Monocarboxylate transporter 12 as a guanidinoacetate efflux transporter in renal proximal tubular epithelial cells

摘要

Guanidinoacetate (GAA), which is a precursor of creatine, is mainly biosynthesized in the renal proximal tubular epithelial cells (RPTECs). Plasma concentration of GAA has been reported to be reduced in patients with monocarboxylate transporter 12 (MCT12) mutation (p.Q215X). However, the mechanism underlying GAA release from the RPTECs remains unclear. Therefore, to elucidate the role of MCT12 in renal GAA release, MCT12-mediated GAA transport was evaluated using the human and rat MCT12-expressing Xenopus laevis oocytes and primary-cultured rat RPTECs. [C-14]GAA uptake by the human and rat MCT12-expressing oocytes was significantly higher than that by the water-injected oocytes. Rat MCT12-mediated uptake of [C-14]GAA by the oocytes was found to be sodium ion (Na+)-independent and exhibited saturable kinetics with a Michaelis-Menten constant of 3.38 mM. Transport activities of rat MCT12 tend to increase along with increasing of extracellular pH. In addition, the efflux transport of [C-14]GAA from the human and rat MCT12-expressing oocytes was significantly higher than that from the water-injected oocytes. These results suggest that both the influx and efflux transport of GAA is mediated by MCT12. In the primary-cultured rat RPTECs, [C-14]GAA efflux transport was significantly reduced by the transfection of MCT12-specific siRNAs, suggesting that MCT12 participates in GAA efflux transport in rat RPTECs. Therefore, it suggests that MCT12 is involved in GAA release from RPTECs to the circulating blood, since MCT12 is known to be localized on the basal membrane of RPTECs.