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Molecular identification of a renal urate–anion exchanger that regulates blood urate levels


Urate, a naturally occurring product of purine metabolism, is a scavenger of biological oxidants implicated in numerous disease processes1,2,3, as demonstrated by its capacity of neuroprotection4,5. It is present at higher levels in human blood (200–500 µM) than in other mammals6, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing6,7,8. The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences6,9,10. Here we identify the long-hypothesized9,10,11 urate transporter in the human kidney (URAT1, encoded by SLC22A12), a urate–anion exchanger regulating blood urate levels and targeted by uricosuric and antiuricosuric agents (which affect excretion of uric acid). Moreover, we provide evidence that patients with idiopathic renal hypouricaemia (lack of blood uric acid) have defects in SLC22A12. Identification of URAT1 should provide insights into the nature of urate homeostasis, as well as lead to the development of better agents against hyperuricaemia, a disadvantage concomitant with human evolution.

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Figure 1: Sequence analysis and localization of URAT1.
Figure 2: Functional expression of URAT1 in Xenopus oocytes.
Figure 3: Urate uptake via URAT1 is trans-stimulated by intracellular anions.
Figure 4: Mutations within SLC22A12 are associated with idiopathic renal hypouricaemia.


  1. Halliwell, B. in Handbook of Antioxidants (eds Cadenas, E. & Packer, L.) 243–255 (Dekker, New York, 1996)

    Google Scholar 

  2. Ames, B. N., Cathcart, R., Schwiers, E. & Hochstein, P. Uric acid provides an antioxidant defence in humans against oxidant- and radical-caused aging and cancer: A hypothesis. Proc. Natl Acad. Sci. USA 78, 6858–6862 (1981)

    ADS  CAS  Article  Google Scholar 

  3. Becker, B. F. Towards the physiological function of uric acid. Free Radical Biol. Med. 14, 615–631 (1993)

    CAS  Article  Google Scholar 

  4. Hooper, D. C. et al. Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis. Proc. Natl Acad. Sci. USA 95, 675–680 (1998)

    ADS  CAS  Article  Google Scholar 

  5. Keller, J. N. et al. Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction. J. Neurosci. 18, 687–697 (1998)

    CAS  Article  Google Scholar 

  6. Abramson, R. G. & Lipkowitz, M. S. in Basic Principles in Transport, Comparative Physiology Vol. 3 (ed. Kinne, R. K. H.) 115–153 (Karger, Basel, 1990)

    Google Scholar 

  7. Wu, X., Lee, C. C., Muzny, D. M. & Caskey, C. T. Urate oxidase: Primary structure and evolutionary implications. Proc. Natl Acad. Sci. USA 86, 9412–9416 (1989)

    ADS  CAS  Article  Google Scholar 

  8. Wu, X., Muzny, D. M., Lee, C. C. & Caskey, C. T. Two independent mutational events in the loss of urate oxidase. J. Mol. Evol. 34, 78–84 (1992)

    ADS  CAS  Article  Google Scholar 

  9. Maesaka, J. K. & Fishbane, S. Regulation of renal urate excretion: A critical review. Am. J. Kidney Dis. 32, 917–933 (1998)

    CAS  Article  Google Scholar 

  10. Sica, D. A. & Schoolwerth, A. C. in The Kidney, 6th edn (ed. Brenner, B. M.) 680–700 (Saunders, Philadelphia, 2000)

    Google Scholar 

  11. Berlinger, R. W., Hilton, J. G., Yü, T. F. & Kennedy, T. J. Jr The renal mechanism for urate excretion in man. J. Clin. Invest. 29, 396–401 (1950)

    Article  Google Scholar 

  12. Sekine, T., Watanabe, N., Hosoyamada, M., Kanai, Y. & Endou, H. Expression cloning and characterization of a novel multispecific organic anion transporter. J. Biol. Chem. 272, 18526–18529 (1997)

    CAS  Article  Google Scholar 

  13. Sweet, D. H., Wolff, N. A. & Pritchard, J. B. Expression cloning and characterization of ROAT1. The basolateral organic anion transporter in rat kidney. J. Biol. Chem. 272, 30088–30095 (1997)

