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Nickel-induced cell death and survival pathways in cultured renal proximal tubule cells: roles of reactive oxygen species, ceramide and ABCB1

  • Inorganic Compounds
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Abstract

Nickel and nickel compounds are carcinogens that target the lungs and kidneys causing cell death or cell survival adaptation. The multidrug resistance P-glycoprotein ABCB1 protects cells against toxic metabolites and xenobiotics and is upregulated in many cancer cell types. Here, we investigated the role of ABCB1 in nickel-induced stress signaling mediated by reactive oxygen species (ROS) and ceramides. In renal proximal tubule cells, nickel chloride (0.1–0.25 mM) increased both ROS formation, detected by 5-(and-6)-carboxy-2′,7′-dichlorodihydrofluorescein diacetate, and cellular ceramides, which were determined by lipid dot blot and surface immunostaining, culminating in decreased cell viability, increased DNA fragmentation, augmented PARP-1 cleavage, and increased ABCB1 mRNA and protein. Inhibitors of the de novo ceramide synthesis pathway (fumonisin B1, l-cycloserine) and an antioxidant (α-tocopherol) attenuated nickel-induced toxicity as well as induction of ABCB1. ABCB1 protects against nickel toxicity as PSC833, an ABCB1 blocker, augmented the decrease in cell viability by nickel. Moreover, nickel toxicity was attenuated in renal MDCK cells stably overexpressing ABCB1. In agreement with previous data that demonstrated extrusion of (glucosyl)ceramides by ABCB1 (Lee et al. in Toxicol Sci 121:343, 2011), PSC833 increased total cellular ceramides by >2-fold after nickel treatment. Further, glucosylceramide synthase (GCS) mRNA is upregulated by nickel at 3 h by ~1.5-fold but declined with prolonged exposures (6–24 h). Inhibition of GCS with C9DGJ or knockdown of GCS with siRNA significantly attenuated nickel toxicity. In conclusion, nickel induces a ROS-ceramide pathway to cause apoptotic cell death as well as activate adaptive survival responses, including upregulation of ABCB1, which improves cell survival by extruding proapoptotic (glucosyl)ceramides.

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Acknowledgments

We thank Dr. Michael M. Gottesman (Laboratory of Cell Biology, National Cancer Institute, Bethesda, MD) and Dr. Ulrich Hopfer (Department of Physiology & Biophysics, Case Western Reserve University, Cleveland, OH) for providing ABCB1-MDCK and rat proximal tubule cell lines, respectively, Sanofi-Aventis for providing PSC833, and B. Scharner and S. Probst for expert technical assistance. F.D. received a fellowship from the Algerian Ministry for Higher Education. This work was funded by a University of Witten/Herdecke internal research program grant (to W.-K.L), the Westermann-Westdorp Foundation (to W.-K.L) and the Deutsche Forschungsgemeinschaft (TH345 10-1 and 11-1 to F.T.).

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  1. Institute for Physiology, Pathophysiology and Toxicology, Centre for Biomedical Research and Training (ZBAF), Faculty of Health, University of Witten/Herdecke, Stockumer Str. 12, 58453, Witten, Germany

    Faouzi Dahdouh, Maximilian Raane, Frank Thévenod & Wing-Kee Lee

  2. Department of Biochemistry, Faculty of Sciences, University of Annaba, El-Hadjar, Annaba, Algeria

    Faouzi Dahdouh

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  1. Faouzi Dahdouh
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  2. Maximilian Raane
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Correspondence to Wing-Kee Lee.

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Dahdouh, F., Raane, M., Thévenod, F. et al. Nickel-induced cell death and survival pathways in cultured renal proximal tubule cells: roles of reactive oxygen species, ceramide and ABCB1. Arch Toxicol 88, 881–892 (2014). https://doi.org/10.1007/s00204-014-1194-x

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