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      Effect of Selenium on Cisplatin-Induced Nephrotoxicity in Rats

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          Cisplatin (CP), a commonly used antineoplastic drug, is nephrotoxic. CP-induced nephrotoxicity involves oxidative pathways. A deficiency of selenium (Se) reduces glutathione peroxidase (GPx) activity resulting in oxidative stress. We investigated how Se deficiency or oral Se administration influences CP-induced nephrotoxicity. Thirty male Wistar rats were fed a Se-deficient or control diet for 4 weeks. Then they were given intraperitoneal (i.p.) CP alone, i.p. saline alone, or Se by gavage 24 and 1 h prior to i.p. CP. Blood and urine samples were collected and the kidneys were removed 5 days after CP treatment. Urinalysis, renal function, GPx activity, and expression of cellular GPx mRNA were measured. Histology was evaluated by light microscopy with immunohistochemistry for 4-hydroxy-2-nonenal (HNE), vimentin, and heme oxygenase (HO)-1. CP induced renal tubular damage with increased expression of vimentin, HO-1 and HNE staining, which represents lipid peroxidation. Se deficiency exacerbated CP-induced nephrotoxicity as shown by deterioration of the above parameters and depressed GPx activity and expression of GPx mRNA. Se treatment ameliorated CP-induced nephrotoxicity, but did not significantly improve renal function. These findings suggest that Se deficiency increases oxidative stress and enhances CP-induced nephrotoxicity, whereas oral Se treatment partially protects against the nephrotoxicity in rats.

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          Most cited references 21

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              CTGF expression is induced by TGF- beta in cardiac fibroblasts and cardiac myocytes: a potential role in heart fibrosis.

              Connective tissue growth factor (CTGF) is a cysteine-rich protein induced by transforming growth factor beta (TGF- beta) in connective tissue cells. CTGF can trigger many of the cellular processes underlying fibrosis, such as cell proliferation, adhesion, migration and the synthesis of extracellular matrix; however, its role in acute and chronic cardiac injury is not fully understood. Here, we show that TGF- beta is a specific inducer of CTGF expression in both cardiac fibroblasts and cardiac myocytes. The activity of a CTGF promoter-based reporter construct correlated with endogenous CTGF expression, suggesting that TGF- beta induces CTGF expression most likely by activating its promoter. Upregulation of CTGF coincided with an increase in fibronectin, collagen type I and plasminogen activator inhibitor-1 production. Forskolin, a stimulator of cyclic AMP, blocked TGF- beta induced CTGF expression and reduced the basal level of CTGF, whereas an inhibitor that blocks the MAP kinase signaling pathway (PD 98059) significantly enhanced TGF- beta induced CTGF expression. Furthermore, we found that both TGF- beta and CTGF mRNAs were significantly elevated in the left ventricles and septa of rat hearts 2-16 weeks following myocardial infarction. This correlated well with concomitant increases in fibronectin, and type I and type III collagen mRNA levels in these animal hearts. Significant upregulation of CTGF was also detected in human heart samples derived from patients diagnosed with cardiac ischemia. Based on these findings, we propose that CTGF is an important mediator of TGF- beta signaling in the heart and abnormal expression of this gene could be used as a diagnostic marker for cardiac fibrosis. Copyright 2000 Academic Press.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                October 2006
                14 July 2006
                : 104
                : 3
                : e112-e122
                aDepartment of Pediatrics, and bFirst Department of Pathology, Kochi Medical School, Kochi University, Nankoku, cDepartment of Pathology, Kochi National Hospital, Kochi, dDepartment of Pharmacology, Kobe Gakuin University, Kobe, and eDepartment of Pediatrics, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
                94550 Nephron Exp Nephrol 2006;104:e112–e122
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 7, Tables: 2, References: 34, Pages: 1
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                Original Paper

                Cardiovascular Medicine, Nephrology

                Nephrotoxicity, Glutathione peroxidase, Selenium, Cisplatin


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