Recent advances in renal urate transport: characterization of candidate transporters indicated by genome-wide association studies.
Humans have higher serum uric acid levels than other mammalian species owing to the genetic silencing of the hepatic enzyme uricase that metabolizes uric acid into allantoin. Urate (the ionized form of uric acid) is generated from purine metabolism and it may provide antioxidant defense in the human body. Despite its potential advantage, sustained hyperuricemia has pathogenetic causes in gout and renal diseases, and putative roles in hypertension and cardiovascular diseases. Since the kidney plays a dominant role in maintaining plasma urate levels through the excretion process, it is important to understand the molecular mechanism of renal urate handling. Although the molecular identification of a kidney-specific urate/anion exchanger URAT1 in 2002 paved the way for successive identification of several urate transport-related proteins, the entire picture of effective renal urate handling in humans has not yet been clarified. Recently, several genome-wide association studies identified a substantial association between uric acid concentration and single nucleotide polymorphisms in at least ten genetic loci including eight transporter-coding genes. In 2008, we functionally characterized the facilitatory glucose transporter family member SLC2A9 (GLUT9), one of the candidate genes for urate handling, as a voltage-driven urate transporter URATv1 at the basolateral side of renal proximal tubules that comprises the main route of the urate reabsorption pathway, in tandem with URAT1 at the apical side. In this review, recent findings concerning these candidate molecules are presented.
Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, Japan. anzai-path@umin.ac.jp
Naohiko
N
Anzai
Promsuk
P
Jutabha
Sirirat
S
Amonpatumrat-Takahashi
Hiroyuki
H
Sakurai
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D055106:Genome-Wide Association Study; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics; D006801:Humans; D033461:Hyperuricemia / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008565:Membrane Proteins / Q000502:physiology; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics*; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D050609:Sodium-Phosphate Cotransporter Proteins, Type I / Q000235:genetics; D014527:Uric Acid / Q000097:blood / Q000378:metabolism*
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D051246:Glucose Transport Proteins, Facilitative; D008565:Membrane Proteins; D027501:Monocarboxylic Acid Transporters; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C509768:PDZK1IP1 protein, human; C549233:SLC16A9 protein, human; C493546:SLC17A1 protein, human; C493550:SLC17A3 protein, human; C491241:SLC22A12 protein, human; C411811:SLC2A9 protein, human; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D014527:Uric Acid