Electrolyte Blood Press.  2014 Jun;12(1):1-6. 10.5049/EBP.2014.12.1.1.

Uric Acid Puzzle: Dual Role as Anti-oxidantand Pro-oxidant

Affiliations
  • 1Division of Nephrology, Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea.
  • 2Ewha Medical Research Center, Ewha Womans University School of Medicine, Seoul, Korea.
  • 3Division of Nephrology, Department of Internal Medicine, Gangnam Severance Hospital, Seoul, Korea. dhkang@ewha.ac.kr

Abstract

Hyperuricemia is known to be associated with the presence of cardiovascular and metabolic syndrome and with the development of incipient kidney disease and an accelerated renal progression. However, an elevated uric acid level was not generally regarded as a true etiology or mediator, but an indicator of these diseases. Uric acid has recently regained the clinical interest and popularity based on emerging data suggesting the causative role of hyperuricemia in cardiovascular and renal disease. Experimental data demonstrates oxidative stress is one of the earliest phenomena observed in vascular, renal, liver cells and adipocytes exposed to uric acid. Since uric acid is one of the major antioxidants of plasma acting as a free radical scavenger and a chelator of transitional metal ion, uric acid-induced oxidative stress seems paradoxical. Data regarding the clinical implication of hyperuricemia is even more confusing, which defines hyperuricemia as a useless parameter to be eliminated from routine follow-up or a major risk factor to be therapeutic target. With a review of experimental and epidemiologic data, the presence of molecular switch to regulate the role of uric acid as anti- or pro-oxidant in different compartment of our body is suggested, which may shed light on understanding the paradoxical role of uric acid and solving the "uric acid debate".

Keyword

Uric acid; Oxidative stress; Anti-oxidant

MeSH Terms

Adipocytes
Antioxidants
Follow-Up Studies
Hyperuricemia
Kidney Diseases
Liver
Oxidative Stress
Plasma
Risk Factors
Uric Acid*
Antioxidants
Uric Acid

Figure

  • Fig. 1 Production & Metabolism of Uric Acid. XO; xanthine oxidase, XDH; xanthine dehydrogenase, NAD; nicotinamice-adenine dinucleotide, O2; superoxide.


Cited by  1 articles

Serum Uric Acid Relation for Hearing Threshold Shift
Hui-Fang Yang, Tung-Wei Kao, Tao-Chun Peng, Yu-Shan Sun, Fang-Yih Liaw, Chung-Ching Wang, Ju-Ting Hsueh, Wei-Liang Chen
Clin Exp Otorhinolaryngol. 2017;10(2):143-147.    doi: 10.21053/ceo.2016.00346.


Reference

1. Davis N. The cardio-vascular and renal relations and manifestations of gout. JAMA. 1897; 29:261–262.
Article
2. Grayson PC, Kim SY, Lavalley M, Choi HK. Hyperuricemia and incident hypertension: A systematic review and meta-analysis. Arthritis Care Res (Hoboken). 2010; 63:102–110. PMID: 20824805.
Article
3. Bellomo G, Venanzi S, Verdura C, Saronio P, Esposito A, Timio M. Association of uric acid with change in kidney function in healthy normotensive individuals. Am J Kidney Dis. 2010; 56:264–272. PMID: 20385436.
Article
4. Obermayr RP, Temml C, Gutjahr G, Knechtelsdorfer M, Oberbauer R, Klauser-Braun R. Elevated uric acid increases the risk for kidney disease. J Am Soc Nephrol. 2008; 19:2407–2413. PMID: 18799720.
Article
5. Weiner DE, Tighiouart H, Elsayed EF, Griffith JL, Salem DN, Levey AS. Uric acid and incident kidney disease in the community. J Am Soc Nephrol. 2008; 19:1204–1211. PMID: 18337481.
Article
6. Rosolowsky ET, Ficociello LH, Maselli NJ, Niewczas MA, Binns AL, Roshan B, et al. High-normal serum uric acid is associated with impaired glomerular filtration rate in nonproteinuric patients with type 1 diabetes. Clin J Am Soc Nephrol. 2008; 3:706–713. PMID: 18272826.
Article
7. Domrongkitchaiporn S, Sritara P, Kitiyakara C, Stitchantrakul W, Krittaphol V, Lolekha P, et al. Risk factors for developing decreased kidney function in a Southeast Asian population: a 12-year cohort study. J Am Soc Nephrol. 2005; 16:791–799. PMID: 15677313.
8. Hsu CY, Iribarren C, McCulloch CE, Darbinian J, Go AS. Risk factors for end-stage renal disease: 25-year follow-up. Arch Intern Med. 2009; 169:342–350. PMID: 19237717.
9. Kim SJ, Kim JH, Gil HW, Yang JO, Lee EY, Hong SY. Hyperuricemia as a marker for progression of immunoglobulin A nephropathy. Kidney Res Clin Pract. 2012; 31:186–191.
Article
10. Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci USA. 1981; 78:6858–6862. PMID: 6947260.
Article
11. Stirpe F, Della Corte E. The regulation of rat liver xanthine oxidase - conversion in vitro of the enzyme activity from dehydrogenase (type D) to oxidase (type O). J Biol Chem. 1969; 244:3855–3863. PMID: 4308738.
12. Berry CE, Hare JM. Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications. J Physiol. 2004; 555:589–606. PMID: 14694147.
Article
13. Maesaka JK, Fishbane S. Regulation of renal urate excretion: A critical review. Am J Kidney Dis. 1998; 32:917–933. PMID: 9856507.
Article
14. 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; 417:447–452. PMID: 12024214.
Article
15. Anzai N, Kanai Y, Endou H. New insight into renal transport of urate. Curr Opin Rheumatol. 2007; 19:151–157. PMID: 17278930.
16. Johnson RJ, Titte S, Cade JR, Rideout BA, Oliver WJ. Uric acid, evolution and primitive cultures. Semin Nephrol. 2005; 25:3–8. PMID: 15660328.
Article
17. Faller J, Fox IH. Ethanol-induced hyperuricemia: Evidence for increased urate production by activation of adenine nucleotide turnover. N Engl J Med. 1982; 307:1598–1602. PMID: 7144847.
18. Emmerson BT. Effect of oral fructose on urate production. Ann Rheum Dis. 1974; 33:276–280. PMID: 4843132.
Article
19. Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, et al. A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol. 2006; 290:F625–F631. PMID: 16234313.
Article
20. Johnson RJ, Segal MS, Sautin Y, Nakagawa T, Feig DI, Kang DH, et al. Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr. 2007; 86:899–906. PMID: 17921363.
21. Kang DH, Park SK, Lee IK, et al. Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells. J Am Soc Nephrol. 2005; 16(12):3553–3562. PMID: 16251237.
Article
22. Yu MA, Sanchez-Lozada LG, Johnson RJ, Kang DH. Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid-induced endothelial dysfunction. J Hypertens. 2010; 28:1234–1242. PMID: 20486275.
Article
23. Sautin YY, Nakagawa T, Zharikov S, Johnson RJ. Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. Am J Physiol Cell Physiol. 2007; 293(2):C584–C596. PMID: 17428837.
Article
24. Ryu ES, Kim MJ, Shin HS, Jang YH, Choi HS, Jo I, et al. Uric acid-induced phenotypic transition of renal tubular cells as a novel mechanism of chronic kidney disease. Am J Physiol Renal Physiol. 2013; 304:F471–F480. PMID: 23283992.
Article
25. Lanaspa MA, Sanchez-Lozada LG, Choi YJ, Cicerchi C, Kanbay M, Roncal-Jimenez CA, et al. Uric acid induces Hepatic Steatosis by Generation of Mitochondrial Oxidative Stress: Potential Role in Fructose-Dependent and- Independent Fatty Liver. J Bio Chem. 2012; 287(48):40732–40744. PMID: 23035112.
26. Sánchez-Lozada LG, Lanaspa-García M, Cristóbal-García M, García-Arroyo F, Soto V, Cruz-Robles David, et al. Uric acid-induced endothelial dysfunction is associated with mitochondrial changes and reduced intracellular ATP concentrations. Nephron Exp Nephrol. 2012; 121(3-4):e71–e78. PMID: 23235493.
27. Glantzounis GK, Tsimoyiannis EC, Kappas AM, Galaris DA. Uric acid and oxidative stress. Curr Pharm Des. 2005; 11:4145–4151. PMID: 16375736.
Article
28. Stocker R, Keaney J. Role of oxidative modifications in atherosclerosis. Physiol Rev. 2004; 84:1381–1478. PMID: 15383655.
Article
29. Waring WC, Webb DJ, Maxwell SR. Systemic uric acid administration increases serum antioxidant capacity in healthy volunteers. J Cardiovasc Pharmacol. 2001; 38:365–371. PMID: 11486241.
30. Sánchez-Lozada LG, Soto V, Tapia E, Avila-Casado C, Sautin YY, Nakagawa T, et al. Role of oxidative stress in the renal abnormalities induced by experimental hyperuricemia. Am J Physiol. 2008; 295:F1134–F1141.
Article
31. Zhang JX, Zhang YP, Wu QN, Chen B. Uric acid induces oxidative stress via an activation of the renin-angiotensin system in 3T3-L1 adipocytes. Endocrine. 2014; accepted.
Article
32. Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ Res. 2005; 96:939–949. PMID: 15890981.
Article
33. Choi YJ, Shin HS, Choi HS, Park JW, Jo I, Oh ES, et al. Uric acid induced fat accumulation via an induction of endoplasmic reticulum stress and SREBP-1c activation in hepatocyte. Lab Invest. 2014; accepted.
34. Baker JK, Krishnan E, Chen L, Schumacher HR. Serum uric acid and cardiovascular disease: recent developments, where do they leave us? Am J Med. 2005; 118:816–826. PMID: 16084170.
35. Wannamethee SG. Serum uric acid and risk of coronary heart disease. Curr Pharm Des. 2005; 11:4125–4132. PMID: 16375733.
Article
36. Wong KY, MacWalter RS, Fraser HW, Crombie I, Ogsten SA, Struthers AD. Urate predicts subsequent cardiac death in stroke survivors. Eur Heart J. 2002; 23:788–793. PMID: 12009718.
Article
37. Weir CJ, Muir SW, Walters MR, Lees KR. Serum urate as an independent predictor of poor outcome and future vascular events after acute stroke. Stroke. 2003; 34:1951–1957. PMID: 12843346.
Article
38. Anker SD, Doehener W, Rauchhaus M, Sharma R, Francis D, Knosalla C, et al. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional and haemodynamic staging. Circulation. 2003; 107:1991–1997. PMID: 12707250.
39. Bickel C, Ruppreeht HJ, Blankerberg S, Rippin G, Hafner G, Daunhauer A, et al. Serum uric acid as an independent predictor of mortality in patients with angiographically proven coronary artery disease. Am J Cardiol. 2002; 89:12–17. PMID: 11779515.
Article
Full Text Links
  • EBP
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr