CISPLATIN-INDUCED APOPTOSIS OF IMMORTALIZED MOUSE PROXIMAL TUBULE CELLS IS MEDIATED BY INTERLEUKIN-1-BETA CONVERTING-ENZYME (ICE) FAMILY OFPROTEASES BUT INHIBITED BY OVEREXPRESSION OF BCL-2

Cisplatin is known to induce serious renal damage including acute rena l failure, the major site of renal injury appears to be localized to t he third segment of the proximal tubule (S-3) Apoptosis occurs during a variety of acute injuries to tubule cell. The purpose of this study was to determine whether cisplatin induces apoptosis of immortalized m ouse S-3 cells, and to define the intracellular pathways leading to ce ll death. S-3 cells exposed to cisplatin exhibited biochemical, morpho logical, and flow cytometric changes characteristic of apoptosis assoc iated with slight necrosis. Cisplatin-induced apoptosis could be inhib ited by overexpression of crmA, a cowpox virus gene, of which the prod uct is known to suppress activities of the interleukin-lp converting e nzyme (ICE) family proteases. On the other hand, overexpression of bcl -2, an antiapoptotic oncogene, rendered S-3 cells partially resistant to cisplatin. These results indicate that cisplatin-induced proximal t ubule damage is associated with apoptosis, which is positively modulat ed by the ICE family of proteases and negatively by the product of bcl -2.