    CAS  Article  Google Scholar 

  14. Cha, S. H. et al. Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta. J. Biol. Chem. 275, 4507–4512 (2000)

    CAS  Article  Google Scholar 

  15. International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001)

    Article  Google Scholar 

  16. Gründemann, D., Gorboulev, V., Gambaryan, S., Veyhl, M. & Koepsell, H. Drug excretion mediated by a new prototype of polyspecific transporter. Nature 372, 549–552 (1994)

    ADS  Article  Google Scholar 

  17. Koepsell, H. Organic cation transporters in intestine, kidney, liver, and brain. Annu. Rev. Physiol. 60, 243–246 (1998)

    CAS  Article  Google Scholar 

  18. Roch-Ramel, F., Werner, D. & Guisan, B. Urate transport in brush-border membrane of human kidney. Am. J. Physiol. 266, F797–F805 (1994)

    CAS  PubMed  Google Scholar 

  19. Guggino, S. E., Martin, G. J. & Aronson, P. S. Specificity and modes of the anion exchanger in dog renal microvillus membranes. Am. J. Physiol. 244, F612–F621 (1983)

    CAS  PubMed  Google Scholar 

  20. Kahn, A. M., Branham, S. & Weinman, E. J. Mechanism of urate and p-aminohippurate transport in rat renal microvillus membrane vesicles. Am. J. Physiol. 245, F151–F158 (1983)

    CAS  Article  Google Scholar 

  21. Emmerson, B. T. The management of gout. N. Engl. J. Med. 334, 445–451 (1996)

    CAS  Article  Google Scholar 

  22. Cullem, J. H., LeVine, M. & Fiore, J. M. Studies on hyperuricemia produced by pyrazinamide. Am. J. Med. 23, 587–595 (1957)

    Article  Google Scholar 

  23. Roch-Ramel, F., Guisan, B. & Schild, L. Indirect coupling of urate and p-aminohippurate transport to sodium in human brush-border membrane vesicles. Am. J. Physiol. 270, F61–F68 (1996)

    CAS  PubMed  Google Scholar 

  24. Mandel, L. J. Metabolic substrates, cellular energy production, and the regulation of proximal tubular transport. Annu. Rev. Physiol. 47, 85–101 (1985)

    CAS  Article  Google Scholar 

  25. Kikuchi, Y. et al. Patients with renal hypouricemia with exercise-induced acute renal failure and chronic renal dysfunction. Clin. Nephrol. 53, 467–472 (2000)

    CAS  PubMed  Google Scholar 

  26. Igarashi, T., Sekine, T., Sugimura, H., Hayakawa, H. & Arayama, T. Acute renal failure after exercise in a child with renal hypouricemia. Pediatr. Nephrol. 7, 292–293 (1993)

    CAS  Article  Google Scholar 

  27. Halabe, A. & Sperling, O. Uric acid nephrolithiasis. Miner. Electrol. Metab. 20, 424–431 (1994)

    CAS  Google Scholar 

  28. Lipkowitz, M. S. et al. Functional reconstitution, membrane targeting, genomic structure, and chromosomal localization of a human urate transporter. J. Clin. Invest. 107, 1103–1115 (2001)

    CAS  Article  Google Scholar 

  29. Johnson, R. J., Kivlighn, S. D., Kim, Y. G., Suga, S. & Fogo, A. B. Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease, and renal disease. Am. J. Kidney Dis. 33, 225–234 (1999)

    CAS  Article  Google Scholar 

  30. Cutler, R. G. Antioxidants and aging. Am. J. Clin. Nutr. 53, 373S–379S (1991)

    CAS  Article  Google Scholar 

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We thank the patients for contributing to this study; Y. Terado for discussions on immunohistochemistry, K. Tachampa and J. Y. Kim for help in characterization of URAT1; A. Toki, M. Takahashi and M. Ikeda for technical assistance; and Merck Research Laboratories for providing losartan and EXP-3174. The anti-URAT1 polyclonal antibody was supplied by Trans Genic Inc. (formerly Kumamoto Immunochemical Laboratory). This work was supported in part by grants from the Japanese Ministry of Education, Science, Sports, Culture and Technology, Grants-in-Aid for Scientific Research, and High-Tech Research Center, the Science Research Promotion Fund of the Japan Private School Promotion Foundation.

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Correspondence to Hitoshi Endou.

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Enomoto, A., Kimura, H., Chairoungdua, A. et al. Molecular identification of a renal urate–anion exchanger that regulates blood urate levels. Nature 417, 447–452 (2002).

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