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Cadmium induces nuclear translocation of β-catenin and increases expression of c-myc and Abcb1a in kidney proximal tubule cells

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Abstract

Cadmium (Cd2+) induces renal proximal tubular (PT) damage, including disruption of the E-cadherin/β-catenin complex of adherens junctions (AJs) and apoptosis. Yet, chronic Cd2+ exposure causes malignant transformation of renal cells. Previously, we have demonstrated that Cd2+-mediated up-regulation of the multidrug transporter Abcb1 causes apoptosis resistance in PT cells. We hypothesized that Cd2+ activates adaptive signaling mechanisms mediated by β-catenin to evade apoptosis and increase proliferation. Here we show that 50 µM Cd2+, which induces cell death via apoptosis and necrosis, also causes a decrease of the trans-epithelial resistance of confluent WKPT-0293 Cl.2 cells, a rat renal PT cell model, within 45 min of Cd2+ exposure, as measured by electric cell-substrate impedance sensing. Immunofluorescence microscopy demonstrates Cd2+-induced decrease of E-cadherin at AJs and redistribution of β-catenin from the E-cadherin/β-catenin complex of AJs to cytosol and nuclei after 3 h. Immunoblotting confirms Cd2+-induced decrease of E-cadherin expression and translocation of β-catenin to cytosol and nuclei of PT cells. RT-PCR shows Cd2+-induced increase of expression of c-myc and of the isoform Abcb1a at 3 h. The data prove for the first time that Cd2+ induces nuclear translocation of β-catenin in PT cells. We speculate that Cd2+ activates β-catenin/T-cell factor signaling to trans-activate proliferation and apoptosis resistance genes and promote carcinogenesis of PT cells.

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Acknowledgments

We thank Dr. U. Hopfer (Case Western Reserve University, Cleveland, OH) for providing the cell line and Dr. Joachim Wegener (Institute for Biochemistry, University of Münster, Germany) for expert advice in setting up the ECIS technology and valuable discussions. This study was supported by the Deutsche Forschungsgemeinschaft (TH 345/8–1 and 8–2) and start-up funds from the University of Witten/Herdecke.

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  1. Department of Physiology & Pathophysiology, University of Witten/Herdecke, Stockumer Str. 12, D-58448, Witten, Germany

    Frank Thévenod, Natascha A. Wolff, Ulrich Bork, Wing-Kee Lee & Marouan Abouhamed

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  1. Frank Thévenod
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  2. Natascha A. Wolff
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  4. Wing-Kee Lee
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  5. Marouan Abouhamed
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Correspondence to Frank Thévenod.

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Thévenod, F., Wolff, N.A., Bork, U. et al. Cadmium induces nuclear translocation of β-catenin and increases expression of c-myc and Abcb1a in kidney proximal tubule cells. Biometals 20, 807–820 (2007). https://doi.org/10.1007/s10534-006-9044-9

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