The roles of caspase-3 and bcl-2 in chemically-induced apoptosis but not necrosis of renal epithelial cells

The kidney is a target for toxicants including cisplatin and S-(1,2-dichlor ovinyl)-L-cysteine (DCVC), a metabolite of the environmental contaminant, t richloroethylene. Necrosis is well characterized in kidney cells, but pathw ays leading to apoptosis are less clear. Cysteine conjugates are useful tox icants because they induce either necrosis or apoptosis depending on chemic al structure or antioxidant status. Herein, we show that in the renal epith elial cell line LLC-PK1, activation of caspase3 (CPP32/Yama/apopain) is cru cial for apoptosis, but not necrosis. Apoptosis was blocked by zVAD.fmk, an d partially by a cathepsin inhibitor. Caspase-3 activity and cleavage of po ly(ADP-ribose) polymerase (PARP) was detected only during apoptosis. S-(1,1 ,2,2-Tetrafluoroethyl)-1-cysteine (TFEC), a metabolite of tetrafluoroethyle ne, kills cells only by necrosis, and did not activate caspases under any c onditions. Apoptosis and activation of caspase3 by cisplatin, but not DCVC, was prevented by bcl-2. Thus, caspase-3 activation by bcl-2-dependent and -independent mechanisms is a terminal event in chemical-apoptosis of renal epithelial cells.