Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress.
Uric acid is considered a major antioxidant in human blood that may protect against aging and oxidative stress. Despite its proposed protective properties, elevated levels of uric acid are commonly associated with increased risk for cardiovascular disease and mortality. Furthermore, recent experimental studies suggest that uric acid may have a causal role in hypertension and metabolic syndrome. All these conditions are thought to be mediated by oxidative stress. In this study we demonstrate that differentiation of cultured mouse adipocytes is associated with increased production of reactive oxygen species (ROS) and uptake of uric acid. Soluble uric acid stimulated an increase in NADPH oxidase activity and ROS production in mature adipocytes but not in preadipocytes. The stimulation of NADPH oxidase-dependent ROS by uric acid resulted in activation of MAP kinases p38 and ERK1/2, a decrease in nitric oxide bioavailability, and an increase in protein nitrosylation and lipid oxidation. Collectively, our results suggest that hyperuricemia induces redox-dependent signaling and oxidative stress in adipocytes. Since oxidative stress in the adipose tissue has recently been recognized as a major cause of insulin resistance and cardiovascular disease, hyperuricemia-induced alterations in oxidative homeostasis in the adipose tissue might play an important role in these derangements.
Sautin
Yuri Y
YY
Division of Nephrology, Hypertension, and Transplantation, Dept of Medicine, University of Florida, Gainesville, FL 32610-0224, USA. sautiyy@medicine.ufl.edu
Nakagawa
Takahiko
T
Zharikov
Sergey
S
Johnson
Richard J
RJ
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000633:toxicity; D002318:Cardiovascular Diseases / Q000209:etiology / Q000378:metabolism; D002454:Cell Differentiation; D004789:Enzyme Activation; D033461:Hyperuricemia / Q000150:complications / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D015227:Lipid Peroxidation; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D015538:Nitrosation; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014527:Uric Acid / Q000378:metabolism* / Q000633:toxicity; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000975:Antioxidants; D007527:Isoenzymes; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D014527:Uric Acid; D009569:Nitric Oxide; D019255:NADPH Oxidases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases