Targeting superoxide dismutase to renal proximal tubule cells attenuates vancomycin-induced nephrotoxicity in rats.
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.
Nishino
Yoshihiro
Y
Department of Gastroenterology and Hepato-Biliary-Pancreatic Surgery, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno, Osaka 545-8585, Japan. nishino@msic.med.osaka-cu.ac.jp
Takemura
Shigekazu
S
Minamiyama
Yukiko
Y
Hirohashi
Kazuhiro
K
Ogino
Tetsuya
T
Inoue
Masayasu
M
Okada
Shigeru
S
Kinoshita
Hiroaki
H
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000633:toxicity; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D004247:DNA / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D008163:Luminescent Measurements; D008297:Male; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014640:Vancomycin / Q000494:pharmacology* / Q000633:toxicity
D000900:Anti-Bacterial Agents; D005609:Free Radicals; D013481:Superoxides; D014640:Vancomycin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D003404:Creatinine; D013482:Superoxide Dismutase; D003849:Deoxyguanosine; D010100:Oxygen