Targeting superoxide dismutase to renal proximal tubule cells attenuates vancomycin-induced nephrotoxicity in rats

Free Radic Res. 2003 Apr;37(4):373-9. doi: 10.1080/1071576031000061002.

Abstract

Vancomycin hydrochloride (VCM), a glycopeptide antibiotic, has a broad spectrum against methicillin-resistant Staphylococcus aureus (MRSA). As it is known to induce renal dysfunction, the dose and the duration of its administration are limited. Moreover, the mechanism of VCM-induced renal dysfunction remains to be unclear. To evaluate the involvement of free radical on VCM-induced renal dysfunction, we carried out analysis with a hexamethylenediamine-conjugated superoxide dismutase (AH-SOD) which rapidly accumulates in renal proximal tubule cells and inhibits oxidative injury of the kidney. Male Wistar rats (weighing 200-210 g) were intraperitonealy administered with 200 mg/kg of VCM twice a day for 7 days. AH-SOD 5 mg/kg/day was subcutaneously injected 5 min before every VCM injection. VCM induced renal injury dose-dependently. Biochemical analyses revealed that plasma levels of blood urea nitrogen and creatinine significantly increased in the VCM-treated group by an AH-SOD-inhibitable mechanism. VCM simultaneously elicited an increase of 8-OHdG levels and chemiluminescence intensity of free radical generation in the kidney. Histological examination revealed that VCM also elicited a marked destruction of glomeruli and necrosis of proximal tubules. AH-SOD inhibited these phenomena in the kidney. These results suggested that oxidative stress might underlie the pathogenesis of VCM-induced nephrotoxicity and targeting SOD and/or related antioxidants to renal proximal tubules might permit the administration of higher doses of VCM sufficient for eradication of MRSA without causing renal injury.

MeSH terms

  • 8-Hydroxy-2'-Deoxyguanosine
  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / toxicity
  • Blood Urea Nitrogen
  • Creatinine / blood
  • DNA / metabolism
  • Deoxyguanosine / analogs & derivatives*
  • Deoxyguanosine / metabolism
  • Dose-Response Relationship, Drug
  • Free Radicals
  • Immunohistochemistry
  • Kidney / drug effects*
  • Kidney / metabolism
  • Kidney Glomerulus / drug effects
  • Kidney Tubules, Proximal / cytology*
  • Luminescent Measurements
  • Male
  • Oxygen / metabolism
  • Rats
  • Rats, Wistar
  • Superoxide Dismutase / metabolism*
  • Superoxides / metabolism
  • Time Factors
  • Vancomycin / pharmacology*
  • Vancomycin / toxicity

Substances

  • Anti-Bacterial Agents
  • Free Radicals
  • Superoxides
  • Vancomycin
  • 8-Hydroxy-2'-Deoxyguanosine
  • DNA
  • Creatinine
  • Superoxide Dismutase
  • Deoxyguanosine
  • Oxygen