Basic ResearchSLC26A6 and NaDC-1 Transporters Interact to Regulate Oxalate and Citrate HomeostasisOhana, Ehud*; Shcheynikov, Nikolay*; Moe, Orson W.†; Muallem, Shmuel* Author Information *Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, and †Department of Internal Medicine, Department of Physiology, and Charles and Jane Pak Center of Mineral Metabolism, University of Texas Southwestern Medical Center, Dallas, Texas E.O. and N.S. contributed equally to this work. Correspondence: Dr. Shmuel Muallem, National Institute of Dental and Craniofacial Research, National Institute of Health, Building 10, Room 1N-112, Bethesda, MD 20892. Email: [email protected]. Received January 21, 2013 Accepted April 24, 2013 Journal of the American Society of Nephrology 24(10):p 1617-1626, October 2013. | DOI: 10.1681/ASN.2013010080 Buy Metrics Abstract The combination of hyperoxaluria and hypocitraturia can trigger Ca2+-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 Ca2+-oxalate stone formation. Copyright © 2013 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.