Involvement of both tumor necrosis factor-alpha-induced necrosis and p53-mediated caspase-dependent apoptosis in nephrotoxicity of cisplatin.
We previously reported that necrosis occurs predominantly in porcine renal tubular LLC-PK1 cells, when the cells were exposed transiently to a high concentration of cisplatin. Moreover, we demonstrated that generation of reactive oxygen species and subsequent production of tumor necrosis factor-alpha (TNF-alpha) through phosphorylation of p38 MAPK are implicated in the pathogenesis of cisplatin-induced renal cell injury. However, some TUNEL-positive cells appeared in renal proximal tubules of rats after systemic injection of cisplatin, suggesting an involvement of apoptosis. In the present study, we found in LLC-PK1 cells that both apoptosis and necrosis were elicited when the cells were exposed to 200 microM cisplatin for 1 h followed by incubation for 24 h in the presence of 20 microM cisplatin. The cisplatin-induced necrosis was largely attenuated by the antioxidant N-acetylcysteine, while apoptosis was prevented by the specific inhibitors for caspases-2, -8, and -3 and a p53 inhibitor pifithrin-alpha but not by the p38 MAPK inhibitor SB203580. On the other hand, SB203580 attenuated the cisplatin-induced increase in TNF-alpha production. These findings suggest that p53-mediated activations of caspases-2, -8 and -3 play a key role in cisplatin-induced renal cell apoptosis, while oxidative stress-induced TNF-alpha synthesis via p38 MAPK phosphorylation contributed to the necrosis.
Yano
Takahisa
T
Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. tyano@pharm.med.kyushu-u.ac.jp
Itoh
Yoshinori
Y
Matsuo
Misaki
M
Kawashiri
Takehiro
T
Egashira
Nobuaki
N
Oishi
Ryozo
R
D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity*; D017209:Apoptosis / Q000502:physiology*; D052160:Benzothiazoles / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology / Q000633:toxicity*; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism; D004789:Enzyme Activation; D016166:Free Radical Scavengers / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009336:Necrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013552:Swine; D014050:Toluene / Q000031:analogs & derivatives / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; D052160:Benzothiazoles; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D016166:Free Radical Scavengers; D009842:Oligopeptides; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; D014050:Toluene; C121565:pifithrin; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; D002945:Cisplatin; D000111:Acetylcysteine