1932

Abstract

Uric acid, generated from the metabolism of purines, has proven and emerging roles in human disease. Serum uric acid is determined by production and the net balance of reabsorption or secretion by the kidney and intestine. A detailed understanding of epithelial absorption and secretion of uric acid has recently emerged, aided in particular by the results of genome-wide association studies of hyperuricemia. Novel genetic and regulatory networks with effects on uric acid homeostasis have also emerged. These developments promise to lead to a new understanding of the various diseases associated with hyperuricemia and to novel, targeted therapies for hyperuricemia.

Keyword(s): ABCG2hyperuricemiaSLC2A9URAT1uric acid
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2015-02-10
2024-03-28
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Literature Cited

  1. Choi HK, Mount DB, Reginato AM. 1.  2005. Pathogenesis of gout. Ann. Intern. Med. 143:499–516 [Google Scholar]
  2. Zhu Y, Pandya BJ, Choi HK. 2.  2011. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007–2008. Arthritis Rheum. 63:3136–41 [Google Scholar]
  3. Singh JA, Strand V. 3.  2008. Gout is associated with more comorbidities, poorer health-related quality of life and higher healthcare utilisation in US veterans. Ann. Rheum. Dis. 67:1310–16 [Google Scholar]
  4. Zhu Y, Pandya BJ, Choi HK. 4.  2012. Comorbidities of gout and hyperuricemia in the US general population: NHANES 2007–2008. Am. J. Med. 125:679–87 [Google Scholar]
  5. Forman JP, Choi H, Curhan GC. 5.  2009. Uric acid and insulin sensitivity and risk of incident hypertension. Arch. Intern. Med. 169:155–62 [Google Scholar]
  6. Perlstein TS, Gumieniak O, Williams GH, Sparrow D, Vokonas PS. 6.  et al. 2006. Uric acid and the development of hypertension: the normative aging study. Hypertension 48:1031–36 [Google Scholar]
  7. Feig DI, Soletsky B, Johnson RJ. 7.  2008. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA 300:924–32 [Google Scholar]
  8. Doria A, Krolewski AS. 8.  2011. Diabetes: lowering serum uric acid levels to prevent kidney failure. Nat. Rev. Nephrol. 7:495–96 [Google Scholar]
  9. Fam AG. 9.  2002. Gout, diet, and the insulin resistance syndrome. J. Rheumatol. 29:1350–55 [Google Scholar]
  10. Choi HK, Ford ES, Li C, Curhan G. 10.  2007. Prevalence of the metabolic syndrome in patients with gout: the Third National Health and Nutrition Examination Survey. Arthritis Rheum. 57:109–15 [Google Scholar]
  11. Hooper DC, Spitsin S, Kean RB, Champion JM, Dickson GM. 11.  et al. 1998. Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis. PNAS 95:675–80 [Google Scholar]
  12. Spitsin S, Koprowski H. 12.  2010. Role of uric acid in Alzheimer's disease. J. Alzheimers Dis. 19:1337–38 [Google Scholar]
  13. Weisskopf MG, O'Reilly E, Chen H, Schwarzschild MA, Ascherio A. 13.  2007. Plasma urate and risk of Parkinson's disease. Am. J. Epidemiol. 166:561–67 [Google Scholar]
  14. Ascherio A, LeWitt PA, Xu K, Eberly S, Watts A. 14.  et al. 2009. Urate as a predictor of the rate of clinical decline in Parkinson disease. Arch. Neurol. 66:1460–68 [Google Scholar]
  15. Peden DB, Hohman R, Brown ME, Mason RT, Berkebile C. 15.  et al. 1990. Uric acid is a major antioxidant in human nasal airway secretions. PNAS 87:7638–42 [Google Scholar]
  16. Kottgen A, Albrecht E, Teumer A, Vitart V, Krumsiek J. 16.  et al. 2013. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat. Genet. 45:145–54 [Google Scholar]
  17. Griebsch A, Zollner N. 17.  1974. Effect of ribomononucleotides given orally on uric acid production in man. Adv. Exp. Med. Biol. 41:443–49 [Google Scholar]
  18. Ahmed M, Taylor W, Smith PR, Becker MA. 18.  1999. Accelerated transcription of PRPS1 in X-linked overactivity of normal human phosphoribosylpyrophosphate synthetase. J. Biol. Chem. 274:7482–88 [Google Scholar]
  19. Wu XW, Lee CC, Muzny DM, Caskey CT. 19.  1989. Urate oxidase: primary structure and evolutionary implications. PNAS 86:9412–16 [Google Scholar]
  20. Wu XW, Muzny DM, Lee CC, Caskey CT. 20.  1992. Two independent mutational events in the loss of urate oxidase during hominoid evolution. J. Mol. Evol. 34:78–84 [Google Scholar]
  21. Ames BN, Cathcart R, Schwiers E, Hochstein P. 21.  1981. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. PNAS 78:6858–62 [Google Scholar]
