Loss of Cystic Fibrosis Transmembrane Regulator Impairs Intestinal Oxalate Secretion

[摘要] Patients with cystic fibrosis have an increased incidence of hyperoxaluria and calcium oxalate nephrolithiasis. Net intestinal\n absorption of dietary oxalate results from passive paracellular oxalate absorption as modified by oxalate back secretion mediated\n by the SLC26A6 oxalate transporter. We used mice deficient in the cystic fibrosis transmembrane conductance regulator gene\n (Cftr) to test the hypothesis that SLC26A6\xe2\x80\x93mediated oxalate secretion is defective in cystic fibrosis. We mounted isolated intestinal\n tissue from C57BL/6 (wild-type) and Cftr\xe2\x88\x92/\xe2\x88\x92 mice in Ussing chambers and measured transcellular secretion of [14C]oxalate. Intestinal tissue isolated from Cftr\xe2\x88\x92/\xe2\x88\x92 mice exhibited significantly less transcellular oxalate secretion than intestinal tissue of wild-type mice. However, glucose\n absorption, another representative intestinal transport process, did not differ in Cftr\xe2\x88\x92/\xe2\x88\x92 tissue. Compared with wild-type mice, Cftr\xe2\x88\x92/\xe2\x88\x92 mice showed reduced expression of SLC26A6 in duodenum by immunofluorescence and Western blot analysis. Furthermore, coexpression\n of CFTR stimulated SLC26A6\xe2\x80\x93mediated Cl\xe2\x88\x92\xe2\x80\x93oxalate exchange in Xenopus oocytes. In association with the profound defect in intestinal oxalate secretion, Cftr\xe2\x88\x92/\xe2\x88\x92 mice had serum and urine oxalate levels 2.5-fold greater than those of wild-type mice. We conclude that defective intestinal\n oxalate secretion mediated by SLC26A6 may contribute to the hyperoxaluria observed in this mouse model of cystic fibrosis.\n Future studies are needed to address whether similar mechanisms contribute to the increased risk for calcium oxalate stone\n formation observed in patients with cystic fibrosis.\n

[学科分类] 泌尿医学