Cadmium (Cd 2+ ) induces nuclear translocation of β‐catenin and increases expression of c‐myc and Abcb1a in kidney proximal tubule (PT) cells

Abstract

Cd2+ induces renal 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 ~60% cell death of immmortalized rat renal PT cells, as measured by MTT assay, also decreases the trans-epithelial resistance of a confluent monolayer, within 45 minutes 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 hours. 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 hours. We speculate that Cd2+ activates β-catenin/T-cell factor signaling to transactivate proliferation and apoptosis resistance genes and promote carcinogenesis of PT cells. Funded by DFG TH 345/8-1