Overexpression of manganese superoxide dismutase protects against ATP depletion-mediated cell death of proximal tubule cells.

We have previously shown that in vivo renal ischemia/reperfusion results in ATP depletion, oxidant production, and manganese superoxide dismutase (MnSOD) inactivation. Current studies were designed to compare the effect of ATP depletion (Antimycin A treatment) on cell death pathways using renal proximal tubular cells and identical cells that overexpress MnSOD. ATP depletion in wild-type cells induced an apoptotic cascade that involved caspase 9 activation; MnSOD overexpressing cells afforded protection against apoptosis. This protection did not appear to involve a cytochrome c-related mechanism, but may be related to altered levels of nitric oxide within the cell. Further studies suggested that nitric oxide was required to protect the renal cells from caspase-mediated cell death. Interestingly, treatment of renal cell extracts with reductants (DTT and ascorbate) enhanced caspase activation. Taken together, these results suggest that cysteine nitrosylation may be playing a role in caspase dysfunction in cells overexpressing MnSOD following ATP depletion.