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

Abstract

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.

• Authors: Jinghui Luo, Takayuki Tsuji, Hideo Yasuda, Yuan Sun, Yoshihide Fujigaki, Akira Hishida
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 23 Issue 7 Pg. 2198-205 (Jul 2008) ISSN: 1460-2385 [Electronic] England
• PMID: 18385389 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Antioxidants
• Cross-Linking Reagents
• Free Radical Scavengers
• NF-kappa B
• Thiocarbamates
• Tumor Necrosis Factor-alpha
• prolinedithiocarbamate
• Proline
• p38 Mitogen-Activated Protein Kinases
• Melatonin
• Cisplatin
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology, therapeutic use)
• Acute Kidney Injury (chemically induced, drug therapy, metabolism)
• Animals
• Antineoplastic Agents (toxicity)
• Antioxidants (pharmacology)
• Cisplatin (toxicity)
• Cross-Linking Reagents
• Disease Models, Animal
• Free Radical Scavengers (pharmacology, therapeutic use)
• Male
• Melatonin (pharmacology)
• NF-kappa B (metabolism)
• Oxidative Stress (drug effects)
• Proline (analogs & derivatives, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Thiocarbamates (pharmacology)
• Tumor Necrosis Factor-alpha (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)