title: 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.affiliation: Institute of Pharmacology, University of Messina, Torre Biologica-Policlinico Universitario, Via C. Valeria Gazzi, 98100 Messina, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Laura
authors.initials: L
authors.lastname: Dugo
authors.forename: Ivana
authors.initials: I
authors.lastname: Serraino
authors.forename: Rosanna
authors.initials: R
authors.lastname: Di Paola
authors.forename: Domenico
authors.initials: D
authors.lastname: Britti
authors.forename: Angela
authors.initials: A
authors.lastname: De Sarro
authors.forename: Simone
authors.initials: S
authors.lastname: Pierpaoli
authors.forename: Achille
authors.initials: A
authors.lastname: Caputi
authors.forename: Emanuela
authors.initials: E
authors.lastname: Masini
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D004789:Enzyme Activation; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005839:Gentamicins / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D015227:Lipid Peroxidation; D008297:Male; D008345:Manganese; D018716:Molecular Mimicry; D020556:Neutrophil Infiltration; D009942:Organometallic Compounds / Q000494:pharmacology*; D016877:Oxidants / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation; D051437:Renal Insufficiency / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D013482:Superoxide Dismutase / Q000737:chemistry; D013481:Superoxides / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis
chemical_list: D000900:Anti-Bacterial Agents; D016166:Free Radical Scavengers; D005839:Gentamicins; D009942:Organometallic Compounds; D016877:Oxidants; D013481:Superoxides; C121876:imisopasem manganese; C002744:3-nitrotyrosine; D014443:Tyrosine; D008345:Manganese; D013482:Superoxide Dismutase; D011065:Poly(ADP-ribose) Polymerases