title: Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans.
abstract: Hyperuricemia is a significant factor in a variety of diseases, including gout and cardiovascular diseases. Although renal excretion largely determines plasma urate concentration, the molecular mechanism of renal urate handling remains elusive. Previously, we identified a major urate reabsorptive transporter, URAT1 (SLC22A12), on the apical side of the renal proximal tubular cells. However, it is not known how urate taken up by URAT1 exits from the tubular cell to the systemic circulation. Here, we report that a sugar transport facilitator family member protein GLUT9 (SLC2A9) functions as an efflux transporter of urate from the tubular cell. GLUT9-expressed Xenopus oocytes mediated saturable urate transport (K(m): 365+/-42 microm). The transport was Na(+)-independent and enhanced at high concentrations of extracellular potassium favoring negative to positive potential direction. Substrate specificity and pyrazinoate sensitivity of GLUT9 was distinct from those of URAT1. The in vivo role of GLUT9 is supported by the fact that a renal hypouricemia patient without any mutations in SLC22A12 was found to have a missense mutation in SLC2A9, which reduced urate transport activity in vitro. Based on these data, we propose a novel model of transcellular urate transport in the kidney; urate [corrected] is taken up via apically located URAT1 and exits the cell via basolaterally located GLUT9, which we suggest be renamed URATv1 (voltage-driven urate transporter 1).
authors.affiliation: Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 181-8611 Tokyo, Japan. anzai@ks.kyorin-u.ac.jp
authors.forename: Naohiko
authors.initials: N
authors.lastname: Anzai
authors.forename: Kimiyoshi
authors.initials: K
authors.lastname: Ichida
authors.forename: Promsuk
authors.initials: P
authors.lastname: Jutabha
authors.forename: Toru
authors.initials: T
authors.lastname: Kimura
authors.forename: Ellappan
authors.initials: E
authors.lastname: Babu
authors.forename: Chun Ji
authors.initials: CJ
authors.lastname: Jin
authors.forename: Sunena
authors.initials: S
authors.lastname: Srivastava
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Kitamura
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hisatome
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Endou
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sakurai
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000150:complications / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D033461:Hyperuricemia / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D017136:Ion Transport / Q000235:genetics; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008954:Models, Biological; D020125:Mutation, Missense; D009865:Oocytes; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D014527:Uric Acid / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; C411811:SLC2A9 protein, human; D014527:Uric Acid