Background: The pathogenesis of cyclosporine A (CsA) nephrotoxicity has not been completely elucidated.
Methods: The ability of CsA to induce apoptosis in cultured murine tubular epithelial cells and its regulation by the cell microenvironment and inhibitors of caspases were studied.
Results: This study found that CsA induces apoptotic death in murine proximal tubular epithelial MCT cells in a dose- (0.1 to 15 micrograms/ml) and time-dependent (24 to 72 hr) manner. Death caused by CsA is additive to apoptosis induced by deprivation of the survival factors present in serum. Primary cultures of murine tubular epithelial cells are also sensitive to CsA-induced apoptosis. Peptide inhibitors of caspases such as zVAD-fmk (which inhibits caspases 8 and 9) and DEVD-CHO (which inhibits caspase 3 and related caspases) prevented CsA-induced apoptosis in MCT cells, although zVAD-fmk was effective at lower concentrations.
Conclusion: These data suggest that tubular cell apoptosis mediated by caspases may play a role in CsA nephrotoxicity and that the microenvironment modulates resistance to CsA lethality as low local levels of survival factors may potentiate nephrotoxicity. Caspases my be new therapeutic targets in the management of nephrotoxic injury.