Sulfate and thiosulfate inhibit oxalate transport via a dPrestin(mSlc26a6)-dependent mechanism in an insect model of calcium oxalate nephrolithiasis

Landry, G. M., Hirata, T., Anderson, J. B., Cabrero, P. , Gallo, C. J.R., Dow, J. A.T. and Romero, M. F. (2016) Sulfate and thiosulfate inhibit oxalate transport via a dPrestin(mSlc26a6)-dependent mechanism in an insect model of calcium oxalate nephrolithiasis. American Journal of Physiology: Renal Physiology, 310(2), F152-F159. (doi:10.1152/ajprenal.00406.2015) (PMID:26538444) (PMCID:PMC4719044)

Landry, G. M., Hirata, T., Anderson, J. B., Cabrero, P. , Gallo, C. J.R., Dow, J. A.T. and Romero, M. F. (2016) Sulfate and thiosulfate inhibit oxalate transport via a dPrestin(mSlc26a6)-dependent mechanism in an insect model of calcium oxalate nephrolithiasis. American Journal of Physiology: Renal Physiology, 310(2), F152-F159. (doi:10.1152/ajprenal.00406.2015) (PMID:26538444) (PMCID:PMC4719044)

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Abstract

Nephrolithiasis is one of the most common urinary tract disorders, with the majority of kidney stones composed of calcium oxalate (CaOx). Given its prevalence (US occurrence 10%), it is still poorly understood, lacking progress in identifying new therapies because of its complex etiology. Drosophila melanogaster (fruitfly) is a recently developed model of CaOx nephrolithiasis. Effects of sulfate and thiosulfate on crystal formation were investigated using the Drosophila model, as well as electrophysiological effects on both Drosophila (Slc26a5/6; dPrestin) and mouse (mSlc26a6) oxalate transporters utilizing the Xenopus laevis oocyte heterologous expression system. Results indicate that both transport thiosulfate with a much higher affinity than sulfate Additionally, both compounds were effective at decreasing CaOx crystallization when added to the diet. However, these results were not observed when compounds were applied to Malpighian tubules ex vivo. Neither compound affected CaOx crystallization in dPrestin knockdown animals, indicating a role for principal cell-specific dPrestin in luminal oxalate transport. Furthermore, thiosulfate has a higher affinity for dPrestin and mSlc26a6 compared with oxalate These data indicate that thiosulfate's ability to act as a competitive inhibitor of oxalate via dPrestin, can explain the decrease in CaOx crystallization seen in the presence of thiosulfate, but not sulfate. Overall, our findings predict that thiosulfate or oxalate-mimics may be effective as therapeutic competitive inhibitors of CaOx crystallization.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cabrero, Mr Pablo and Dow, Professor Julian
Authors: Landry, G. M., Hirata, T., Anderson, J. B., Cabrero, P., Gallo, C. J.R., Dow, J. A.T., and Romero, M. F.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:American Journal of Physiology: Renal Physiology
Publisher:American Physiological Society
ISSN:1931-857X
ISSN (Online):1522-1466

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
538311Drosophila model of oxalate nephrolithiasisJulian DowNational Institute of Health (NIH-BETH)1R01DK092408-01RI MOLECULAR CELL & SYSTEMS BIOLOGY
538312Drosophila model of oxalate nephrolithiasisJulian DowNational Institute of Health (NIH-BETH)5R01DK092408-02RI MOLECULAR CELL & SYSTEMS BIOLOGY