Sulfate and thiosulfate inhibit oxalate transport via a dPrestin (Slc26a6)-dependent mechanism in an insect model of calcium oxalate nephrolithiasis

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.

Progress in Understanding the Genetics of Calcium-Containing Nephrolithiasis

“…Indeed, the Drosophila homolog of SLC26A6 (encoding dPrestin) seems to have conserved chloride and oxalate exchange function and has been used very recently to explore therapeutic inhibitors of calcium oxalate crystallization. 84 Such basic biologic research may have important future translational effects in human stone disease.…”

Garcinia cambogia extract removes calcium oxalate kidney stones in both genetic and non-genetic Drosophila models of nephrolithiasis

“…Mutations of Slc26a6 have been identified from patients with nephrolithiasis. It also has been shown that RNAi knockdown of dPrestin specifically in principal cells, the Drosophila homolog of Slc26a6, led to decreased calcium oxalate stone formation in Malpighian tubules (Landry et al, 2016). These results strongly suggest that fruit fly could be an ideal genetic kidney stone disease model to screen novel genes involved in the pathogenesis of nephrolithiasis and validate the function of candidate genes identified from patients with nephrolithiasis in vivo (Hirata et al, 2012a).…”

Physiology, Development, and Disease Modeling in the Drosophila Excretory System

“…One of the limited treatments available for humans is consumption of citrate, as metal citrate salts tend to be highly soluble. Administration of citrate (Chen et al 2011;Ho et al 2013), thiosulfate, or sulfate (Landry et al 2016) in Drosophila similarly reduces stone burden and extends lifespan.…”