A role for superoxide in gentamicin-mediated nephropathy in rats.
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.
Cuzzocrea
Salvatore
S
Institute of Pharmacology, University of Messina, Torre Biologica-Policlinico Universitario, Via C. Valeria Gazzi, 98100 Messina, Italy.
Mazzon
Emanuela
E
Dugo
Laura
L
Serraino
Ivana
I
Di Paola
Rosanna
R
Britti
Domenico
D
De Sarro
Angela
A
Pierpaoli
Simone
S
Caputi
Achille
A
Masini
Emanuela
E
Salvemini
Daniela
D
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
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