Title: An Oxalate/Citrate Homeostatic Pathway: The Oxalate Slc26a6 and Citrate NaDC-1 Transporters Interplay
Abstract: Stone formation is one of the most common urologic diseases in industrialized societies, most prevalent in the kidney and salivary glands. A predominant component of kidney stones is the Ca2+-oxalate crystals found in more than 70% of cases. The stones are formed when renal oxalate and Ca2+ loads increase as a result of their increased level in the filtrate. Stone formation is normally prevented by chelation of urinary Ca2+ by citrate. A change in the oxalate/citrate balance is also required for stone formation. A link between Ca2+-oxalate kidney stones and the oxalate transporter Slc26a6 has been described in Slc26a6-/- mice, where the major phenotype is Ca2+-oxalate stone formation. Nevertheless, the molecular mechanism that maintains oxalate/citrate balance remains unknown. Here, we report in-vivo and in-vitro interplay between the oxalate transporter Slc26a6 and the citrate transporter NaDC-1 to achieve a balanced citrate/oxalate homeostasis. Thus, Slc26a6 markedly inhibits NaDC-1 to limit citrate absorption at increased oxalate loads. At the same time, NaDC-1 activates Slc26a6 to allow oxalate clearance when citrate load is high. The interaction between the oxalate and citrate transporters is mediated by the Slc26a6 STAS domain and the NaDC-1 first intracellular loop. The STAS domain and the first intracellular loop are sufficient to mediate the reciprocal regulation. Accordingly, deletion of Slc26a6 in mice enhanced the activity of the native NaDC-1. These findings reveal a molecular pathway that senses and tightly regulates renal oxalate and citrate that likely function in other organs, such as the salivary glands, to guard against Ca2+-oxalate stone formation.