title: SLC26A6 and NaDC-1 transporters interact to regulate oxalate and citrate homeostasis.
abstract: The combination of hyperoxaluria and hypocitraturia can trigger Ca(2+)-oxalate stone formation, even in the absence of hypercalciuria, but the molecular mechanisms 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 wild-type mice, Slc26a6-null mice 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 a molecular pathway that senses and tightly regulates oxalate and citrate levels and may control Ca(2+)-oxalate stone formation.
authors.affiliation: Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, and.
authors.forename: Ehud
authors.initials: E
authors.lastname: Ohana
authors.forename: Nikolay
authors.initials: N
authors.lastname: Shcheynikov
authors.forename: Orson W
authors.initials: OW
authors.lastname: Moe
authors.forename: Shmuel
authors.initials: S
authors.lastname: Muallem
mesh_terms: D000818:Animals; D017920:Antiporters / Q000378:metabolism*; D002951:Citrates / Q000652:urine*; D029382:Dicarboxylic Acid Transporters / Q000378:metabolism*; D005260:Female; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D007669:Kidney Calculi / Q000209:etiology* / Q000378:metabolism / Q000652:urine; D051379:Mice; D018345:Mice, Knockout; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism*; D010070:Oxalates / Q000652:urine*; D017434:Protein Structure, Tertiary; D000076988:Sulfate Transporters; D027981:Symporters / Q000378:metabolism*; D014981:Xenopus
chemical_list: D017920:Antiporters; D002951:Citrates; D029382:Dicarboxylic Acid Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D010070:Oxalates; C490479:Slc13a2 protein, mouse; C466900:Slc26a6 protein, mouse; D000076988:Sulfate Transporters; D027981:Symporters