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

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.

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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.

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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.

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

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