Initiation of caspase-independent death in mouse mesangial cells by Cd2+: involvement of p38 kinase and CaMK-II.

Abstract

Cadmium (Cd) is a toxic metal with multiple effects on cell signaling and cell death. We studied the effects of Cd(2+) on quiescent mouse mesangial cells in serum-free conditions. Cadmium induces cell death over 6 h through annexin V+ states without or with causing uptake of propidium iodide, termed apoptotic and apoptosis-like death, respectively. Little or no necrosis is observed, and cell death is caspase-independent and associated with nuclear translocation of the apoptosis-inducing factor, AIF. We previously showed that Cd(2+) increased phosphorylation of Erk and CaMK-II, and CaMK-II activation increased cell death in an Erk-independent manner. Here we demonstrate that Cd(2+) increases Jnk and p38 kinase phosphorylation, and inhibition of p38-but not of Jnk-increases cell viability by suppressing apoptosis in preference to apoptosis-like death. Neither p38 kinase nor CaMK-II inhibition protects against a decrease in mitochondrial membrane potential, psi, indicating that kinase-mediated death is either independent of, or involves events downstream of a mitochondrial pathway. However, both the antioxidant N-acetyl cysteine (NAC) and the mitochondrial membrane-stabilizing agent cyclosporine A (CsA) partially preserve psi, suppress activation of p38 kinase, and partially protect the cells from Cd(2+)-induced death. Whereas the effect of CsA is on apoptosis, NAC acts on apoptosis-like death. Inhibition of glutathione synthesis exacerbates a Cd(2+)-dependent increase in cellular peroxides and favors apoptosis-like death over apoptosis. The caspase-independence of these modes of cell death is not due to an absence of this machinery in the mesangial cells: when they are exposed to Cd(2+) for longer periods in the presence of serum, procaspase-3 and PARP are cleaved and caspase inhibition is protective. We conclude that Cd(2+) can kill mesangial cells by multiple pathways, including caspase-dependent and -independent apoptotic and apoptosis-like death. Necrosis is not prominent. Activation of p38 kinase and of CaMK-II by Cd(2+) are associated with caspase-independent apoptosis that is not dependent on mitochondrial destabilization.

• Authors: Ying Liu, Douglas M Templeton
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 217 Issue 2 Pg. 307-18 (Nov 2008) ISSN: 1097-4652 [Electronic] United States
• PMID: 18506790 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2008 Wiley-Liss, Inc

Chemical References

• Antioxidants
• Apoptosis Inducing Factor
• Culture Media, Serum-Free
• Pdcd8 protein, mouse
• Protein Kinase Inhibitors
• Reactive Oxygen Species
• Adenosine Triphosphate
• Parp1 protein, mouse
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Caspases
• Glutathione
• Cadmium Chloride

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Antioxidants (pharmacology)
• Apoptosis (drug effects)
• Apoptosis Inducing Factor (metabolism)
• Cadmium Chloride (toxicity)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (metabolism)
• Caspases (metabolism)
• Cell Survival (drug effects)
• Cells, Cultured
• Culture Media, Serum-Free
• Dose-Response Relationship, Drug
• Glutathione (metabolism)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Membrane Potential, Mitochondrial (drug effects)
• Mesangial Cells (drug effects, enzymology, pathology)
• Mice
• Mitochondria (drug effects, metabolism)
• Phosphorylation
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Time Factors
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)