert B
RB
Thomson
Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts; and.
John F
JF
Heneghan
Departments of Internal Medicine.
Zhirong
Z
Jiang
Departments of Internal Medicine.
Adedotun
A
Adebamiro
Departments of Internal Medicine.
Claire L
CL
Thomson
Pediatrics, and.
Christina
C
Barone
Litholink Corporation, Laboratory Corporation of America Holdings, Chicago, Illinois.
John R
JR
Asplin
Pediatrics, and.|Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut.
Marie E
ME
Egan
Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts; and.
Seth L
SL
Alper
Departments of Internal Medicine, Felix.Knauf@uk-erlangen.de Peter.Aronson@yale.edu.|Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut.
Peter S
PS
Aronson
D000818:Animals; D017920:Antiporters / Q000502:physiology; D002129:Calcium Oxalate / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000502:physiology*; D006959:Hyperoxaluria / Q000209:etiology; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000076988:Sulfate Transporters
D017920:Antiporters; C466900:Slc26a6 protein, mouse; D000076988:Sulfate Transporters; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002129:Calcium Oxalate
Cell & Transport Physiology; Cystic fibrosis; kidney stones