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ORIGINAL RESEARCH ARTICLE

Coordinated Upregulation of a Series of Endogenous Antioxidants and Phase 2 Enzymes as a Novel Strategy for Protecting Renal Tubular Cells from Oxidative and Electrophilic Stress

Hong Zhu^*, Li Zhang, Ashok R. Amin and Yunbo Li^*,,1

^* Division of Biomedical Sciences, Edward Via Virginia College of Osteopathic Medicine, Virginia Tech Corporate Research Center, Blacksburg, Virginia 24060; Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, Ohio 43210; Research Department, Carilion Clinic, Roanoke, Virginia 24013; and Department of Biomedical Sciences and Pathobiology, Virginia–Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia 24061

To whom requests for reprints should be addressed at ¹ 1861 Pratt Drive, Blacksburg, VA 24060. E-mail: yli{at}vcom.vt.edu

In view of the crucial involvement of oxidative and electrophilic stress in various kidney disorders, this study was undertaken to test the hypothesis that pharmacologically-mediated coordinated upregulation of endogenous renal antioxidants and phase 2 enzymes is an effective strategy for renal protection. Notably, studies on the pharmacological inducibility of a series of antioxidants and phase 2 enzymes in renal tubular cells are lacking. Here we reported that incubation of normal rat kidney (NRK-52E) proximal tubular cells with low micromolar concentrations (10–50 µM) of the cruciferous nutraceutical, 1,2-dithiole-3-thione (D3T), led to a significant concentration-dependent induction of a wide spectrum of antioxidants and phase 2 enzymes, including catalase (CAT), reduced form of glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1 (NQO1), and heme oxygenase (HO). We further observed that D3T treatment also increased the protein and mRNA expression for CAT, -glutamylcysteine ligase, GR, GST-A, GST-M, NQO1, and HO-1. Incubation of the renal tubular cells with H₂O₂, SIN-1-derived peroxynitrite, or 4-hydroxy-2-nonenal led to concentration-dependent decreases in cell viability. Pretreatment of the renal tubular cells with 10–50 µM D3T afforded remarkable protection against the nephrocytotoxicity elicited by the above oxidative and electrophilic species. The D3T-mediated cytoprotection showed a concentration-dependent relationship. Taken together, this study for the first time comprehensively characterized the inducibility by a unique nutraceutical of a wide spectrum of antioxidative and phase 2 defenses in renal tubular cells at the levels of enzyme activity as well as protein and mRNA expression, and demonstrated that such a coordinated upregulation of cellular defenses led to remarkable protection of renal tubular cell from oxidative and electrophilic stress. Because of the crucial role of oxidative and electrophilic stress in inflammatory injury, D3T-mediated coordinated induction of endogenous antioxidative and phase 2 defenses may also serve as an important anti-inflammatory mechanism in kidneys.

Key Words: antioxidants • phase 2 enzymes • 1,2-dithiole-3-thione • renal tubular cells • oxidative stress • electrophilic stress