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

J Cell Physiol. 2008 Nov;217(2):307-18. doi: 10.1002/jcp.21499.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Mesangial Cells / enzymology
  • Mesangial Cells / pathology
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / 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
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • 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