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Biol Pharm Bull. 2017;40(7):975-983. doi: 10.1248/bpb.b16-00932.

Time-Dependent Alterations of Vancomycin-Induced Nephrotoxicity in Mice.

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Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology.
Department of Pharmacy, Tokyo Metropolitan Geriatric Hospital.
Department of Nephrology, Tokyo Metropolitan Geriatric Hospital.
Department of Pathology, Tokyo Metropolitan Geriatric Hospital.
Department of Pharmacy, Pusan National University.
Department of Practical Pharmacy, Faculty of Pharmaceutical Sciences, Toho University.


Vancomycin hydrochloride (VCM) is a glycopeptide antibiotic that is commonly used against methicillin-resistant, Gram-positive cocci despite the nephrotoxic side effects. VCM-induced nephrotoxicity has been reported in 5-28% of recipient patients. Therefore, renal failure induced by VCM has become an important clinical problem. However, the exceedingly complex mechanism of VCM-induced nephrotoxicity is not fully understood. Therefore, this study was designed to clarify time-dependent alterations of VCM-induced nephrotoxicity in mice as a step toward decreasing the risks of kidney injury associated with VCM therapy. VCM was injected intraperitoneally into mice at a dose of 400 mg/kg body weight at 24-h intervals for 3, 5, 7, and 14 d. At 24 h after the last injection, we examined histopathological alterations of the kidney as well as blood biochemistry. VCM administration resulted in a decrease of body weight and increase of kidney weight. Histological examination revealed renal damage such as dilated proximal tubules with occasional casts and interstitial fibrosis in VCM-treated mice. Furthermore, immunohistochemical staining with anti-CD10 and anti-single-stranded DNA antibodies highlighted damaged renal proximal tubules with marked dilatation as well as numerous apoptotic cells as early as day 4 of VCM-treatment. The severity of symptoms progressed until day 15. These results suggest that VCM-induced renal damage and incipient renal failure begin soon after the start of treatment and progressively worsen. This is the first report describing the time-dependence of VCM-induced nephrotoxicity in mice and depicting a model that clarifies the mechanisms of this tissue damage.


CD10; apoptosis; kidney; nephrotoxicity; vancomycin

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