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

Abstract

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 <i>via</i> the gut in CKD. Feeding a diet high in soluble oxalate or weekly injections of aristolochic acid induced CKD in age- and sex-matched wild-type and <i>Slc26a6</i>^<i>-/-</i> mice. qPCR, immunohistochemistry, and western blot analysis assessed intestinal <i>Slc26a6</i> expression. An oxalate oxidase assay measured fecal and P_ox concentrations. Fecal oxalate excretion was enhanced in wild-type mice with CKD. This increase was abrogated in <i>Slc26a6</i>^<i>-/-</i> mice associated with a significant elevation in plasma oxalate concentration. <i>Slc26a6</i> 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 <i>Slc26a6</i> expression, suggesting that changes associated with CKD regulate transporter expression rather than elevations in P_ox. 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.