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

Cadmium (Cd2+) induces renal proximal tubular (PT) damage, including disruption of the E-cadherin/ss-catenin complex of adherens junctions (AJs) and apoptosis. Yet, chronic Cd2+ exposure causes malignant transformation of renal cells. Previously, we have demonstrated that Cd(2+-)mediated up-regulation of the multidrug transporter Abcb1 causes apoptosis resistance in PT cells. We hypothesized that Cd2+ activates adaptive signaling mechanisms mediated by ss-catenin to evade apoptosis and increase proliferation. Here we show that 50 mu M 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 Cd(2+-)induced decrease of E-cadherin at AJs and redistribution of ss-catenin from the E-cadherin/ss-catenin complex of AJs to cytosol and nuclei after 3 h. Immunoblotting confirms Cd(2+-)induced decrease of E-cadherin expression and translocation of ss-catenin to cytosol and nuclei of PT cells. RT-PCR shows Cd(2+-)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 ss-catenin in PT cells. We speculate that Cd2+ activates ss-catenin/T-cell factor signaling to trans-activate proliferation and apoptosis resistance genes and promote carcinogenesis of PT cells.