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 processes, as demonstrated by its capacity of neuroprotection. It is present at higher levels in human blood (200 500 microM) than in other mammals, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing. The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences. Here we identify the long-hypothesized 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.
Enomoto
Atsushi
A
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo 181-8611, Japan.
Kimura
Hiroaki
H
Chairoungdua
Arthit
A
Shigeta
Yasuhiro
Y
Jutabha
Promsuk
P
Cha
Seok Ho
SH
Hosoyamada
Makoto
M
Takeda
Michio
M
Sekine
Takashi
T
Igarashi
Takashi
T
Matsuo
Hirotaka
H
Kikuchi
Yuichi
Y
Oda
Takashi
T
Ichida
Kimiyoshi
K
Hosoya
Tatsuo
T
Shimokata
Kaoru
K
Niwa
Toshimitsu
T
Kanai
Yoshikatsu
Y
Endou
Hitoshi
H
D000595:Amino Acid Sequence; D000818:Animals; D000838:Anions / Q000097:blood* / Q000378:metabolism; D001692:Biological Transport; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D003001:Cloning, Molecular; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000737:chemistry* / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D014527:Uric Acid / Q000097:blood* / Q000378:metabolism; D014981:Xenopus
D000838:Anions; D002352:Carrier Proteins; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; D012333:RNA, Messenger; C491241:SLC22A12 protein, human; C103862:urate transporter; D014527:Uric Acid