A role for superoxide in gentamicin-mediated nephropathy in rats.

Abstract

Gentamicin is an antibiotic effective against Gram-negative infection, whose clinical use is limited by its nephrotoxicity. Oxygen free radicals are considered to be important mediators of gentamicin-mediated nephrotoxicity, but the exact nature of the radical in question is not known with certainty. We have investigated the potential role of superoxide in gentamicin-induced renal toxicity by using M40403, a low molecular weight synthetic manganese containing superoxide dismutase mimetic, which selectively removes superoxide. Administration of gentamicin at 100 mg/kg, s.c. for 5 days to rats induced a marked renal failure, characterised by a significant decrease in creatinine clearance and increased plasma creatinine levels, fractional excretion of sodium, lithium, urine gamma glutamyl transferase (gamma GT) and daily urine volume. A significant increase in kidney myeloperoxidase activity and lipid peroxidation was also observed in gentamicin-treated rats. M40403 (10 mg/kg, i.p. for 5 days) attenuated all these parameters of damage. Immunohistochemical localisation demonstrated nitrotyrosine formation and poly(ADP-ribose) synthetase (PARS) activation in the proximal tubule of gentamicin-treated rats. Renal histology examination confirmed tubular necrosis. M40403 significantly prevented gentamicin-induced nitrotyrosine formation, poly(ADP-ribose) synthetase activation and tubular necrosis. These results confirm our hypothesis that superoxide anions play an important role in gentamicin-mediated nephropathy and support the possible clinical use of low molecular weight synthetic superoxide dismutase mimetics in those conditions that are associated with over production of superoxide.

• Authors: Salvatore Cuzzocrea, Emanuela Mazzon, Laura Dugo, Ivana Serraino, Rosanna Di Paola, Domenico Britti, Angela De Sarro, Simone Pierpaoli, Achille Caputi, Emanuela Masini, Daniela Salvemini
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 450 Issue 1 Pg. 67-76 (Aug 16 2002) ISSN: 0014-2999 [Print] Netherlands
• PMID: 12176111 (Publication Type: Journal Article)

Chemical References

• Anti-Bacterial Agents
• Free Radical Scavengers
• Gentamicins
• Organometallic Compounds
• Oxidants
• Superoxides
• imisopasem manganese
• 3-nitrotyrosine
• Tyrosine
• Manganese
• Superoxide Dismutase
• Poly(ADP-ribose) Polymerases

Topics

• Animals
• Anti-Bacterial Agents (toxicity)
• Enzyme Activation
• Free Radical Scavengers (pharmacology)
• Gentamicins (toxicity)
• Kidney (drug effects, metabolism, physiopathology)
• Lipid Peroxidation
• Male
• Manganese
• Molecular Mimicry
• Neutrophil Infiltration
• Organometallic Compounds (pharmacology)
• Oxidants (pharmacology)
• Poly(ADP-ribose) Polymerases (metabolism)
• Rats
• Rats, Sprague-Dawley
• Renal Circulation
• Renal Insufficiency (chemically induced, pathology, physiopathology, prevention & control)
• Superoxide Dismutase (chemistry)
• Superoxides (metabolism)
• Tyrosine (analogs & derivatives, biosynthesis)