title: Role of the cytoskeleton in Cd2+-induced death of mouse mesangial cells.
abstract: Cadmium induces apoptotic cell death in mouse mesangial cells that is in part dependent on reactive oxygen species (ROS). Cadmium also activates multiple kinases in these cells, including the Ca2+/calmodulin-dependent protein kinase II (CaMK-II) and p38 kinase, and also leads to disruption of the filamentous actin cytoskeleton. We investigated the role of the cytoskeleton in Cd2+-induced cell death. Cell viability was decreased by Cd2+ and two types of apoptotic death, defined by flow cytometry, were increased. Disruption of actin filaments with cytochalasin D was partially protective, whereas stabilization of the cytoskeleton with jasplakinolide was without effect, indicating that cytoskeletal disruption contributes to, but is not necessary for, induction of apoptosis. Inhibition of CaMK-II and p38 kinase, mitochondrial stabilization with cyclosporine A, and the antioxidant N-acetyl cysteine all protected against apoptosis and prevented disruption of the cytoskeleton. Cytochalasin D decreased Cd2+-dependent ROS production, reduced the decline in mitochondrial membrane potential, and decreased phosphorylation of p38 kinase. We conclude that Cd2+-dependent actin disruption is a downstream event facilitating apoptotic death. Cadmium-dependent cell death involves actin-dependent mitochondrial changes, ROS production, and p38 activation.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Templeton
mesh_terms: D000818:Animals; D019256:Cadmium Chloride / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D015638:Cytochalasin D / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D047630:Depsipeptides / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000235:genetics; D050527:Mesangial Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D047630:Depsipeptides; D017382:Reactive Oxygen Species; C057531:jasplakinolide; D015638:Cytochalasin D; D019256:Cadmium Chloride