CYCLOSPORINE-A INDUCES APOPTOSIS IN MURINE TUBULAR EPITHELIAL-CELLS -ROLE OF CASPASES

Background. The pathogenesis of cyclosporine A (CsA) nephrotoxicity ha s not been completely elucidated. Methods. The ability of CsA to induc e apoptosis in cultured murine tubular epithelial cells and its regula tion by the cell microenvironment and inhibitors of caspases were stud ied. Results. This study found that CsA induces apoptotic death in mur ine proximal tubular epithelial MCT cells in a dose- (0.1 to 15 mu g/m l) and time-dependent (24 to 72 hr) manner. Death caused by CsA is add itive to apoptosis induced by deprivation of the survival factors pres ent in serum. Primary cultures of murine tubular epithelial cells are also sensitive to CsA-induced apoptosis. Peptide inhibitors of caspase s such as zVAD-fmk (which inhibits caspases 8 and 9) and DEVD-CHO (whi ch inhibits caspase 3 and related caspases) prevented CsA-induced apop tosis in MCT cells, although zVAD-fmk was effective at lower concentra tions. Conclusion. These data suggest that tubular cell apoptosis medi ated by caspases may play a role in CsA nephrotoxicity and that the mi croenvironment modulates resistance to CsA lethality as low local leve ls of survival factors may potentiate nephrotoxicity. Caspases my be n ew therapeutic targets in the management of nephrotoxic injury.