A role for superoxide in gentamicin-mediated nephropathy in rats

Salvatore Cuzzocrea, Emanuela Mazzon, Laura Dugo, Ivana Serraino, Rosanna Di Paola, Domenico Britti, Angela De Sarro, Simone Pierpaoli, Achille P. Caputi, Emanuela Masini, Daniela Salvemini

Research output: Contribution to journalArticlepeer-review

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 γ glutamyl transferase (γGT) 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.

Original languageEnglish
Pages (from-to)67-76
Number of pages10
JournalEuropean Journal of Pharmacology
Volume450
Issue number1
DOIs
Publication statusPublished - Aug 16 2002

Keywords

  • Compound M40403
  • Gentamicin
  • Superoxide anion
  • Superoxide dismutase mimetic

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

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