Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature volume 417, pages 447–452 (2002)Cite this article

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  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)

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  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)

    Article  ADS  CAS  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)

    Article  CAS  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)

    Article  ADS  CAS  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)

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  ADS  Google Scholar 

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

    Article  CAS  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, 181-8611, Japan

    Atsushi Enomoto, Hiroaki Kimura, Arthit Chairoungdua, Yasuhiro Shigeta, Promsuk Jutabha, Seok Ho Cha, Makoto Hosoyamada, Michio Takeda, Hirotaka Matsuo, Yoshikatsu Kanai & Hitoshi Endou

  2. Department of Clinical Preventive Medicine, Nagoya University School of Medicine, Nagoya, 466-8560, Japan

    Atsushi Enomoto, Kaoru Shimokata & Toshimitsu Niwa

  3. Division of Kidney and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan

    Hiroaki Kimura, Kimiyoshi Ichida & Tatsuo Hosoya

  4. Department of Urology, Chiba University School of Medicine, Chiba, 260-8670, Japan

    Yasuhiro Shigeta

  5. Department of Pediatrics, Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan

    Takashi Sekine & Takashi Igarashi

  6. First Department of Physiology, National Defense Medical College, Saitama, 359-8513, Japan

    Hirotaka Matsuo

  7. Second Department of Internal Medicine, National Defense Medical College, Saitama, 359-8513, Japan

    Yuichi Kikuchi

  8. Department of Medicine, JSDF Kumamoto Hospital, Kumamoto, 862-0902, Japan

    Takashi Oda

Authors
  1. Atsushi Enomoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroaki Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arthit Chairoungdua
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasuhiro Shigeta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Promsuk Jutabha
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Seok Ho Cha
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Makoto Hosoyamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michio Takeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Takashi Sekine
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Takashi Igarashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hirotaka Matsuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yuichi Kikuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Takashi Oda
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Kimiyoshi Ichida
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Tatsuo Hosoya
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Kaoru Shimokata
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Toshimitsu Niwa
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Yoshikatsu Kanai
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Hitoshi Endou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hitoshi Endou.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

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). https://doi.org/10.1038/nature742

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature742

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing