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Clinical and Experimental Nephrology
Published in: Clinical and Experimental Nephrology 1/2012

01-02-2012 | Review article

Recent advances in renal urate transport: characterization of candidate transporters indicated by genome-wide association studies

Authors: Naohiko Anzai, Promsuk Jutabha, Sirirat Amonpatumrat-Takahashi, Hiroyuki Sakurai

Published in: Clinical and Experimental Nephrology | Issue 1/2012

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Abstract

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.
Literature
1.
Sica DA, Schoolwerth AC. Renal handling of organic anions and cations: excretion of uric acid. In: Brenner BM, editor. The Kidney. 6th ed. Philadelphia: WB Saunders; 2000. p. 680–700.
2.
Anzai N, Kanai Y, Endou H. New insights into renal transport of urate. Curr Opin Rheumatol. 2007;19:151–7.PubMedCrossRef
3.
Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, Cha SH, et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature. 2002;417:447–52.PubMed
4.
Anzai N, Kanai Y, Endou H. Organic anion transporter family: current knowledge. J Pharmacol Sci. 2006;100:411–26.PubMedCrossRef
5.
Jutabha P, Kanai Y, Hosoyamada H, Chairoungdua A, Kim DK, Iribe Y, et al. Identification of a novel voltage-driven organic anion transporter present at apical membrane of renal proximal tubule. J Biol Chem. 2003;278:27930–8.PubMedCrossRef
6.
van Aubel RA, Smeets PH, van den Heuvel JJ, Russel FG. Human organic anion transporter MRP4 (ABCC4) is an efflux pump for the purine end metabolite urate with multiple allosteric substrate binding sites. Am J Physiol Renal Physiol. 2005;288:F327–33.PubMedCrossRef
7.
Gopal E, Fei YJ, Sugawara M, Miyauchi S, Zhuang L, Martin P, et al. Expression of slc5a8 in kidney and its role in Na+-coupled transport of lactate. J Biol Chem. 2004;279:44522–32.PubMedCrossRef
8.
Gopal E, Umapathy NS, Martin PM, Ananth S, Gnana-Prakasam JP, Becker H, et al. Cloning and functional characterization of human SMCT2 (SLC5A12) and expression pattern of the transporter in kidney. Biochim Biophys Acta. 2007;1768:2690–7.PubMedCrossRef
9.
Bahn A, Hagos Y, Reuter S, Balen D, Brzica H, Krick W, et al. Identification of a new urate and high affinity nicotinate transporter, hOAT10 (SLC22A13). J Biol Chem. 2008;283:16332–41.PubMedCrossRef
10.
Vitart V, Rudan I, Hayward C, Gray NK, Floyd J, Palmer CN, et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet. 2008;40:437–42.PubMedCrossRef
11.
Anzai N, Ichida K, Jutabha P, Kimura T, Babu E, Jin CJ, et al. Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans. J Biol Chem. 2008;283:26834–8.PubMedCrossRef
12.
Caulfield MJ, Munroe PB, O’Neill D, Witkowska K, Charchar FJ, Doblado M, et al. SLC2A9 is a high-capacity urate transporter in humans. PLoS Med. 2008;5:e197.PubMedCrossRef
13.
Woodward OM, Köttgen A, Coresh J, Boerwinkle E, Guggino WB, Köttgen M. Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc Natl Acad Sci USA. 2009;106:10338–42.PubMedCrossRef
14.
Anzai N, Miyazaki H, Noshiro R, Khamdang S, Chairoungdua A, Shin HJ, et al. The multivalent PDZ domain-containing protein PDZK1 regulates transport activity of renal urate-anion exchanger URAT1 via its C terminus. J Biol Chem. 2004;279:45942–50.PubMedCrossRef
15.
McCarthy MI, Abecasis GR, Cardon LR, Goldstein DB, Little J, Ioannidis JP, et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet. 2008;9:356–69.PubMedCrossRef
16.
Li S, Sanna S, Maschio A, Busonero F, Usala G, Mulas A, et al. The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts. PLoS Genet. 2007;3:e194.PubMedCrossRef
17.
Wallace C, Newhouse SJ, Braund P, Zhang F, Tobin M, Falchi M, et al. Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Am J Hum Genet. 2008;82:139–49.PubMedCrossRef
18.
Döring A, Gieger C, Mehta D, Gohlke H, Prokisch H, Coassin S, et al. SLC2A9 influences uric acid concentrations with pronounced sex-specific effects. Nat Genet. 2008;40:430–6.PubMedCrossRef
19.
Stark K, Reinhard W, Neureuther K, Wiedmann S, Sedlacek K, Baessler A, et al. Association of common polymorphisms in GLUT9 gene with gout but not with coronary artery disease in a large case-control study. PLoS One. 2008;3:e1948.PubMedCrossRef
20.
Brandstätter A, Kiechl S, Kollerits B, Hunt SC, Heid IM, Coassin S, et al. Sex-specific association of the putative fructose transporter SLC2A9 variants with uric acid levels is modified by BMI. Diabetes Care. 2008;31:1662–7.PubMedCrossRef
21.
Dehghan A, Köttgen A, Yang Q, Hwang SJ, Kao WL, Rivadeneira F, et al. Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study. Lancet. 2008;372:1953–61.PubMedCrossRef
22.
Kolz M, Johnson T, Sanna S, Teumer A, Vitart V, Perola M, et al. Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations. Plos Genet. 2009;5:1–10.CrossRef
23.
Hollis-Moffatt JE, Xu X, Dalbeth N, Merriman ME, Topless R, Waddell C, et al. Role of the urate transporter SLC2A9 gene in susceptibility to gout in New Zealand Māori, Pacific Island, and Caucasian case-control sample sets. Arthritis Rheum. 2009;60:3485–92.PubMedCrossRef
24.
Tu HP, Chen CJ, Tovosia S, Ko AM, Lee CH, Ou TT, et al. Associations of a nonsynonymous variant in SLC2A9 with gouty arthritis and uric acid levels in Han Chinese and Solomon Islanders. Ann Rheum Dis. 2010;69:887–90.PubMedCrossRef
25.
Hediger MA, Johnson RJ, Miyazaki H, Endou H. Molecular physiology of urate transport. Physiology (Bethesda). 2005;20:125–33.CrossRef
26.
Enomoto A, Endou H. Roles of organic anion transporters (OATs) and a urate transporter (URAT1) in the pathophysiology of human disease. Clin Exp Nephrol. 2005;9:195–205.PubMedCrossRef
27.
Anzai N, Enomoto A, Endou H. Renal urate handling: clinical relevance of recent advances. Curr Rheumatol Rep. 2005;7:227–34.PubMedCrossRef
28.
Mount DB, Kwon CY, Zandi-Nejad K. Renal urate transport. Rheum Dis Clin North Am. 2006;32:313–31.PubMedCrossRef
29.
Taniguchi A, Kamatani N. Control of renal uric acid excretion and gout. Curr Opin Rheumatol. 2008;20:192–7.PubMedCrossRef
30.
Augustin R, Carayannopoulos MO, Dowd LO, Phay JE, Moley JF, Moley KH. Identification and characterization of human glucose transporter-like protein-9 (GLUT9): alternative splicing alters trafficking. J Biol Chem. 2004;279:16229–36.PubMedCrossRef
31.
Ekaratanawong S, Anzai N, Jutabha P, Miyazaki H, Noshiro R, Takeda M. Human organic anion transporter 4 is a renal apical organic anion/dicarboxylate exchanger in the proximal tubules. J Pharmacol Sci. 2004;94:297–304.PubMedCrossRef
32.
Anzai N, Jutabha P, Kimura T, Fukutomi T. Urate transport: relationship with serum urate disorder. Curr Rheumatol Rev. 2011;7:123–31.CrossRef
33.
Bibert S, Hess SK, Firsov D, Thorens B, Geering K, Horisberger JD, et al. Mouse GLUT9: evidences for a urate uniporter. Am J Physiol Renal Physiol. 2009;297:F612–9.PubMedCrossRef
34.
Dinour D, Gray NK, Campbell S, Shu X, Sawyer L, Richardson W, et al. Homozygous SLC2A9 mutations cause severe renal hypouricemia. J Am Soc Nephrol. 2010;21:64–72.PubMedCrossRef
35.
Preitner F, Bonny O, Laverrière A, Rotman S, Firsov D, Da Costa A, et al. Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy. Proc Natl Acad Sci USA. 2009;106:15501–6.PubMedCrossRef
36.
Krishnamurthy P, Schuetz JD. Role of ABCG2/BCRP in biology and medicine. Annu Rev Pharmacol Toxicol. 2006;46:381–410.PubMedCrossRef
37.
Ishikawa T, Nakagawa H. Human ABC transporter ABCG2 in cancer chemotherapy and pharmacogenomics. J Exp Ther Oncol. 2009;8:5–24.PubMed
38.
Huls M, Brown CD, Windass AS, Sayer R, van den Heuvel JJ, Heemskerk S, et al. The breast cancer resistance protein transporter ABCG2 is expressed in the human kidney proximal tubule apical membrane. Kidney Int. 2008;73:220–5.PubMedCrossRef
39.
Doyle LA, Ross DD. Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene. 2003;22:7340–58.PubMedCrossRef
40.
Reimer RJ, Edwards RH. Organic anion transport is the primary function of the SLC17/type I phosphate transporter family. Pflugers Arch. 2004;447:629–35.PubMedCrossRef
41.
Uchino H, Tamai I, Yamashita K, Minemoto Y, Sai Y, Yabuuchi H, et al. p-Aminohippuric acid transport at renal apical membrane mediated by human inorganic phosphate transporter NPT1. Biochem Biophys Res Commun. 2000;270:254–9.PubMedCrossRef
42.
Urano W, Taniguchi A, Anzai N, Inoue E, Kanai Y, Yamanaka M, et al. Sodium-dependent phosphate cotransporter type 1 (NPT1) sequence polymorphisms in male patients with gout. Ann Rheum Dis. 2010;69:932–3.PubMedCrossRef
43.
Melis D, Havelaar AC, Verbeek E, Smit GP, Benedetti A, Mancini GM, et al. NPT4, a new microsomal phosphate transporter: mutation analysis in glycogen storage disease type Ic. J Inherit Metab Dis. 2004;27:725–33.PubMedCrossRef
44.
Jutabha P, Anzai N, Kitamura K, Taniguchi A, Kaneko S, Yan K, et al. Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate. J Biol Chem. 2010;285:35123–32.PubMedCrossRef
45.
Shibui A, Tsunoda T, Seki N, Suzuki Y, Sugane K, Sugano S. Isolation and chromosomal mapping of a novel human gene showing homology to Na+/PO4 cotransporter. J Hum Genet. 1999;44:190–2.PubMedCrossRef
46.
Halestrap AP, Meredith D. The SLC16 gene family—from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch. 2004;447:619–28.PubMedCrossRef
47.
van der Harst P, Bakker SJ, de Boer RA, Wolffenbuttel BH, Johnson T, et al. Replication of the five novel loci for uric acid concentrations and potential mediating mechanisms. Hum Mol Genet. 2010;19:387–95.PubMedCrossRef
48.
Kocher O, Comella N, Tognazzi K, Brown LF. Identification and partial characterization of PDZK1: a novel protein containing PDZ interaction domains. Lab Invest. 1998;78:117–25.PubMed
49.
Lamprecht G, Seidler U. The emerging role of PDZ adapter proteins for regulation of intestinal ion transport. Am J Physiol Gastrointest Liver Physiol. 2006;291:G766–77.PubMedCrossRef
50.
Miyazaki H, Anzai N, Ekaratanawong S, Sakata T, Shin HJ, Jutabha P, et al. Modulation of renal apical organic anion transporter 4 function by two PDZ domain-containing proteins. J Am Soc Nephrol. 2005;16:3498–506.PubMedCrossRef
51.
Noshiro R, Anzai N, Sakata T, Miyazaki H, Terada T, Shin HJ, et al. The PDZ domain protein PDZK1 interacts with human peptide transporter PEPT2 and enhances its transport activity. Kidney Int. 2006;70:275–82.PubMedCrossRef
52.
Jutabha P, Anzai N, Endou H, Kanai Y. Interaction of the multivalent PDZ domain protein PDZK1 with type I sodium-phosphate cotransporter (NPT1). J Am Soc Nephrol. 2005;16:350A.
53.
Fukutomi T, Anzai N, Jutabha P, Kanai Y, Sakurai H. Interaction of the multivalent PDZ proteins with sodium-phosphate transporter 4 (NPT4). J Pharmacol Sci. 2011;115:68P.
54.
Thomson RB, Wang T, Thomson BR, Tarrats L, Girardi A, Mentone S, et al. Role of PDZK1 in membrane expression of renal brush border ion exchangers. Proc Natl Acad Sci USA. 2005;102:13331–6.PubMedCrossRef
55.
Anzai N, Endou H. Drug discovery for hyperuricemia. Expert Opin Drug Discov. 2007;2:1251–61.CrossRef
56.
Srivastava S, Anzai N, Miyauchi S, Miura D, Fukutomi T, et al. Identification of the multivalent PDZ protein PDZK1 as a binding partner of sodium-coupled monocarboxylate cotransporter SMCT1 (SLC5A8) and SMCT2 (SLC5A12) by yeast two-hybrid assay. J Pharmacol Sci. 2009;109:68.
57.
Wu XW, Muzny DM, Lee CC, Caskey CT. Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol. 1992;34:78–84.PubMedCrossRef
58.
Watanabe S, Kang DH, Feng L, Nakagawa T, Kanellis J, Lan H, et al. Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity. Hypertension. 2002;40:355–60.PubMedCrossRef
59.
Wu X, Wakamiya M, Vaishnav S, Geske R, Montgomery C Jr, Jones P, et al. Hyperuricemia and urate nephropathy in urate oxidase-deficient mice. Proc Natl Acad Sci USA. 1994;91:742–6.PubMedCrossRef
Metadata
Title
Recent advances in renal urate transport: characterization of candidate transporters indicated by genome-wide association studies
Authors
Naohiko Anzai
Promsuk Jutabha
Sirirat Amonpatumrat-Takahashi
Hiroyuki Sakurai
Publication date
01-02-2012
Publisher
Springer Japan
Published in
Clinical and Experimental Nephrology / Issue 1/2012
Print ISSN: 1342-1751
Electronic ISSN: 1437-7799
DOI
https://doi.org/10.1007/s10157-011-0532-z

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