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      Time course study of oxidative and nitrosative stress and antioxidant enzymes in K 2Cr 2O 7-induced nephrotoxicity

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          Abstract

          Background

          Potassium dichromate (K 2Cr 2O 7)-induced nephrotoxicity is associated with oxidative and nitrosative stress. In this study we investigated the relation between the time course of the oxidative and nitrosative stress with kidney damage and alterations in the following antioxidant enzymes: Cu, Zn superoxide dismutase (Cu, Zn-SOD), Mn-SOD, glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (CAT).

          Methods

          Nephrotoxicity was induced in rats by a single injection of K 2Cr 2O 7. Groups of animals were sacrificed on days 1,2,3,4,6,8,10, and 12. Nephrotoxicity was evaluated by histological studies and by measuring creatinine clearance, serum creatinine, blood urea nitrogen (BUN), and urinary excretion of N-acetyl-β-D-glucosaminidase (NAG) and total protein. Oxidative and nitrosative stress were measured by immunohistochemical localization of protein carbonyls and 3-nitrotyrosine, respectively. Cu, Zn-SOD, Mn-SOD, and CAT were studied by immunohistochemical localization. The activity of total SOD, CAT, GPx, and GR was also measured as well as serum and kidney content of chromium and urinary excretion of NO 2 -/NO 3 -. Data were compared by two-way analysis of variance followed by a post hoc test.

          Results

          Serum and kidney chromium content increased reaching the highest value on day 1. Nephrotoxicity was made evident by the decrease in creatinine clearance (days 1–4) and by the increase in serum creatinine (days 1–4), BUN (days 1–6), urinary excretion of NAG (days 1–4), and total protein (day 1–6) and by the structural damage to the proximal tubules (days 1–6). Oxidative and nitrosative stress were clearly evident on days 1–8. Urinary excretion of NO 2 -/NO 3 - decreased on days 2–6. Mn-SOD and Cu, Zn-SOD, estimated by immunohistochemistry, and total SOD activity remained unchanged. Activity of GPx decreased on days 3–12 and those of GR and CAT on days 2–10. Similar findings were observed by immunohistochemistry of CAT.

          Conclusion

          These data show the association between oxidative and nitrosative stress with functional and structural renal damage induced by K 2Cr 2O 7. Renal antioxidant enzymes were regulated differentially and were not closely associated with oxidative or nitrosative stress or with kidney damage. In addition, the decrease in the urinary excretion of NO 2 -/NO 3 - was associated with the renal nitrosative stress suggesting that nitric oxide was derived to the formation of reactive nitrogen species involved in protein nitration.

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          Most cited references45

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          Macrophage oxidation of L-arginine to nitrite and nitrate: nitric oxide is an intermediate.

          Previous studies have shown that murine macrophages immunostimulated with interferon gamma and Escherichia coli lipopolysaccharide synthesize NO2-, NO3-, and citrulline from L-arginine by oxidation of one of the two chemically equivalent guanido nitrogens. The enzymatic activity for this very unusual reaction was found in the 100,000g supernatant isolated from activated RAW 264.7 cells and was totally absent in unstimulated cells. This activity requires NADPH and L-arginine and is enhanced by Mg2+. When the subcellular fraction containing the enzyme activity was incubated with L-arginine, NADPH, and Mg2+, the formation of nitric oxide was observed. Nitric oxide formation was dependent on the presence of L-arginine and NADPH and was inhibited by the NO2-/NO3- synthesis inhibitor NG-monomethyl-L-arginine. Furthermore, when incubated with L-[guanido-15N2]arginine, the nitric oxide was 15N-labeled. The results show that nitric oxide is an intermediate in the L-arginine to NO2-, NO3-, and citrulline pathway. L-Arginine is required for the activation of macrophages to the bactericidal/tumoricidal state and suggests that nitric oxide is serving as an intracellular signal for this activation process in a manner similar to that very recently observed in endothelial cells, where nitric oxide leads to vascular smooth muscle relaxation [Palmer, R. M. J., Ashton, D. S., & Moncada, S. (1988) Nature (London) 333, 664-666].
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            Cytotoxicity and oxidative mechanisms of different forms of chromium.

