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1 Department of Physiology and Pathophysiology, University of Witten/Herdecke, Witten, Germany; Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom
2 Department of Physiology and Pathophysiology, University of Witten/Herdecke, Witten, Germany
* To whom correspondence should be addressed. E-mail: frank.thevenod{at}uni-wh.de.
The nephrotoxic metal cadmium at micromolar concentrations induces apoptosis of rat kidney proximal tubule (PT) cells within 3-6 hours of exposure. The underlying cell death pathways remain poorly defined. Using Hoechst 33342 / ethidium bromide nuclear staining and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) cell death assays, 10-50 µM cadmium induced apoptosis of immortalized rat kidney cells derived from the S1-segment of PT at 6 and 24 hours, but necrosis at 24 hours only. 10-50 µM cadmium also caused mitochondrial cytochrome c (cyt. c) and apoptosis inducing factor release at 24 hours, but not at 6 hours, as measured by immunofluorescence imaging and immunoblotting. Caspases-9 and -3 were activated only by 10 µM cadmium for 24 hours, and accordingly apoptosis was significantly reduced by the respective inhibitors (z-LEHD-fmk, z-DEVD-fmk; 10 µg/ml), at 24 hours, but not at 6 hours, without affecting necrosis. At 6 hours 10 µM cadmium increased the activity of calcium-activated proteases calpains, but not at 24 hours, and calpain inhibitors (ALLN, PD 150606; 10-30 µM) blocked apoptosis by 10 µM cadmium at 3-6 hours. But PD 150606 also attenuated caspase-3 activity and apoptosis at 24 hours suggesting calpain-dependent caspase activation. Thus cadmium-induced apoptosis of PT cells involves a complex and sensitive interplay of signalling cascades involving mitochondrial pro-apoptotic factors, calpains and caspases, whose activation is also determined by the cadmium concentration and the duration of cadmium exposure.
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