Inhibition of vancomycin-induced nephrotoxicity by targeting superoxide dismutase to renal proximal tubule cells in the rat.
Vancomycin, a glycopeptide antibiotic, has a broad spectrum against methicillin-resistant Staphylococcus aureus (MRSA). Because vancomycin induces renal dysfunction, the dose and the duration of its administration are limited. The mechanism of vancomycin-induced renal dysfunction is not known. We recently synthesized a hexamethylenediamine-conjugated cationic superoxide dismutase (AH-SOD) which rapidly accumulates in renal proximal tubule cells and inhibits oxidative injury of the kidney. The present work reports the protective effects of AH-SOD against vancomycin-induced renal dysfunction. Male Wistar rats (200-210 g) were intraperitoneally administered with either 200 or 400 mg/kg of vancomycin twice a day for 7 days. Either 5 mg/kg/day AH-SOD or saline was subcutaneously injected 5 min before every vancomycin injection. Biochemical analysis revealed that plasma levels of blood urea nitrogen and creatinine increased significantly in vancomycin-treated group by an AH-SOD-inhibitable mechanism. Histological examination revealed that vancomycin also elicited a marked destruction of glomeruli and necrosis of proximal tubule by an AH-SOD inhibitable mechanism. These results suggest that oxidative stress underlies the pathogenesis of vancomycin-induced nephrotoxicity and that targeting SOD and/or related antioxidants to renal proximal tubule cells might permit the administration of higher doses of vancomycin sufficient for eradication of MRSA without causing renal injury.
Nishino
Yoshihiro
Y
Department of Gastroenterology and Hepato-Biliary-Pancreatic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan. nishino@msic.med.osaka-cu.ac.jp
Takemura
Shigekazu
S
Minamiyama
Yukiko
Y
Hirohashi
Kazuhiro
K
Tanaka
Hiromu
H
Inoue
Masayasu
M
Okada
Shigeru
S
Kinoshita
Hiroaki
H
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000633:toxicity; D004247:DNA / Q000378:metabolism; D007668:Kidney / Q000187:drug effects*; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000187:drug effects*; D008297:Male; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase / Q000378:metabolism*; D013997:Time Factors; D014640:Vancomycin / Q000494:pharmacology* / Q000633:toxicity
D000900:Anti-Bacterial Agents; D017382:Reactive Oxygen Species; D014640:Vancomycin; D004247:DNA; D013482:Superoxide Dismutase