The molecular mechanisms of the attenuation of cisplatin-induced acute renal failure by N-acetylcysteine in rats.

BACKGROUND: The clinical use of cisplatin (cis-diamminedichloro-platinum II, CDDP) is highly limited by its nephrotoxicity. Although N-acetylcysteine (NAC), a thiol-containing antioxidant, has been documented to be effective in attenuating renal injury induced by CDDP, the precise mechanisms involved in its renoprotection have not been completely clarified.
METHODS: We investigated the effects of NAC on oxidative stress and oxidation-associated signals, such as p38 mitogen-activated protein kinase (MAPK), NF-kappaB and TNF-alpha, in CDDP-induced acute renal failure (ARF) rats, in comparison to the effects of melatonin (MT), one of the physiological TNF-alpha inhibitors, and pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor.
RESULTS: NAC blocked oxidative stress, p38 MAPK activation, caspase-3 cleavage, tissue apoptosis, renal dysfunction and morphological damage induced by CDDP. CDDP-triggered NF-kappaB translocation into the nucleus and TNF-alpha mRNA increase in the kidney were also inhibited in NAC-treated rats. MT downregulated the TNF-alpha mRNA level, and PDTC inhibited the increases in both NF-kappaB translocation and TNF-alpha mRNA. Neither MT nor PDTC were capable of interfering with oxidative stress, p38 MAPK phosphorylation, caspase-3 cleavage, tissue apoptosis and kidney injury induced by CDDP.
CONCLUSIONS: These data suggest that oxidative stress and p38 MAPK-mediated apoptotic cell death pathways are involved, at least in part, in the pathogenesis of CDDP-induced ARF, and negative regulation of p38 MAPK activation through inhibition of oxidative stress appears to play a central role in the beneficial effects of NAC.