Abstract
Hyperuricemia is associated with cardiovascular and renal diseases, as glomerulosclerosis. Noncrystalline uric acid induces deleterious effects on endothelial and vascular smooth muscle cells. In the present study, we analyzed the damage induced by UA on human mesangial cells (HMC), the potential mechanism involved in this injury, and its consequences during infection. HMC were exposed to noncrystalline UA (8 mg/dl) and/or lipopolysaccharide (LPS, 100 μg/ml) for 24 h. In the experiments of cellular viability, HMC were exposed to 8–50 mg/dl of UA. Necrosis was assessed by acridine orange and ethidium bromide. Reactive oxygen species (ROS) were analyzed by 2′,7′-dichlorofluorescein. Prostaglandin E2 (PGE2) was evaluated by ELISA. Cyclooxygenase 2 (COX-2) expression was assessed by real-time PCR. UA induced necrosis only at supraphysiological concentrations. Nevertheless, it significantly increased ROS production at 8 mg/dl. LPS increased necrosis and ROS production. Interestingly, the association between UA and LPS decreased ROS and necrosis. UA associated or not with LPS induced COX-2 expression and PGE2 increases in HMC. Results suggest that UA has pro- and anti-oxidant effects in HMC. During infections, it acts like scavenger increasing cellular viability, but alone it can induce ROS production and cellular death in higher concentrations. Additionally, UA has direct pro-inflammatory effects inducing COX-2 expression and PGE2 synthesis. It is concluded that elevated concentrations of uric acid potentially contributes to glomerular damage.
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Ames BN, Cathcart R, Schwiers E, Hochstein P (1981) Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci USA 78(11):6858–6862
Selby JV, Friedman GD, Quesenberry CP Jr (1990) Precursors of essential hypertension: pulmonary function, heart rate, uric acid, serum cholesterol, and other serum chemistries. Am J Epidemiol 131(6):1017–1027
Emmerson BT, Row PG (1975) An evaluation of the pathogenesis of the gout kidney. Kidney Int 8:65–71
Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S, Tuttle KR, Rodriguez-Iturbe B, Herrera-Acosta J, Mazzali M (2003) Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 41(6):1183–1190
Fang J, Alderman MH (2000) Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study. 1971–1992 National Health and Nutrition Examination Survey. JAMA 283(18):2404–2410
Niskanen LK, Laaksonen DE, Nyyssonen K, Alfthan G, Lakka HM, Lakka TA, Salonen JT (2004) Uric acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men: a prospective cohort study. Arch Intern Med 164(14):1546–1551
Kang DH, Park SK, Lee IK, Johnson RJ (2005) Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells. J Am Soc Nephrol 16:3553–3562
Rao GN, Corson MA, Berk BC (1991) Uric acid stimulates vascular smooth muscle cell proliferation by increasing platelet derived growth factor A-chain expression. J Biol Chem 266:8604–8608
Mazzali M, Kanellis J, Han L, Feng L, Xia YY, Chen Q, Kang DH, Gordon KL, Watanabe S, Nakagawa T, Lan HY, Johnson RJ (2002) Hyperuricemia induces a primary arteriolopathy in rats by a blood pressure-independent mechanism. Am J Physiol Renal Physiol 282:F991–F997
Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, Krotova K, Block ER, Prabhakar S, Johnson RJ (2005) Hyperuricemia induces endothelial dysfunction. Kidney Int 67:1739–1742
Han HJ, Lim MJ, Lee YJ, Lee JH, Yang IS, Taub M (2007) Uric acid inhibits renal proximal tubule cell proliferation via at least two signaling pathways involving PKC, MAPK, cPLA2, and NF-kB. Am J Physiol Renal Physiol 292:F373–F381
Lin SD, Tsai DH, Hsu SR (2006) Association between serum uric acid level and components of the metabolic syndrome. J Chin Med Assoc 69(11):512–516
Talbott JH, Terplan KL (1960) The kidney in gout. Medicine 39:405–467
Gonick HC, Rubini MD, Gleason IO, Sommers SC (1965) The renal lesion in gout. Ann Int Med 62:667–674
Sohshang HL, Singh MA, Singh NG, Singh SR (2000) Biochemical and bacteriological study of urinary calculi. J Commun Dis 32(3):216–221
Banas B, Luckow B, Möller M, Klier C, Nelson PJ, Schadde E, Brigl M, Halevy D, Holthöfer H, Reinhart B, Schlöndorff D (1999) Chemokine and chemokine receptor expression in a novel human mesangial cell line. J Am Soc Nephrol 10(11):2314–2322
Ubezio P, Civoli F (1994) Flow cytometric detection of hydrogen peroxide production induced by doxorubicin in cancer cells. Free Radic Biol Med 16:509
Seim S (1982) Production of reactive oxygen species and chemiluminescence by human monocytes during differentiation and lymphokine activation in vitro. Acta Pathol Microbiol Immunol Scand C 90(3):179–185
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin-Phenol reagents. J Biol Chem 193:265–275
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-∆∆CT method. Methods 25:402
Keane WF, Gekker G, Schlievert PM, Peterson PK (1986) Enhancement of endotoxin-induced isolated renal tubular cell injury by toxic shock syndrome toxin. Am J Pathol 122(1):169–176
Sautin YY, Johnson RJ (2008) Uric Acid: the oxidant-antioxidant paradox. Nucleosides Nucleotides Nucleic Acids 27(6):608–619
Gersch C, Palii SP, Imaram W, Kim KM, Kammanchi SA, Angerhofer A, Johnson RJ, Henderson GN (2009) Reactions of peroxynitrite with uric acid: formation of reactive intermediates, alkylated products and triuret, and in vivo production of triuret under conditions of oxidative stress. Nucleosides Nucleotides Nucleic Acids 28(2):118–149
Berger L, Yu T (1975) Renal function in gout: IV: an analysis of 524 gouty subjects including long-term follow-up studies. Am J Med 59:605–613
Kang DH, Nakagawa T, Feng L, Watanabe S, Han L, Mazzali M, Truong L, Harris R, Johnson RJ (2002) A role for uric acid in the progression of renal disease. J Am Soc Nephrol 13:2888–2897
MacKinnon KL, Molnar Z, Lowe D, Watson ID, Shearer E (1999) Measures of total free radical activity in critically ill patients. Clin Biochem 32(4):263–268
Chuang CC, Shiesh SC, Chi CH, Tu YF, Hor LI, Shieh CC, Chen MF (2006) Serum total antioxidant capacity reflects severity of illness in patients with severe sepsis. Crit Care 10(1):R36–R43
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This work was aided by grants from Conselho Nacional de Desenvolvimento Científico Tecnológico (CnPQ), Financiadora de Estudos e Projetos (FINEP), Fundação Oswaldo Ramos (FOR), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) e Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).
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Convento, M.S., Pessoa, E., Dalboni, M.A. et al. Pro-inflammatory and oxidative effects of noncrystalline uric acid in human mesangial cells: contribution to hyperuricemic glomerular damage. Urol Res 39, 21–27 (2011). https://doi.org/10.1007/s00240-010-0282-5
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DOI: https://doi.org/10.1007/s00240-010-0282-5