NDT Advance Access originally published online on April 2, 2008
Nephrology Dialysis Transplantation 2008 23(7):2198-2205; doi:10.1093/ndt/gfn090
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The molecular mechanisms of the attenuation of cisplatin-induced acute renal failure by N-acetylcysteine in rats
First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Correspondence and offprint requests to: Hideo Yasuda, First Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan. E-mail: ysdh{at}hama-med.ac.jp, ysdh{at}mac.com
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Abstract |
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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-
B and TNF-
, in CDDP-induced acute renal failure (ARF) rats, in comparison to the effects of melatonin (MT), one of the physiological TNF- inhibitors, and pyrrolidine dithiocarbamate (PDTC), a NF-B 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-B translocation into the nucleus and TNF- mRNA increase in the kidney were also inhibited in NAC-treated rats. MT downregulated the TNF- mRNA level, and PDTC inhibited the increases in both NF-B translocation and TNF- 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.
Keywords: acute renal failure; cisplatin; N-acetlycysteine; p38 mitogen-activated protein kinase
Received for publication: 21. 6.07
Accepted in revised form: 30. 1.08
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