  22. Davies KJ, Sevanian A, Muakkassah-Kelly SF, Hochstein P. 22.  1986. Uric acid–iron ion complexes. A new aspect of the antioxidant functions of uric acid. Biochem. J. 235:747–54 [Google Scholar]
  23. Watanabe S, Kang DH, Feng L, Nakagawa T, Kanellis J. 23.  et al. 2002. Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity. Hypertension 40:355–60 [Google Scholar]
  24. Oda M, Satta Y, Takenaka O, Takahata N. 24.  2002. Loss of urate oxidase activity in hominoids and its evolutionary implications. Mol. Biol. Evol. 19:640–53 [Google Scholar]
  25. Kramer HJ, Choi HK, Atkinson K, Stampfer M, Curhan GC. 25.  2003. The association between gout and nephrolithiasis in men: the Health Professionals' Follow-Up Study. Kidney Int. 64:1022–26 [Google Scholar]
  26. Xu P, LaVallee PA, Lin JJ, Hoidal JR. 26.  2004. Characterization of proteins binding to E-box/Ku86 sites and function of Ku86 in transcriptional regulation of the human xanthine oxidoreductase gene. J. Biol. Chem. 279:16057–63 [Google Scholar]
  27. Xu P, LaVallee P, Hoidal JR. 27.  2000. Repressed expression of the human xanthine oxidoreductase gene. E-box and TATA-like elements restrict ground state transcriptional activity. J. Biol. Chem. 275:5918–26 [Google Scholar]
  28. Berry CE, Hare JM. 28.  2004. Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications. J. Physiol. 555:589–606 [Google Scholar]
  29. Roch-Ramel F, Guisan B. 29.  1999. Renal transport of urate in humans. News Physiol. Sci. 14:80–84 [Google Scholar]
  30. Guggino SE, Martin GJ, Aronson PS. 30.  1983. Specificity and modes of the anion exchanger in dog renal microvillus membranes. Am. J. Physiol. Ren. Physiol. 244:F612–21 [Google Scholar]
  31. Martinez F, Manganel M, Montrose-Rafizadeh C, Werner D, Roch-Ramel F. 31.  1990. Transport of urate and p-aminohippurate in rabbit renal brush-border membranes. Am. J. Physiol. Ren. Physiol. 258:F1145–53 [Google Scholar]
  32. Roch-Ramel F, Diezi-Chomety F, De Rougemont D, Tellier M, Widmer J, Peters G. 32.  1976. Renal excretion of uric acid in the rat: a micropuncture and microperfusion study. Am. J. Physiol. 230:768–76 [Google Scholar]
  33. Simmonds HA, Hatfield PJ, Cameron JS, Cadenhead A. 33.  1976. Uric acid excretion by the pig kidney. Am. J. Physiol. 230:1654–61 [Google Scholar]
  34. Roch-Ramel F, Weiner IM. 34.  1973. Excretion of urate by the kidneys of Cebus monkeys: a micropuncture study. Am. J. Physiol. 224:1369–74 [Google Scholar]
  35. Weiner IM. 35.  1979. Urate transport in the nephron. Am. J. Physiol. 237:F85–92 [Google Scholar]
  36. Fanelli GM Jr, Bohn DL, Reilly SS. 36.  1971. Renal urate transport in the chimpanzee. Am. J. Physiol. 220:613–20 [Google Scholar]
  37. Dinour D, Gray NK, Campbell S, Shu X, Sawyer L. 37.  et al. 2010. Homozygous SLC2A9 mutations cause severe renal hypouricemia. J. Am. Soc. Nephrol. 21:64–72 [Google Scholar]
  38. Matsuo H, Takada T, Ichida K, Nakamura T, Nakayama A. 38.  et al. 2009. Common defects of ABCG2, a high-capacity urate exporter, cause gout: a function-based genetic analysis in a Japanese population. Sci. Transl. Med. 1:5ra11 [Google Scholar]
  39. Woodward OM, Kottgen A, Coresh J, Boerwinkle E, Guggino WB, Kottgen M. 39.  2009. Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. PNAS 106:10338–42 [Google Scholar]
  40. Jutabha P, Anzai N, Kitamura K, Taniguchi A, Kaneko S. 40.  et al. 2010. Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate. J. Biol. Chem. 285:35123–32 [Google Scholar]
  41. Diamond HS, Paolino JS. 41.  1973. Evidence for a postsecretory reabsorptive site for uric acid in man. J. Clin. Investig. 52:1491–99 [Google Scholar]
  42. Guggino SE, Aronson PS. 42.  1985. Paradoxical effects of pyrazinoate and nicotinate on urate transport in dog renal microvillus membranes. J. Clin. Investig. 76:543–47 [Google Scholar]
  43. Steele TH. 43.  1973. Urate secretion in man: the pyrazinamide suppression test. Ann. Intern. Med. 79:734–37 [Google Scholar]
  44. Weiner IM, Tinker JP. 44.  1972. Pharmacology of pyrazinamide: metabolic and renal function studies related to the mechanism of drug-induced urate retention. J. Pharmacol. Exp. Ther. 180:411–34 [Google Scholar]
  45. Davis BB, Field JB, Rodnan GP, Kedes LH. 45.  1965. Localization and pyrazinamide inhibition of distal transtubular movement of uric acid-2-C14 with a modified stop-flow technique. J. Clin. Investig. 44:716–21 [Google Scholar]
