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J. Biol. Chem., Vol. 283, Issue 40, 26834-26838, October 3, 2008

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Plasma Urate Level Is Directly Regulated by a Voltage-driven Urate Efflux Transporter URATv1 (SLC2A9) in Humans^*

Naohiko Anzai¹, Kimiyoshi Ichida, Promsuk Jutabha^¶, Toru Kimura, Ellappan Babu, Chun Ji Jin, Sunena Srivastava, Kenichiro Kitamura^||, Ichiro Hisatome^**, Hitoshi Endou^¶, and Hiroyuki Sakurai

From the Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 181-8611 Tokyo, the Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, 192-0392 Tokyo, the ^¶Kobuchisawa Research Laboratories, Fuji Biomedix Co. Ltd., 408-0044 Yamanashi, the ^||Department of Nephrology, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, 860-8556 Kumamoto, the ^**Department of Cardiovascular Medicine, Tottori University Faculty of Medicine, 680-8550 Tottori, and the J-Pharma Co. Ltd., 160-0022 Tokyo, Japan

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 µM). 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; Remunurate 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).

Received for publication, August 6, 2008

^* This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Japan Society for the Promotion of Science, the Takeda Science Foundation, the Salt Science Research Foundation (Grant 0721), the Gout Research Foundation of Japan, and the Shimabara Foundation and Kyorin University School of Medicine (Collaborative Project 2008). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains three supplemental figures and supplemental text.

¹ To whom correspondence should be addressed: 6-20-2, Shinkawa, Mitakashi, Tokyo 181-8611, Japan. Tel.: 81-422-47-5511; Fax: 81-422-79-1321; E-mail: anzai{at}ks.kyorin-u.ac.jp.

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