            D Bagchi (2002)
            Chromium exists mostly in two valence states in nature: hexavalent chromium [chromium(VI)] and trivalent chromium [chromium(III)]. Chromium(VI) is commonly used in industrial chrome plating, welding, painting, metal finishes, steel manufacturing, alloy, cast iron and wood treatment, and is a proven toxin, mutagen and carcinogen. The mechanistic cytotoxicity of chromium(VI) is not completely understood, however, a large number of studies demonstrated that chromium(VI) induces oxidative stress, DNA damage, apoptotic cell death and altered gene expression. Conversely, chromium(III) is essential for proper insulin function and is required for normal protein, fat and carbohydrate metabolism, and is acknowledged as a dietary supplement. In this paper, comparative concentration- and time-dependent effects of chromium(VI) and chromium(III) were demonstrated on increased production of reactive oxygen species (ROS) and lipid peroxidation, enhanced excretion of urinary lipid metabolites, DNA fragmentation and apoptotic cell death in both in vitro and in vivo models. Chromium(VI) demonstrated significantly higher toxicity as compared with chromium(III). To evaluate the role of p53 gene, the dose-dependent effects of chromium(VI) were assessed in female C57BL/6Ntac and p53-deficient C57BL/6TSG p53 mice on enhanced production of ROS, lipid peroxidation and DNA fragmentation in hepatic and brain tissues. Chromium(VI) induced more pronounced oxidative damage in multiple target organs in p53 deficient mice. Comparative studies of chromium(III) picolinate and niacin-bound chromium(III), two popular dietary supplements, reveal that chromium(III) picolinate produces significantly more oxidative stress and DNA damage. Studies have implicated the toxicity of chromium picolinate in renal impairment, skin blisters and pustules, anemia, hemolysis, tissue edema, liver dysfunction; neuronal cell injury, impaired cognitive, perceptual and motor activity; enhanced production of hydroxyl radicals, chromosomal aberration, depletion of antioxidant enzymes, and DNA damage. Recently, chromium picolinate has been shown to be mutagenic and picolinic acid moiety appears to be responsible as studies show that picolinic acid alone is clastogenic. Niacin-bound chromium(III) has been demonstrated to be more bioavailable and efficacious and no toxicity has been reported. In summary, these studies demonstrate that a cascade of cellular events including oxidative stress, genomic DNA damage and modulation of apoptotic regulatory gene p53 are involved in chromium(VI)-induced toxicity and carcinogenesis. The safety of chromium(III) is largely dependent on the ligand, and adequate clinical studies are warranted to demonstrate the safety and efficacy of chromium(III) for human consumption.
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              Inactivation of glutathione peroxidase by superoxide radical.

              The selenium-containing glutathione peroxidase, when in its active reduced form, was inactivated during exposure to the xanthine oxidase reaction. Superoxide dismutase completely prevented this inactivation, whereas catalase, hydroxyl radical scavengers, or chelators did not, indicating that O2 was the responsible agent. Conversion of GSH peroxidase to its oxidized form, by exposure to hydroperoxides, rendered it insensitive toward O2. The oxidized enzyme regained susceptibility toward inactivation by O2 when reduced with GSH. The inactivation by O2 could be reversed by GSH; however, sequential exposure to O2 and then hydroperoxides caused irreversible inactivation. Reactivity toward CN- has been used as a measure of the oxidized form of GSH peroxidase, whereas reactivity toward iodoacetate has been taken as an indicator of the reduced form. By these criteria both O2 and hydroperoxides convert the reduced form to oxidized forms. A mechanism involving oxidation of the selenocysteine residue at the active site has been proposed to account for these observations.
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                Author and article information

                Journal
                BMC Nephrol
                BMC Nephrology
                BioMed Central (London )
                1471-2369
                2005
                26 April 2005
                : 6
                : 4
                Affiliations
                [1 ]Facultad de Química, Departamento de Biología, Edificio B, Segundo Piso, Laboratorio 209, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, 04510, México, D.F., México
                [2 ]Facultad de Medicina, Departamento de Farmacología, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, 04510, México, D.F., México
                [3 ]Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Departamento de Patología, 14000, México, D.F., México
                [4 ]Facultad de Química, Edificio B, Laboratorio 124, Departamento de Química Orgánica, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria 04510, México, D.F., México
                [5 ]Departamento de Nefrología, Instituto Nacional de Cardiología "Ignacio Chávez", Juan Badiano #1, Col Sección XVI, 14080 Tlalpan, México, D.F., México
                [6 ]Facultad de Química, Edificio B, Departamento de Química Analítica, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria 04510, México, D.F., México
                Article
                1471-2369-6-4
                10.1186/1471-2369-6-4
                1142323
                15854231
                bc37ab1a-62d3-4b48-95a9-09bc8507a361
                Copyright © 2005 Pedraza-Chaverrí et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 October 2004
                : 26 April 2005
                Categories
                Research Article

                Nephrology
                Nephrology

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