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, 27 (6), 608-19

Uric Acid: The Oxidant-Antioxidant Paradox

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Uric Acid: The Oxidant-Antioxidant Paradox

Yuri Y Sautin et al. Nucleosides Nucleotides Nucleic Acids.

Abstract

Uric acid, despite being a major antioxidant in the human plasma, both correlates and predicts development of obesity, hypertension, and cardiovascular disease, conditions associated with oxidative stress. While one explanation for this paradox could be that a rise in uric acid represents an attempted protective response by the host, we review the evidence that uric acid may function either as an antioxidant (primarily in plasma) or pro-oxidant (primarily within the cell). We suggest that it is the pro-oxidative effects of uric acid that occur in cardiovascular disease and may have a contributory role in the pathogenesis of these conditions.

Conflict of interest statement

Conflict of Interest: Dr. Johnson has patent applications related to the lowering of uric acid as a means for treating cardiovascular disease and obesity via the University of Florida and University of Washington.

Figures

FIGURE 1
FIGURE 1
Uric acid induces production of reactive oxygen species in mouse adipocytes. Differentiated mouse adipocytes were treated with 15 mg/ml uric acid for 30 minutes with or wirhout 25 μM Mn(II) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP), N-acetyl cysteine (10 mM), apocynin (200 μM) and diphenylene-iodonium (DPI, 10 μM), rotenone (100 μM), and thenoyltrifluoroacetone (TTFA, 100 μM) followed by the measurement of ROS with the ROS-specific fluorescent probe 5 (and 6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate-acetyl ester (CM-H2DCFDA) as described in details in (33). (A) Effect of uric acid is blocked by the superoxide scavenger MnTMPyP; (B) Effect of uric acid is blocked by inhibitors of NADPH oxidase apocynin and DPI but not the inhibitors of mitochondrial respiratory chain rotenone and TTPA. *— the effect of uric acid is significant (P < 0.05, nonparametric U-test); & —the effect of the inhibitor is significant (P < 0.05, U-test, n = 3). (Reproduced from (33)—used with the permission from the American Physiological Society)
FIGURE 2
FIGURE 2
Uric acid induces production of reactive oxygen species in human subcutaneous primary adipocytes. Treatment with uric acid and inhibitors were performed as described in Figure 1. (A) ROS-induced fluorescence is shown in the left panels; images of the adipocytes by differential interference contrast (DIC) are shown in the right panels. (B) The effect of uric acid is blocked by the superoxide scavenger MnTMPyP and an inhibitor of NADPH oxidase apocynin. *— the effect of uric acid is significant (P < 0.05, nonparametric U-test); and — the effect of the inhibitor is significant (P < 0.05, U-test, n = 3).
FIGURE 3
FIGURE 3
Activation of p38 kinase in adipocytes in response to uric acid is mediated by NADPH oxidase- and superoxide-dependent redox mechanism. Adipocytes were treated with 15 mg/dl uric acid for varying periods of time with or without antioxidants or an inhibitor of NADPH oxidase. Activated (phosphorylated p38 was detected by immunoblotting with phosphospecific (Thr180/Tyr182) p38 antibody and reprobed with GAPDH antibody as a control of equal protein loading/transfer. Reproduced from (33) —used with the permission from the American Physiological Society)
FIGURE 4
FIGURE 4
Uric acid induces NADPH oxidase-dependent lipid oxidation in mouse adipocytes. Adipocytes were treated with 15 mg/ml uric acid with or without superoxide scavenger MnTMPyP and an inhibitor of NADPH oxidase apocynin as indicated in Figure 1. Cells were loaded with the oxidation-sensitive lipid probe C11-BODIPY581,591 followed by washing cells to remove unincorporated probe. Detection of lipid peroxidation by live imaging was started immediately after addition of uric acid. (A) Green fluorescence representing oxidized probe was detected every 60 seconds for 100 ms after addition uric acid. (B) Ratiometric analysis of lipid oxidation: ratio of green/red fluorescence measured every 60 seconds is shown. The values for 12–20 different cells (mean ± SD) are shown.
FIGURE 5
FIGURE 5
A model for urate-induced oxidative stress in adipocytes.

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