Pro-inflammatory and oxidative effects of noncrystalline uric acid in human mesangial cells: contribution to hyperuricemic glomerular damage.
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.
Nephrology Division, Department of Medicine, Federal University of São Paulo, Rua Pedro de Toledo 740, 2° andar, São Paulo, CEP 04023-900, Brazil.
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D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D033461:Hyperuricemia / Q000378:metabolism* / Q000473:pathology*; D007674:Kidney Diseases / Q000473:pathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D050527:Mesangial Cells / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014527:Uric Acid / Q000494:pharmacology*
D005452:Fluoresceins; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D014527:Uric Acid; C037631:2',7'-dichlorofluorescein; D051546:Cyclooxygenase 2; D015232:Dinoprostone