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      Free Reactive Oxygen Species and Nephrotoxicity of Contrast Agents

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          Background: The nephrotoxicity induced by contrast media remains a serious clinical problem, and the underlying mechanism has not been completely understood. Experimental and clinical investigations suggest that reactive oxygen species (ROS) are critical determinants of radiocontrast nephropathy (RCN), and that antioxidants can prevent this damage. Methods: Cultured human proximal renal tubule cells (HK-2) were exposed to hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) at different concentrations. H<sub>2</sub>O<sub>2</sub>-induced tubular DNA damage was examined in the presence of the antioxidant MESNA (sodium-2-mercaptoethane sulphonate). The induction of DNA damage was measured with the alkaline comet assay (single cell gel electrophoresis). We also studied 12 patients with stable renal impairment (median baseline creatinine 296 µmol/l; range: 203–495 µmol/l) undergoing cardiac catheterization/intervention prospectively. Patients received 800 mg MESNA intravenously 30 min before exposure to the contrast agent in addition to 0.9% saline hydration. Results: In the cell cultures, oxidative stress on HK-2 cells induced increased DNA migration in the comet assay. Treatment of tubular cells with the antioxidant MESNA prior to the addition of H<sub>2</sub>O<sub>2</sub> significantly reduced DNA migration in the comet assay. In the clinical study, treatment of the patients with MESNA prevented the adverse renal effect of contrast media (median serum creatinine 293; range: 187–433 µmol/l) 48 h after coronary angiography/intervention. Conclusion: Both the in vivo and the in vitro studies suggest that the ROS-mediated renal injury could be inhibited by a potent antioxidant such as MESNA.

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          Most cited references 7

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          Direct enzymic detection of endogenous oxidative base damage in human lymphocyte DNA.

          The endogenous production of oxidative damage in DNA by free radicals released as a by-product of respiration is a likely cause of mutations which, if they occur in appropriate genes, may lead to cancer. Using an endonuclease specific for oxidized pyrimidines, in conjunction with the highly sensitive method of single cell gel electrophoresis, we have detected significant oxidative damage in untreated, freshly isolated lymphocytes from normal, healthy individuals.
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            HK-2: An immortalized proximal tubule epithelial cell line from normal adult human kidney

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              Oxidative DNA damage and repair in experimental atherosclerosis are reversed by dietary lipid lowering.

              Increased oxidative stress is a major characteristic of hypercholesterolemia-induced atherosclerosis. The oxidative environment is mainly created by the production of reactive oxygen species, which are assumed to mediate vascular tissue injury. Oxidative DNA damage resulting from free radical attack remains, however, a poorly examined field in atherosclerosis. Male New Zealand White rabbits were fed a cholesterol-rich diet (0.3%) for 24 weeks. The induced atherosclerotic plaques showed elevated levels of the DNA damage marker 7,8-dihydro-8-oxoguanine (8-oxoG) as demonstrated by immunohistochemistry. 8-oxoG immunoreactivity was found predominantly in the superficial layer of the plaque containing numerous macrophage-derived foam cells but not in the media or in arteries of age-matched control animals. Alkaline single-cell gel electrophoresis revealed that the number of DNA strand breaks was significantly higher in the plaque as compared with control samples of normolipemic animals. These changes were associated with the upregulation of DNA repair enzymes (poly[ADP-ribose] polymerase-1, p53, phospho-p53 [phosphorylated at Ser392], and XRCC1 [x-ray repair cross-complementing 1]). DNA strand breaks normalized after 4 weeks of dietary lipid lowering. However, a significant reduction of 8-oxoG immunoreactivity was only observed after a prolonged period of lipid lowering (12 to 24 weeks). Repair pathways started to decline progressively when cholesterol-fed animals were placed on a normal diet. In conclusion, oxidative DNA damage and increased levels of DNA repair, both associated with diet-induced hypercholesterolemia, are strongly reduced during dietary lipid lowering. These findings may provide a better insight into the benefits of lipid-lowering therapy on plaque stabilization.

                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                April 2004
                12 August 2004
                : 27
                : 3
                : 167-171
                Nephrology, Medical Faculty University of Ulm, Ulm, Germany
                79805 Kidney Blood Press Res 2004;27:167–171
                © 2004 S. Karger AG, Basel

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                Page count
                Figures: 3, References: 15, Pages: 5
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/79805
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