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-dichlorovinyl)-L-cysteine (DCVC), a metabolite of the environmental contaminant, trichloroethylene. Necrosis is well characterized in kidney cells, but pathways leading to apoptosis are less clear. Cysteine conjugates are useful toxicants because they induce either necrosis or apoptosis depending on chemical structure or antioxidant status. Herein, we show that in the renal epithelial cell line LLC-PK1, activation of caspase-3 (CPP32/Yama/apopain) is crucial for apoptosis, but not necrosis. Apoptosis was blocked by zVAD.fmk, and partially by a cathepsin inhibitor. Caspase-3 activity and cleavage of poly(ADP-ribose) polymerase (PARP) was detected only during apoptosis. S-(1,1,2,2-Tetrafluoroethyl)-L-cysteine (TFEC), a metabolite of tetrafluoroethylene, kills cells only by necrosis, and did not activate caspases under any conditions. Apoptosis and activation of caspase-3 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.
Zhan
Y
Y
Department of Pathology, College of Medicine, University of Vermont, Burlington 05405, USA.
van de Water
B
B
Wang
Y
Y
Stevens
J L
JL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000502:physiology*; D002945:Cisplatin / Q000494:pharmacology; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D018374:LLC-PK1 Cells; D009336:Necrosis; D011480:Protease Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D015398:Signal Transduction; D013552:Swine
D011480:Protease Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D053148:Caspase 3; D020169:Caspases; D002945:Cisplatin