Molecular identification of a renal urate-anion exchanger that regulates blood urate levels
Molecular identification of a renal urate-anion exchanger that regulates blood urate levels
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DOI：
10.1038/nature742
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发表时间：
2002-05-23
期刊：
影响因子：
64.8
通讯作者：
Endou, H
中科院分区：
文献类型：
--
作者：
Enomoto, A;Kimura, H;Endou, H
尿酸盐是嘌呤代谢的自然产物，是许多疾病过程中涉及的生物氧化剂的清除剂(1-3)，其神经保护能力(4，5)证明了这一点。它在人类血液中的含量(200-500微米)高于其他哺乳动物6，因为人类有一个有效的肾脏尿酸重吸收系统，尽管他们通过突变沉默而进化地丢失了肝脏尿酸酶(6-8)。由于很难理解不同的尿酸盐转运系统和物种差异(6，9，10)，人类肾脏中尿酸盐处理的分子基础仍然不清楚。在这里，我们确定了人类肾脏中长期假设的(9-11)尿酸盐转运体(URAT1，由SLC22A12编码)，一种调节血尿酸水平的尿酸-阴离子交换器，并以尿酸和抗尿酸药物(影响尿酸排泄)为靶标。此外，我们还提供了特发性肾功能低尿酸血症(缺乏血尿酸)患者存在SLC22A12缺陷的证据。URAT1的鉴定应有助于深入了解尿酸稳态的本质，并有助于开发出更好的治疗高尿酸血症的药物，而高尿酸血症是人类进化过程中的一个不利因素。
Urate, a naturally occurring product of purine metabolism, is a scavenger of biological oxidants implicated in numerous disease processes(1-3), as demonstrated by its capacity of neuroprotection(4,5). It is present at higher levels in human blood (200-500 muM) than in other mammals 6, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing(6-8). The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences(6,9,10). Here we identify the long-hypothesized(9-11) urate transporter in the human kidney (URAT1, encoded by SLC22A12), a urate-anion exchanger regulating blood urate levels and targeted by uricosuric and anti-uricosuric agents (which affect excretion of uric acid). Moreover, we provide evidence that patients with idiopathic renal hypo-uricaemia (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.