Enteric Oxalate Secretion Mediated by Slc26a6 Defends against Hyperoxalemia in Murine Models of Chronic Kidney Disease

Significance Statement Fecal oxalate excretion is critical in oxalate balance with progression of CKD. However, the identity of the transporter(s) responsible for increased intestinal oxalate secretion in CKD is unknown. Intestinal expression of oxalate transporter Slc26a6 is strongly upregulated in two murine models of CKD. Deletion of Slc26a6 completely abrogates enhanced fecal oxalate excretion in CKD, increasing plasma oxalate concentration. This study demonstrates that Slc26a6 mediates intestinal oxalate secretion and mitigates hyperoxalemia in murine CKD models. The findings suggest that pharmacologic approaches enhancing intestinal Slc26a6 activity may stimulate extrarenal clearance of oxalate and prevent hyperoxalemia in CKD. Future studies are needed to address whether similar mechanisms contribute to intestinal oxalate elimination in humans to enhance extrarenal oxalate clearance. Background A state of oxalate homeostasis is maintained in patients with healthy kidney function. However, as GFR declines, plasma oxalate (P ox ) concentrations start to rise. Several groups of researchers have described augmentation of oxalate secretion in the colon in models of CKD, but the oxalate transporters remain unidentified. The oxalate transporter Slc26a6 is a candidate for contributing to the extrarenal clearance of oxalate via the gut in CKD. Methods Feeding a diet high in soluble oxalate or weekly injections of aristolochic acid induced CKD in age- and sex-matched wild-type and Slc26a6 −/− mice. qPCR, immunohistochemistry, and western blot analysis assessed intestinal Slc26a6 expression. An oxalate oxidase assay measured fecal and P ox concentrations. Results Fecal oxalate excretion was enhanced in wild-type mice with CKD. This increase was abrogated in Slc26a6 −/− mice associated with a significant elevation in plasma oxalate concentration. Slc26a6 mRNA and protein expression were greatly increased in the intestine of mice with CKD. Raising P ox without inducing kidney injury did not alter intestinal Slc26a6 expression, suggesting that changes associated with CKD regulate transporter expression rather than elevations in P ox . Conclusions Slc26a6-mediated enteric oxalate secretion is critical in decreasing the body burden of oxalate in murine CKD models. Future studies are needed to address whether similar mechanisms contribute to intestinal oxalate elimination in humans to enhance extrarenal oxalate clearance.