SLC26A6 and NaDC-1 transporters interact to regulate oxalate and citrate homeostasis

The combination of hyperoxaluria and hypocitraturia can trigger Ca ²⁺-oxalate stone formation, even in the absence of hypercalciuria, but the molecularmechanisms that control urinary oxalate and citrate levels are not understood completely. Here, we examined the relationship between the oxalate transporter SLC26A6 and the citrate transporter NaDC-1 in citrate and oxalate homeostasis. Compared with wildtypemice, Slc26a6-nullmice exhibited increased renal and intestinal sodium-dependent succinate uptake, as well as urinary hyperoxaluria and hypocitraturia, but no change in urinary pH, indicating enhanced transport activity of NaDC-1. When co-expressed in Xenopus oocytes, NaDC-1 enhanced Slc26a6 transport activity. In contrast, Slc26a6 inhibited NaDC-1 transport activity in an activity dependent manner to restricted tubular citrate absorption. Biochemical and physiologic analysis revealed that the STAS domain of Slc26a6 and the first intracellular loop of NaDC-1 mediated both the physical and functional interactions of these transporters. These findings reveal amolecular pathway that senses and tightly regulates oxalate and citrate levels and may control Ca²⁺-oxalate stone formation.