Role of the cytoskeleton in Cd2+-induced death of mouse mesangial cells.
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.
Liu
Ying
Y
Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
Templeton
Douglas M
DM
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
D047630:Depsipeptides; D017382:Reactive Oxygen Species; C057531:jasplakinolide; D015638:Cytochalasin D; D019256:Cadmium Chloride