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      Antioxidants: A Possible Role in Kidney Protection

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          Oxidative stress contributes to the pathophysiology of kidney injury. Beneficial renal effects of some medications, such as angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor antagonists, calcium channel blockers, β-blockers and lipid lowering agents depend at least partially on the ability to alleviate oxidative stress. The administration of various natural or synthetic antioxidants has been shown to be of benefit in prevention and attenuation of renal scaring in numerous animal models of kidney diseases. These include vitamins, N-acetylcysteine, α-lipoic acid, melatonin, dietary flavonoids and phytoestrogens, and many others. Human studies are limited in this regard. Under certain conditions, surprisingly, the antioxidant supplements may exhibit pro-oxidant properties and even worsen renal damage. To date, the evidence is insufficient to recommend antioxidant supplements in patients with kidney disease. Prospective, controlled clinical trials on safety and effectiveness of different therapeutic antioxidant strategies are indispensable.

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          Most cited references 51

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          Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease.

          Lung cancer and cardiovascular disease are major causes of death in the United States. It has been proposed that carotenoids and retinoids are agents that may prevent these disorders. We conducted a multicenter, randomized, double-blind, placebo-controlled primary prevention trial -- the Beta Carotene and Retinol Efficacy Trial -- involving a total of 18,314 smokers, former smokers, and workers exposed to asbestos. The effects of a combination of 30 mg of beta carotene per day and 25,000 IU of retinol (vitamin A) in the form of retinyl palmitate per day on the primary end point, the incidence of lung cancer, were compared with those of placebo. A total of 388 new cases of lung cancer were diagnosed during the 73,135 person-years of follow-up (mean length of follow-up, 4.0 years). The active-treatment group had a relative risk of lung cancer of 1.28 (95 percent confidence interval, 1.04 to 1.57; P=0.02), as compared with the placebo group. There were no statistically significant differences in the risks of other types of cancer. In the active-treatment group, the relative risk of death from any cause was 1.17 (95 percent confidence interval, 1.03 to 1.33); of death from lung cancer, 1.46 (95 percent confidence interval, 1.07 to 2.00); and of death from cardiovascular disease, 1.26 (95 percent confidence interval, 0.99 to 1.61). On the basis of these findings, the randomized trial was stopped 21 months earlier than planned; follow-up will continue for another 5 years. After an average of four years of supplementation, the combination of beta carotene and vitamin A had no benefit and may have had an adverse effect on the incidence of lung cancer and on the risk of death from lung cancer, cardiovascular disease, and any cause in smokers and workers exposed to asbestos.
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            p22phox is a critical component of the superoxide-generating NADH/NADPH oxidase system and regulates angiotensin II-induced hypertrophy in vascular smooth muscle cells.

            Superoxide anion formation is vital to the microbicidal activity of phagocytes. Recently, however, there is accumulating evidence that it is also involved in cell growth in vascular smooth muscle cells (VSMCs). We have shown that the hypertrophic agent angiotensin II stimulates superoxide production by activating the membrane-bound NADH/NADPH oxidase and that inhibition of this oxidase attenuates vascular hypertrophy. However, the molecular identity of this oxidase in VSMCs is unknown. We have recently cloned the cytochrome b558 alpha-subunit, p22(phox) (one of the key electron transfer elements of the NADPH oxidase in phagocytes), from a rat VSMC cDNA library, but its role in VSMC oxidase activity remains unclarified. Here we report that the complete inhibition of p22(phox) mRNA expression by stable transfection of antisense p22(phox) cDNA into VSMCs results in a decrease in cytochrome b content, which is accompanied by a significant inhibition of angiotensin II-stimulated NADH/NADPH-dependent superoxide production, subsequent hydrogen peroxide production, and [3H]leucine incorporation. We provide the first evidence that p22(phox) is a critical component of superoxide-generating vascular NADH/NADPH oxidase and suggest a central role for this oxidase system in vascular hypertrophy.
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              Cellular antioxidant effects of atorvastatin in vitro and in vivo.

              3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may exert direct effects on vascular cells and beneficially influence endothelial dysfunction. Because reactive oxygen species (ROS) may lead to vascular damage and dysfunction, we investigated the effect of atorvastatin on ROS production and the underlying mechanisms in vitro and in vivo. Cultured rat aortic vascular smooth muscle cells were incubated with 10 micromol/L atorvastatin. Angiotensin II-induced and epidermal growth factor-induced ROS production were significantly reduced by atorvastatin (dichlorofluorescein fluorescence laser microscopy). Atorvastatin downregulated mRNA expression of the NAD(P)H oxidase subunit nox1, whereas p22phox mRNA expression was not significantly altered (reverse transcription-polymerase chain reaction, Northern analysis). Membrane translocation of rac1 GTPase, which is required for the activation of NAD(P)H oxidase, was inhibited by atorvastatin (Western blot). mRNA expression of superoxide dismutase isoforms and glutathione peroxidase was not modified by atorvastatin, whereas catalase expression was upregulated at mRNA and protein levels, resulting in an increased enzymatic activity. Effects of atorvastatin on ROS production and nox1, rac1, and catalase expression were inhibited by L-mevalonate but not by 25-hydroxycholesterol. In addition, spontaneously hypertensive rats were treated with atorvastatin for 30 days. ROS production in aortic segments was significantly reduced in statin-treated rats (lucigenin chemiluminescence). Treatment with atorvastatin reduced vascular mRNA expression of p22phox and nox1 and increased aortic catalase expression. mRNA expression of superoxide dismutases, glutathione peroxidase, and NAD(P)H oxidase subunits gp91phox, p40phox, p47phox, and p67phox remained unchanged. Translocation of rac1 from the cytosol to the cell membrane was also reduced in vivo. Thus, atorvastatin exerts cellular antioxidant effects in cultured rat vascular smooth muscle cells and in the vasculature of spontaneously hypertensive rats mediated by decreased expression of essential NAD(P)H oxidase subunits and by upregulation of catalase expression. These effects of atorvastatin may contribute to the vasoprotective effects of statins.

                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                19 November 2003
                : 26
                : 5-6
                : 303-314
                aDepartment of Nephrology, Transplantology and Internal Medicine, Medical University, Gdansk, Poland; bDivision of Nephrology and Dialysis, Department of Medicine III, University of Vienna, Vienna, Austria
                73936 Kidney Blood Press Res 2003;26:303–314
                © 2003 S. Karger AG, Basel

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                Page count
                Figures: 1, Tables: 4, References: 177, Pages: 12
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                Review Article

                Cardiovascular Medicine, Nephrology

                Oxidative stress, Free radical, Antioxidant, Kidney disease, Vitamins


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