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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 586/5/1291    most recent jphysiol.2007.143222v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clark, J. S. Articles by Alper, S. L. Search for Related Content PubMed PubMed Citation Articles by Clark, J. S. Articles by Alper, S. L. Related Collections Molecular and Genomic Related Article

¹ Molecular and Vascular Medicine Unit and Renal Division, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA

The mouse is refractory to lithogenic agents active in rats and humans, and so has been traditionally considered a poor experimental model for nephrolithiasis. However, recent studies have identified slc26a6 as an oxalate nephrolithiasis gene in the mouse. Here we extend our earlier demonstration of different anion selectivities of the orthologous mouse and human SLC26A6 polypeptides to investigate the correlation between species-specific differences in SLC26A6 oxalate/anion exchange properties as expressed in Xenopus oocytes and in reported nephrolithiasis susceptibility. We find that human SLC26A6 mediates minimal rates of Cl^– exchange for Cl^–, sulphate or formate, but rates of oxalate/Cl^– exchange roughly equivalent to those of mouse slc2a6. Both transporters exhibit highly cooperative dependence of oxalate efflux rate on extracellular [Cl^–], but whereas the K_1/2 for extracellular [Cl^–] is only 8 mM for mouse slc26a6, that for human SLC26A6 is 62 mM. This latter value approximates the reported mean luminal [Cl^–] of postprandial human jejunal chyme, and reflects contributions from both transmembrane and C-terminal cytoplasmic domains of human SLC26A6. Human SLC26A6 variant V185M exhibits altered [Cl^–] dependence and reduced rates of oxalate/Cl^– exchange. Whereas mouse slc26a6 mediates bidirectional electrogenic oxalate/Cl^– exchange, human SLC26A6-mediated oxalate transport appears to be electroneutral. We hypothesize that the low extracellular Cl^– affinity and apparent electroneutrality of oxalate efflux characterizing human SLC26A6 may partially explain the high human susceptibility to nephrolithiasis relative to that of mouse. SLC26A6 sequence variant(s) are candidate risk modifiers for nephrolithiasis.

(Received 15 August 2007; accepted after revision 19 December 2007; first published online 3 January 2008)
Corresponding author S. L. Alper: Molecular and Vascular Medicine Unit, Beth Israel Deaconess Medical Center E/RW763, 330 Brookline Avenue, Boston, MA 02215, USA. Email: salper{at}bidmc.harvard.edu

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				M. Soleimani The role of SLC26A6-mediated chloride/oxalate exchange in causing susceptibility to nephrolithiasis J. Physiol., March 1, 2008; 586(5): 1205 - 1206. [Full Text] [PDF]