  46. Gutman AB, Yu TF. 46.  1961. A three-component system for regulation of renal excretion of uric acid in man. Trans. Assoc. Am. Phys. 74:353–65 [Google Scholar]
  47. Steele TH, Boner G. 47.  1973. Origins of the uricosuric response. J. Clin. Investig. 52:1368–75 [Google Scholar]
  48. Lemieux G, Vinay P, Gougoux A, Michaud G. 48.  1973. Nature of the uricosuric action of benziodarone. Am. J. Physiol. 224:1440–49 [Google Scholar]
  49. Gutman AB, Yu TF, Berger L. 49.  1959. Tubular secretion of urate in man. J. Clin. Investig. 38:1778–81 [Google Scholar]
  50. Blomstedt JW, Aronson PS. 50.  1980. pH gradient–stimulated transport of urate and p-aminohippurate in dog renal microvillus membrane vesicles. J. Clin. Investig. 65:931–34 [Google Scholar]
  51. Kahn AM, Aronson PS. 51.  1983. Urate transport via anion exchange in dog renal microvillus membrane vesicles. Am. J. Physiol. Ren. Physiol. 244:F56–63 [Google Scholar]
  52. Kahn AM, Branham S, Weinman EJ. 52.  1983. Mechanism of urate and p-aminohippurate transport in rat renal microvillus membrane vesicles. Am. J. Physiol. Ren. Physiol. 245:F151–58 [Google Scholar]
  53. Werner D, Martinez F, Roch-Ramel F. 53.  1990. Urate and p-aminohippurate transport in the brush border membrane of the pig kidney. J. Pharmacol. Exp. Ther. 252:792–99 [Google Scholar]
  54. Roch-Ramel F, Werner D, Guisan B. 54.  1994. Urate transport in brush-border membrane of human kidney. Am. J. Physiol. Ren. Physiol. 266:F797–805 [Google Scholar]
  55. Boner G, Steele TH. 55.  1973. Relationship of urate and p-aminohippurate secretion in man. Am. J. Physiol. 225:100–4 [Google Scholar]
  56. Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P. 56.  et al. 2002. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 417:447–52 [Google Scholar]
  57. Mori K, Ogawa Y, Ebihara K, Aoki T, Tamura N. 57.  et al. 1997. Kidney-specific expression of a novel mouse organic cation transporter–like protein. FEBS Lett. 417:371–74 [Google Scholar]
  58. Hosoyamada M, Ichida K, Enomoto A, Hosoya T, Endou H. 58.  2004. Function and localization of urate transporter 1 in mouse kidney. J. Am. Soc. Nephrol. 15:261–68 [Google Scholar]
  59. Uetake D, Ohno I, Ichida K, Yamaguchi Y, Saikawa H. 59.  et al. 2010. Effect of fenofibrate on uric acid metabolism and urate transporter 1. Intern. Med. 49:89–94 [Google Scholar]
  60. Nakashima M, Uematsu T, Kosuge K, Kanamaru M. 60.  1992. Pilot study of the uricosuric effect of DuP-753, a new angiotensin II receptor antagonist, in healthy subjects. Eur. J. Clin. Pharmacol. 42:333–35 [Google Scholar]
  61. Roch-Ramel F, Guisan B, Schild L. 61.  1996. Indirect coupling of urate and p-aminohippurate transport to sodium in human brush-border membrane vesicles. Am. J. Physiol. Ren. Physiol. 270:F61–68 [Google Scholar]
  62. Ichida K, Hosoyamada M, Hisatome I, Enomoto A, Hikita M. 62.  et al. 2004. Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion. J. Am. Soc. Nephrol. 15:164–73 [Google Scholar]
  63. Ekaratanawong S, Anzai N, Jutabha P, Miyazaki H, Noshiro R. 63.  et al. 2004. Human organic anion transporter 4 is a renal apical organic anion/dicarboxylate exchanger in the proximal tubules. J. Pharmacol. Sci. 94:297–304 [Google Scholar]
  64. Hagos Y, Stein D, Ugele B, Burckhardt G, Bahn A. 64.  2007. Human renal organic anion transporter 4 operates as an asymmetric urate transporter. J. Am. Soc. Nephrol. 18:430–39 [Google Scholar]
  65. Bahn A, Hagos Y, Reuter S, Balen D, Brzica H. 65.  et al. 2008. Identification of a new urate and high affinity nicotinate transporter, hOAT10 (SLC22A13). J. Biol. Chem. 283:16332–41 [Google Scholar]
  66. Schulz C, Fork C, Bauer T, Golz S, Geerts A. 66.  et al. 2014. SLC22A13 catalyses unidirectional efflux of aspartate and glutamate at the basolateral membrane of type A intercalated cells in the renal collecting duct. Biochem. J. 457:243–51 [Google Scholar]
  67. Tin A, Woodward OM, Kao WH, Liu CT, Lu X. 67.  et al. 2011. Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele. Hum. Mol. Genet. 20:4056–68 [Google Scholar]
  68. Flynn TJ, Phipps-Green A, Hollis-Moffatt JE, Merriman ME, Topless R. 68.  et al. 2013. Association analysis of the SLC22A11 (organic anion transporter 4) and SLC22A12 (urate transporter 1) urate transporter locus with gout in New Zealand case-control sample sets reveals multiple ancestral-specific effects. Arthritis Res. Ther. 15:R220 [Google Scholar]
  69. Garcia ML, Benavides J, Valdivieso F. 69.  1980. Ketone body transport in renal brush border membrane vesicles. Biochim. Biophys. Acta 600:922–30 [Google Scholar]
  70. Manganel M, Roch-Ramel F, Murer H. 70.  1985. Sodium-pyrazinoate cotransport in rabbit renal brush border membrane vesicles. Am. J. Physiol. Ren. Physiol. 249:F400–8 [Google Scholar]
  71. Boumendil-Podevin EF, Podevin RA. 71.  1981. Nicotinic acid transport by brush border membrane vesicles from rabbit kidney. Am. J. Physiol. Ren. Physiol. 240:F185–91 [Google Scholar]
  72. Goldfinger S, Klinenberg E Jr., Seegmiller JE. 72.  1965. Renal retention of uric acid induced by infusion of beta-hydroxybutyrate and acetoacetate. N. Engl. J. Med. 272:351–55 [Google Scholar]
  73. Padova J, Bendersky G. 73.  1962. Hyperuricemia in diabetic ketoacidosis. N. Engl. J. Med. 267:530–34 [Google Scholar]
  74. Lieber CS, Jones DP, Losowsky MS, Davidson CS. 74.  1962. Interrelation of uric acid and ethanol metabolism in man. J. Clin. Investig. 41:1863–70 [Google Scholar]
  75. Fanelli GM Jr., Bohn D, Stafford S. 75.  1970. Functional characteristics of renal urate transport in the Cebus monkey. Am. J. Physiol. 218:627–36 [Google Scholar]
  76. Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. 76.  2004. Alcohol intake and risk of incident gout in men: a prospective study. Lancet 363:1277–81 [Google Scholar]
  77. Gibson HV, Doisy EA. 77.  1923. A note on the effect of some organic acids upon the uric acid excretion of man. J. Biol. Chem. 55:605–10 [Google Scholar]
  78. Michael ST. 78.  1944. The relation of uric acid excretion to blood lactic acid in man. Am. J. Physiol. 141:71–74 [Google Scholar]
  79. Harding VJ, Allin KD, Eagles BA. 79.  1927. The influence of fat and carbohydrate diets upon the level of blood uric acid. J. Biol. Chem. 74:631–43 [Google Scholar]
  80. Drenick EJ. 80.  1965. Hyperuricemia, acute gout, renal insufficiency and urate nephrolithiasis due to starvation. Arthritis Rheum. 8:988–97 [Google Scholar]
  81. Gershon SL, Fox IH. 81.  1974. Pharmacologic effects of nicotinic acid on human purine metabolism. J. Lab. Clin. Med. 84:179–86 [Google Scholar]
  82. Shapiro M, Hyde L. 82.  1957. Hyperuricemia due to pyrazinamide. Am. J. Med. 23:596–99 [Google Scholar]
  83. Akalin E, Chandrakantan A, Keane J, Hamburger RJ. 83.  2001. Normouricemia in the syndrome of inappropriate antidiuretic hormone secretion. Am. J. Kidney Dis. 37:E8 [Google Scholar]
  84. Srinivas SR, Gopal E, Zhuang L, Itagaki S, Martin PM. 84.  et al. 2005. Cloning and functional identification of slc5a12 as a sodium-coupled low-affinity transporter for monocarboxylates (SMCT2). Biochem. J. 392:655–64 [Google Scholar]
  85. Coady MJ, Chang MH, Charron FM, Plata C, Wallendorff B. 85.  et al. 2004. The human tumour suppressor gene SLC5A8 expresses a Na+-monocarboxylate cotransporter. J. Physiol. 557:719–31 [Google Scholar]
  86. Barac-Nieto M, Murer H, Kinne R. 86.  1980. Lactate-sodium cotransport in rat renal brush border membranes. Am. J. Physiol. Ren. Physiol. 239:F496–506 [Google Scholar]
  87. Barbarat B, Podevin RA. 87.  1988. Stoichiometry of the renal sodium-L-lactate cotransporter. J. Biol. Chem. 263:12190–93 [Google Scholar]
  88. Plata C, Sussman CR, Sindic A, Liang JO, Mount DB. 88.  et al. 2007. Zebrafish Slc5a12 encodes an electroneutral sodium monocarboxylate transporter (SMCTn). A comparison with the electrogenic SMCT (SMCTe/Slc5a8). J. Biol. Chem. 282:11996–2009 [Google Scholar]
  89. Thangaraju M, Ananth S, Martin PM, Roon P, Smith SB. 89.  et al. 2006. c/ebpδ null mouse as a model for the double knock-out of slc5a8 and slc5a12 in kidney. J. Biol. Chem. 281:26769–73 [Google Scholar]
  90. Wallace C, Newhouse SJ, Braund P, Zhang F, Tobin M. 90.  et al. 2008. Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Am. J. Hum. Genet. 82:139–49 [Google Scholar]
  91. Doring A, Gieger C, Mehta D, Gohlke H, Prokisch H. 91.  et al. 2008. SLC2A9 influences uric acid concentrations with pronounced sex-specific effects. Nat. Genet. 40:430–36 [Google Scholar]
  92. Vitart V, Rudan I, Hayward C, Gray NK, Floyd J. 92.  et al. 2008. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat. Genet. 40:437–42 [Google Scholar]
  93. Wei W, Hemani G, Hicks AA, Vitart V, Cabrera-Cardenas C. 93.  et al. 2011. Characterisation of genome-wide association epistasis signals for serum uric acid in human population isolates. PLOS ONE 6:e23836 [Google Scholar]
  94. Eraly SA, Vallon V, Rieg T, Gangoiti JA, Wikoff WR. 94.  et al. 2008. Multiple organic anion transporters contribute to net renal excretion of uric acid. Physiol. Genomics 33:180–92 [Google Scholar]
  95. Augustin R, Carayannopoulos MO, Dowd LO, Phay JE, Moley JF, Moley KH. 95.  2004. Identification and characterization of human glucose transporter-like protein-9 (GLUT9): Alternative splicing alters trafficking. J. Biol. Chem. 279:16229–36 [Google Scholar]
  96. Kimura T, Takahashi M, Yan K, Sakurai H. 96.  2014. Expression of SLC2A9 isoforms in the kidney and their localization in polarized epithelial cells. PLOS ONE 9:e84996 [Google Scholar]
  97. Bibee KP, Augustin R, Gazit V, Moley KH. 97.  2013. The apical sorting signal for human GLUT9b resides in the N-terminus. Mol. Cell. Biochem. 376:163–73 [Google Scholar]
  98. Preitner F, Bonny O, Laverriere A, Rotman S, Firsov D. 98.  et al. 2009. Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy. PNAS 106:15501–6 [Google Scholar]
  99. Bibert S, Hess SK, Firsov D, Thorens B, Geering K. 99.  et al. 2009. Mouse GLUT9: evidences for a urate uniporter. Am. J. Physiol. Ren. Physiol. 297:F612–19 [Google Scholar]
  100. Manolescu AR, Augustin R, Moley K, Cheeseman C. 100.  2007. A highly conserved hydrophobic motif in the exofacial vestibule of fructose transporting SLC2A proteins acts as a critical determinant of their substrate selectivity. Mol. Membr. Biol. 24:455–63 [Google Scholar]
  101. Mandal A, Emerling DE, Serafini TA, Mount DB. 101.  2011. Tranilast inhibits urate transport mediated by URAT1 and GLUT9. Am. Coll. Rheumatol. 62:Suppl. 10164 (Abstr.) [Google Scholar]
  102. Caulfield MJ, Munroe PB, O'Neill D, Witkowska K, Charchar FJ. 102.  et al. 2008. SLC2A9 is a high-capacity urate transporter in humans. PLOS Med. 5:e197 [Google Scholar]
  103. Anzai N, Ichida K, Jutabha P, Kimura T, Babu E. 103.  et al. 2008. Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans. J. Biol. Chem. 283:26834–38 [Google Scholar]
  104. Mandal AK, Mount DB. 104.  2013. Transcriptional and translational heterogeneity of the SLC2A9 gene encoding the GLUT9 urate transporter. J. Am. Soc. Nephrol. 24:237A [Google Scholar]
  105. Witkowska K, Smith KM, Yao SY, Ng AM, O'Neill D. 105.  et al. 2012. Human SLC2A9a and SLC2A9b isoforms mediate electrogenic transport of urate with different characteristics in the presence of hexoses. Am. J. Physiol. Ren. Physiol. 303:F527–39 [Google Scholar]
  106. Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M. 106.  2012. An integrated encyclopedia of DNA elements in the human genome. Nature 489:57–74 [Google Scholar]
  107. Charles BA, Shriner D, Doumatey A, Chen G, Zhou J. 107.  et al. 2011. A genome-wide association study of serum uric acid in African Americans. BMC Med. Genomics 4:17 [Google Scholar]
  108. So A, Thorens B. 108.  2010. Uric acid transport and disease. J. Clin. Investig. 120:1791–99 [Google Scholar]
  109. Merriman TR. 109.  2011. Population heterogeneity in the genetic control of serum urate. Semin. Nephrol. 31:420–25 [Google Scholar]
  110. Urano W, Taniguchi A, Anzai N, Inoue E, Sekita C. 110.  et al. 2010. Association between GLUT9 and gout in Japanese men. Ann. Rheum. Dis. 69:932–33 [Google Scholar]
  111. Tu HP, Chen CJ, Tovosia S, Ko AM, Lee CH. 111.  et al. 2010. Associations of a non-synonymous variant in SLC2A9 with gouty arthritis and uric acid levels in Han Chinese subjects and Solomon Islanders. Ann. Rheum. Dis. 69:887–90 [Google Scholar]
  112. Hollis-Moffatt JE, Gow PJ, Harrison AA, Highton J, Jones PB. 112.  et al. 2011. The SLC2A9 non-synonymous Arg265His variant and gout; evidence for a population-specific effect on severity. Arthritis Res. Ther. 13:R85 [Google Scholar]
  113. McArdle PF, Parsa A, Chang YP, Weir MR, O'Connell JR. 113.  et al. 2008. Association of a common nonsynonymous variant in GLUT9 with serum uric acid levels in Old Order Amish. Arthritis Rheum. 58:2874–81 [Google Scholar]
  114. Phay JE, Hussain HB, Moley JF. 114.  2000. Cloning and expression analysis of a novel member of the facilitative glucose transporter family, SLC2A9 (GLUT9). Genomics 66:217–20 [Google Scholar]
  115. Mobasheri A, Neama G, Bell S, Richardson S, Carter SD. 115.  2002. Human articular chondrocytes express three facilitative glucose transporter isoforms: GLUT1, GLUT3 and GLUT9. Cell Biol. Int. 26:297–300 [Google Scholar]
  116. Shikhman AR, Brinson DC, Valbracht J, Lotz MK. 116.  2001. Cytokine regulation of facilitated glucose transport in human articular chondrocytes. J. Immunol. 167:7001–8 [Google Scholar]
  117. Kimura T, Amonpatumrat S, Tsukada A, Fukutomi T, Jutabha P. 117.  et al. 2011. Increased expression of SLC2A9 decreases urate excretion from the kidney. Nucleosides Nucleotides Nucleic Acids 30:1295–301 [Google Scholar]
  118. Roch-Ramel F, Wong NL, Dirks JH. 118.  1976. Renal excretion of urate in mongrel and Dalmatian dogs: a micropuncture study. Am. J. Physiol. 231:326–31 [Google Scholar]
  119. Friedman M, Byers SO. 119.  1948. Observations concerning the causes of the excess excretion of uric acid in the Dalmatian dog. J. Biol. Chem. 175:727–35 [Google Scholar]
  120. Kahn AM, Shelat H, Weinman EJ. 120.  1985. Urate and p-aminohippurate transport in rat renal basolateral vesicles. Am. J. Physiol. Ren. Physiol. 249:F654–61 [Google Scholar]
  121. Werner D, Roch-Ramel F. 121.  1991. Indirect Na+ dependency of urate and p-aminohippurate transport in pig basolateral membrane vesicles. Am. J. Physiol. Ren. Physiol. 261:F265–72 [Google Scholar]
  122. Sweet DH, Chan LM, Walden R, Yang XP, Miller DS, Pritchard JB. 122.  2003. Organic anion transporter 3 (Slc22a8) is a dicarboxylate exchanger indirectly coupled to the Na+ gradient. Am. J. Physiol. Ren. Physiol. 284:F763–69 [Google Scholar]
  123. Aslamkhan A, Han YH, Walden R, Sweet DH, Pritchard JB. 123.  2003. Stoichiometry of organic anion/dicarboxylate exchange in membrane vesicles from rat renal cortex and hOAT1-expressing cells. Am. J. Physiol. Ren. Physiol. 285:F775–83 [Google Scholar]
  124. Bakhiya A, Bahn A, Burckhardt G, Wolff N. 124.  2003. Human organic anion transporter 3 (hOAT3) can operate as an exchanger and mediate secretory urate flux. Cell. Physiol. Biochem. 13:249–56 [Google Scholar]
  125. Enomoto A, Takeda M, Shimoda M, Narikawa S, Kobayashi Y. 125.  et al. 2002. Interaction of human organic anion transporters 2 and 4 with organic anion transport inhibitors. J. Pharmacol. Exp. Ther. 301:797–802 [Google Scholar]
  126. Sato M, Mamada H, Anzai N, Shirasaka Y, Nakanishi T, Tamai I. 126.  2010. Renal secretion of uric acid by organic anion transporter 2 (OAT2/SLC22A7) in human. Biol. Pharm. Bull. 33:498–503 [Google Scholar]
  127. Uchino H, Tamai I, Yamashita K, Minemoto Y, Sai Y. 127.  et al. 2000. p-Aminohippuric acid transport at renal apical membrane mediated by human inorganic phosphate transporter NPT1. Biochem. Biophys. Res. Commun. 270:254–59 [Google Scholar]
  128. Biber J, Custer M, Werner A, Kaissling B, Murer H. 128.  1993. Localization of NaPi-1, a Na/Pi cotransporter, in rabbit kidney proximal tubules. II. Localization by immunohistochemistry. Pflüg. Arch. 424:210–15 [Google Scholar]
  129. Urano W, Taniguchi A, Anzai N, Inoue E, Kanai Y. 129.  et al. 2010. Sodium-dependent phosphate cotransporter type 1 sequence polymorphisms in male patients with gout. Ann. Rheum. Dis. 69:1232–34 [Google Scholar]
  130. Dehghan A, Kottgen A, Yang Q, Hwang SJ, Kao WL. 130.  et al. 2008. Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study. Lancet 372:1953–61 [Google Scholar]
  131. Togawa N, Miyaji T, Izawa S, Omote H, Moriyama Y. 131.  2012. A Na+-phosphate cotransporter homologue (SLC17A4 protein) is an intestinal organic anion exporter. Am. J. Physiol. Cell Physiol. 302:C1652–60 [Google Scholar]
  132. Van Aubel RA, Smeets PH, Van Den Heuvel JJ, Russel FG. 132.  2004. 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. Ren. Physiol. 288:F327–33 [Google Scholar]
  133. van Aubel RA, Smeets PH, Peters JG, Bindels RJ, Russel FG. 133.  2002. The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP. J. Am. Soc. Nephrol. 13:595–603 [Google Scholar]
  134. Bataille AM, Goldmeyer J, Renfro JL. 134.  2008. Avian renal proximal tubule epithelium urate secretion is mediated by Mrp4. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295:R2024–33 [Google Scholar]
  135. El-Sheikh AA, van den Heuvel JJ, Koenderink JB, Russel FG. 135.  2008. Effect of hypouricaemic and hyper-uricaemic drugs on the renal urate efflux transporter, multidrug resistance protein 4. Br. J. Pharmacol. 155:1066–75 [Google Scholar]
  136. Woodward OM, Tukaye DN, Cui J, Greenwell P, Constantoulakis LM. 136.  et al. 2013. Gout-causing Q141K mutation in ABCG2 leads to instability of the nucleotide-binding domain and can be corrected with small molecules. PNAS 110:5223–28 [Google Scholar]
  137. Rieselbach RE, Sorensen LB, Shelp WD, Steele TH. 137.  1970. Diminished renal urate secretion per nephron as a basis for primary gout. Ann. Intern. Med. 73:359–66 [Google Scholar]
  138. Boss GR, Seegmiller JE. 138.  1979. Hyperuricemia and gout. Classification, complications and management. N. Engl. J. Med. 300:1459–68 [Google Scholar]
  139. Perez-Ruiz F, Calabozo M, Erauskin GG, Ruibal A, Herrero-Beites AM. 139.  2002. Renal underexcretion of uric acid is present in patients with apparent high urinary uric acid output. Arthritis Rheum. 47:610–13 [Google Scholar]
  140. Ichida K, Matsuo H, Takada T, Nakayama A, Murakami K. 140.  et al. 2012. Decreased extra-renal urate excretion is a common cause of hyperuricemia. Nat. Commun. 3:764 [Google Scholar]
  141. Matsuo H, Nakayama A, Sakiyama M, Chiba T, Shimizu S. 141.  et al. 2014. ABCG2 dysfunction causes hyperuricemia due to both renal urate underexcretion and renal urate overload. Sci. Rep. 4:3755 [Google Scholar]
  142. Nakayama A, Matsuo H, Nakaoka H, Nakamura T, Nakashima H. 142.  et al. 2014. Common dysfunctional variants of ABCG2 have stronger impact on hyperuricemia progression than typical environmental risk factors. Sci. Rep. 4:5227 [Google Scholar]
  143. Anzai N, Miyazaki H, Noshiro R, Khamdang S, Chairoungdua A. 143.  et al. 2004. The multivalent PDZ domain–containing protein PDZK1 regulates transport activity of renal urate-anion exchanger URAT1 via its C-terminus. J. Biol. Chem. 279:45942–50 [Google Scholar]
  144. Gisler SM, Pribanic S, Bacic D, Forrer P, Gantenbein A. 144.  et al. 2003. PDZK1. I. A major scaffolder in brush borders of proximal tubular cells. Kidney Int. 64:1733–45 [Google Scholar]
  145. Kolz M, Johnson T, Sanna S, Teumer A, Vitart V. 145.  et al. 2009. Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations. PLOS Genet. 5:e1000504 [Google Scholar]
  146. Cunningham R, Brazie M, Kanumuru S, E X, Biswas R. 146.  et al. 2007. Sodium-hydrogen exchanger regulatory factor-1 interacts with mouse urate transporter 1 to regulate renal proximal tubule uric acid transport. J. Am. Soc. Nephrol. 18:1419–25 [Google Scholar]
  147. Hoque MT, Conseil G, Cole SP. 147.  2009. Involvement of NHERF1 in apical membrane localization of MRP4 in polarized kidney cells. Biochem. Biophys. Res. Commun. 379:60–64 [Google Scholar]
  148. Hoque MT, Cole SP. 148.  2008. Down-regulation of Na+/H+ exchanger regulatory factor 1 increases expression and function of multidrug resistance protein 4. Cancer Res. 68:4802–9 [Google Scholar]
  149. Park J, Kwak JO, Riederer B, Seidler U, Cole SP. 149.  et al. 2014. Na+/H+ exchanger regulatory factor 3 is critical for multidrug resistance protein 4–mediated drug efflux in the kidney. J. Am. Soc. Nephrol. 25:726–36 [Google Scholar]
  150. Wilkinson SP, Grove A. 150.  2004. HucR, a novel uric acid–responsive member of the MarR family of transcriptional regulators from Deinococcus radiodurans. J. Biol. Chem. 279:51442–50 [Google Scholar]
  151. Perera IC, Grove A. 151.  2010. Urate is a ligand for the transcriptional regulator PecS. J. Mol. Biol. 402:539–51 [Google Scholar]
  152. Baillie JK, Bates MG, Thompson AA, Waring WS, Partridge RW. 152.  et al. 2007. Endogenous urate production augments plasma antioxidant capacity in healthy lowland subjects exposed to high altitude. Chest 131:1473–78 [Google Scholar]
  153. Wu W, Dnyanmote AV, Nigam SK. 153.  2011. Remote communication through solute carriers and ATP binding cassette drug transporter pathways: an update on the remote sensing and signaling hypothesis. Mol. Pharmacol. 79:795–805 [Google Scholar]
  154. Maesaka JK, Fishbane S. 154.  1998. Regulation of renal urate excretion: a critical review. Am. J. Kidney Dis. 32:917–33 [Google Scholar]
  155. Pascual E, Perdiguero M. 155.  2006. Gout, diuretics and the kidney. Ann. Rheum. Dis. 65:981–82 [Google Scholar]
  156. Weinman EJ, Eknoyan G, Suki WN. 156.  1975. The influence of the extracellular fluid volume on the tubular reabsorption of uric acid. J. Clin. Investig. 55:283–91 [Google Scholar]
  157. Cappuccio FP, Strazzullo P, Farinaro E, Trevisan M. 157.  1993. Uric acid metabolism and tubular sodium handling. Results from a population-based study. JAMA 270:354–59 [Google Scholar]
  158. Page LB, Damon A, Moellering RC Jr. 158.  1974. Antecedents of cardiovascular disease in six Solomon Islands societies. Circulation 49:1132–46 [Google Scholar]
  159. Egan BM, Lackland DT. 159.  2000. Biochemical and metabolic effects of very-low-salt diets. Am. J. Med. Sci. 320:233–39 [Google Scholar]
  160. Masugi F, Ogihara T, Hashizume K, Hasegawa T, Sakaguchi K, Kumahara Y. 160.  1988. Changes in plasma lipids and uric acid with sodium loading and sodium depletion in patients with essential hypertension. J. Hum. Hypertens. 1:293–98 [Google Scholar]
  161. Del Rio A, Rodriguez-Villamil JL. 161.  1993. Metabolic effects of strict salt restriction in essential hypertensive patients. J. Intern. Med. 233:409–14 [Google Scholar]
  162. Skrabal F, Aubock J, Hortnagl H. 162.  1981. Low sodium/high potassium diet for prevention of hypertension: probable mechanisms of action. Lancet 2:895–900 [Google Scholar]
  163. Ruppert M, Diehl J, Kolloch R, Overlack A, Kraft K. 163.  et al. 1991. Short-term dietary sodium restriction increases serum lipids and insulin in salt-sensitive and salt-resistant normotensive adults. Klin. Wochenschr. 69:Suppl. 2551–57 [Google Scholar]
  164. 164.  Deleted in proof
  165. Ferris TF, Gorden P. 165.  1968. Effect of angiotensin and norepinephrine upon urate clearance in man. Am. J. Med. 44:359–65 [Google Scholar]
  166. Moriwaki Y, Yamamoto T, Tsutsumi Z, Takahashi S, Hada T. 166.  2002. Effects of angiotensin II infusion on renal excretion of purine bases and oxypurinol. Metabolism 51:893–95 [Google Scholar]
  167. Yamamoto T, Moriwaki Y, Takahashi S, Tsutsumi Z, Hada T. 167.  2001. Effect of norepinephrine on the urinary excretion of purine bases and oxypurinol. Metabolism 50:1230–33 [Google Scholar]
  168. Perlstein TS, Gumieniak O, Hopkins PN, Murphey LJ, Brown NJ. 168.  et al. 2004. Uric acid and the state of the intrarenal renin-angiotensin system in humans. Kidney Int. 66:1465–70 [Google Scholar]
  169. Abiko H, Konta T, Hao Z, Takasaki S, Suzuki K. 169.  et al. 2009. Factors correlated with plasma renin activity in general Japanese population. Clin. Exp. Nephrol. 13:130–37 [Google Scholar]
  170. Facchini F, Chen YD, Hollenbeck CB, Reaven GM. 170.  1991. Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. JAMA 266:3008–11 [Google Scholar]
  171. Quinones Galvan A, Natali A, Baldi S, Frascerra S, Sanna G. 171.  et al. 1995. Effect of insulin on uric acid excretion in humans. Am. J. Physiol. Endocrinol. Metab. 268:E1–5 [Google Scholar]
  172. Muscelli E, Natali A, Bianchi S, Bigazzi R, Galvan AQ. 172.  et al. 1996. Effect of insulin on renal sodium and uric acid handling in essential hypertension. Am. J. Hypertens. 9:746–52 [Google Scholar]
  173. Ter Maaten JC, Voorburg A, Heine RJ, Ter Wee PM, Donker AJ, Gans RO. 173.  1997. Renal handling of urate and sodium during acute physiological hyperinsulinaemia in healthy subjects. Clin. Sci. 92:51–58 [Google Scholar]
  174. Choi HK, Ford ES. 174.  2007. Prevalence of the metabolic syndrome in individuals with hyperuricemia. Am. J. Med. 120:442–47 [Google Scholar]
  175. Christensson T. 175.  1977. Serum urate in subjects with hypercalcaemic hyperparathyroidism. Clin. Chim. Acta 80:529–33 [Google Scholar]
  176. Miller PD, Schwartz EN, Chen P, Misurski DA, Krege JH. 176.  2007. Teriparatide in postmenopausal women with osteoporosis and mild or moderate renal impairment. Osteoporos. Int. 18:59–68 [Google Scholar]
  177. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA. 177.  et al. 2001. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N. Engl. J. Med. 344:1434–41 [Google Scholar]
  178. Hui JY, Choi JW, Mount DB, Zhu Y, Zhang Y, Choi HK. 178.  2012. The independent association between parathyroid hormone levels and hyperuricemia: a national population study. Arthritis Res. Ther. 14:R56 [Google Scholar]
  179. Ayvazian JH, Ayvazian IF. 179.  1963. Changes in serum and urinary uric acid with the development of symptomatic gout. J. Clin. Investig. 42:1835–39 [Google Scholar]
  180. Urano W, Yamanaka H, Tsutani H, Nakajima H, Matsuda Y. 180.  et al. 2002. The inflammatory process in the mechanism of decreased serum uric acid concentrations during acute gouty arthritis. J. Rheumatol. 29:1950–53 [Google Scholar]
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