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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