Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans
Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans
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DOI：
10.1074/jbc.c800156200
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发表时间：
2008-10-03
影响因子：
4.8
通讯作者：
Sakurai, Hiroyuki
中科院分区：
文献类型：
--
作者：
Anzai, Naohiko;Ichida, Kimiyoshi;Sakurai, Hiroyuki
高尿酸血症是多种疾病的重要因素，包括痛风和心血管疾病。尽管肾脏排泄在很大程度上决定了血浆尿酸盐浓度，但肾脏尿酸盐处理的分子机制仍然难以捉摸。先前，我们在肾近端小管细胞的顶端侧发现了一个主要的尿酸重吸收转运蛋白URAT1 （SLC22A12）。然而，目前尚不清楚URAT1摄取的尿酸如何从管状细胞进入体循环。在这里，我们报道了糖转运促进剂家族成员蛋白GLUT9 （SLC2A9）作为肾小管细胞尿酸的外排转运体。glut9表达的爪蟾卵母细胞介导饱和不饱和转运（K-m: 365 +/- 42 μ m）。这种转运是不依赖于Na+的，在高浓度的细胞外钾离子下，转运倾向于负电位向正电位方向增强。GLUT9的底物特异性和吡嗪酸盐敏感性与URAT1不同。一个SLC22A12没有任何突变的肾性低尿酸血症患者被发现有SLC2A9错义突变，这降低了体外尿酸转运活性，这一事实支持了GLUT9在体内的作用。基于这些数据，我们提出了肾脏跨细胞尿酸转运的新模型；报酬通过位于顶端的URAT1被摄取，并通过位于基底侧的GLUT9离开细胞，我们建议将其重新命名为URATv1（电压驱动的URAT1转运蛋白）。
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 mu m). 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).