Urolithiasis is one of the most common urologic diseases in industrialized societies. Calcium oxalate is the predominant component in 70–80% of kidney stones1, and small changes in urinary oxalate concentration affect the risk of stone formation2. SLC26A6 is an anion exchanger expressed on the apical membrane in many epithelial tissues, including kidney and intestine3,4,5,6. Among its transport activities, SLC26A6 mediates Cl−-oxalate exchange5,6,7,8,9. Here we show that mutant mice lacking Slc26a6 develop a high incidence of calcium oxalate urolithiasis. Slc26a6-null mice have significant hyperoxaluria and elevation in plasma oxalate concentration that is greatly attenuated by dietary oxalate restriction. In vitro flux studies indicated that mice lacking Slc26a6 have a defect in intestinal oxalate secretion resulting in enhanced net absorption of oxalate. We conclude that the anion exchanger SLC26A6 has a major constitutive role in limiting net intestinal absorption of oxalate, thereby preventing hyperoxaluria and calcium oxalate urolithiasis.
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Asplin, J.R. Hyperoxaluric calcium nephrolithiasis. Endocrinol. Metab. Clin. North Am. 31, 927–949 (2002).
Robertson, W.G. & Peacock, M. The cause of idiopathic calcium stone disease: hypercalciuria or hyperoxaluria? Nephron 26, 105–110 (1980).
Waldegger, S. et al. Cloning and characterization of SLC26A6, a novel member of the solute carrier 26 gene family. Genomics 72, 43–50 (2001).
Lohi, H. et al. Mapping of five new putative anion transporter genes in human and characterization of SLC26A6, a candidate gene for pancreatic anion exchanger. Genomics 70, 102–112 (2000).
Knauf, F. et al. Identification of a chloride-formate exchanger expressed on the brush border membrane of renal proximal tubule cells. Proc. Natl. Acad. Sci. USA 98, 9425–9430 (2001).
Wang, Z., Petrovic, S., Mann, E. & Soleimani, M. Identification of an apical Cl−/HCO3− exchanger in the small intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 282, G573–G579 (2002).
Jiang, Z., Grichtchenko, I.I., Boron, W.F. & Aronson, P.S. Specificity of anion exchange mediated by mouse Slc26a6. J. Biol. Chem. 277, 33963–33967 (2002).
Xie, Q., Welch, R., Mercado, A., Romero, M.F. & Mount, D.B. Molecular characterization of the murine Slc26a6 anion exchanger: functional comparison with Slc26a1. Am. J. Physiol. Renal Physiol. 283, F826–F838 (2002).
Chernova, M.N. et al. Functional comparison of mouse Slc26a6 anion exchanger with human SLC26A6 polypeptide variants: differences in anion selectivity, regulation, and electrogenicity. J. Biol. Chem. 280, 8564–8580 (2005).
Wang, Z. et al. Renal and intestinal transport defects in Slc26a6-null mice. Am. J. Physiol. Cell Physiol. 288, C957–C965 (2005).
Werness, P.G., Brown, C.M., Smith, L.H. & Finlayson, B. EQUIL2: a BASIC computer program for the calculation of urinary saturation. J. Urol. 134, 1242–1244 (1985).
Asplin, J. et al. Supersaturation and stone composition in a network of dispersed treatment sites. J. Urol. 159, 1821–1825 (1998).
Wang, T., Giebisch, G. & Aronson, P.S. Effects of formate and oxalate on volume absorption in rat proximal tubule. Am. J. Physiol. 263, F37–F42 (1992).
Wang, T., Segal, A.S., Giebisch, G. & Aronson, P.S. Stimulation of chloride transport by cAMP in rat proximal tubules. Am. J. Physiol. 268, F204–F210 (1995).
Wang, T., Egbert, A.L. Jr., Abbiati, T., Aronson, P.S. & Giebisch, G. Mechanisms of stimulation of proximal tubule chloride transport by formate and oxalate. Am. J. Physiol. 271, F446–F450 (1996).
Holmes, R.P., Ambrosius, W.T. & Assimos, D.G. Dietary oxalate loads and renal oxalate handling. J. Urol. 174, 943–947 (2005).
Hatch, M., Freel, R.W. & Vaziri, N.D. Intestinal excretion of oxalate in chronic renal failure. J. Am. Soc. Nephrol. 5, 1339–1343 (1994).
Holmes, R.P. & Assimos, D.G. The impact of dietary oxalate on kidney stone formation. Urol. Res. 32, 311–316 (2004).
Kuo, S.M. & Aronson, P.S. Pathways for oxalate transport in rabbit renal microvillus membrane vesicles. J. Biol. Chem. 271, 15491–15497 (1996).
Freel, R.W., Hatch, M., Green, M. & Soleimani, M. Ileal oxalate absorption and urinary oxalate excretion are enhanced in Slc26a6-null mice. Am. J. Physiol. Gastrointest. Liver Physiol. advanced online publication 22 December 2005 (10.1152/ajpgi.00481.2005).
Deng, C., Wynshaw-Boris, A., Zhou, F., Kuo, A. & Leder, P. Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 84, 911–921 (1996).
Kocinsky, H.S. et al. Use of phospho-specific antibodies to determine the phosphorylation of endogenous Na+/H+ exchanger NHE3 at PKA consensus sites. Am. J. Physiol. Renal Physiol. 289, F249–F258 (2005).
Karniski, L.P. et al. Formate-stimulated NaCl absorption in the proximal tubule is independent of the pendrin protein. Am. J. Physiol. Renal Physiol. 283, F952–F956 (2002).
McConnell, K.R. & Aronson, P.S. Effects of inhibitors on anion exchangers in rabbit renal brush border membrane vesicles. J. Biol. Chem. 269, 21489–21494 (1994).
Wu, M.S., Biemesderfer, D., Giebisch, G. & Aronson, P.S. Role of NHE3 in mediating renal brush border Na+-H+ exchange. Adaptation to metabolic acidosis. J. Biol. Chem. 271, 32749–32752 (1996).
Yasue, T. Histochemical identification of calcium oxalate. Acta Histochem. et Cytochem. 2, 83–95 (1969).
Hoppe, B., Kemper, M.J., Hvizd, M.G., Sailer, D.E. & Langman, C.B. Simultaneous determination of oxalate, citrate and sulfate in children's plasma with ion chromatography. Kidney Int. 53, 1348–1352 (1998).
Palgi, N., Vatnick, I. & Pinshow, B. Oxalate, calcium and ash intake and excretion balances in fat sand rats (Psammomys obesus) feeding on two different diets. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 141, 48–53 (2005).
Vidyasagar, S., Rajendran, V.M. & Binder, H.J. Three distinct mechanisms of HCO3− secretion in rat distal colon. Am. J. Physiol. Cell Physiol. 287, C612–C621 (2004).
This work was supported by US National Institutes of Health grants DK33793, DK17433, DK56788 and DK60699.
The authors declare no competing financial interests.
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Jiang, Z., Asplin, J., Evan, A. et al. Calcium oxalate urolithiasis in mice lacking anion transporter Slc26a6. Nat Genet 38, 474–478 (2006). https://doi.org/10.1038/ng1762
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