Takigawa Masaki, Masutomi Hirofumi, Kishimoto Yuki, Shimazaki Yoshitomo, Hamano Yoshitomo, Kondo Yoshitaka, Arai Tomio, Lee Jaewon, Ishii Toshihiro, Mori Yoshiko, Ishigami Akihito
Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology.
Department of Pharmacy, Tokyo Metropolitan Geriatric Hospital.
Biol Pharm Bull. 2017;40(7):975-983. doi: 10.1248/bpb.b16-00932.
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.
盐酸万古霉素（VCM）是一种糖肽类抗生素，尽管有肾毒性副作用，但常用于治疗耐甲氧西林的革兰氏阳性球菌。据报道，接受治疗的患者中有5%-28%出现了VCM诱导的肾毒性。因此，VCM引起的肾衰竭已成为一个重要的临床问题。然而，VCM诱导肾毒性的极其复杂的机制尚未完全明确。因此，本研究旨在阐明VCM诱导的小鼠肾毒性的时间依赖性变化，作为降低与VCM治疗相关的肾损伤风险的第一步。以400mg/kg体重的剂量，每隔24小时给小鼠腹腔注射VCM，持续3、5、7和14天。在最后一次注射后24小时，我们检查了肾脏的组织病理学变化以及血液生化指标。VCM给药导致体重下降和肾脏重量增加。组织学检查显示，VCM处理的小鼠出现肾损伤，如近端肾小管扩张，偶见管型和间质纤维化。此外，用抗CD10和抗单链DNA抗体进行免疫组化染色显示，早在VCM治疗第4天，受损的肾近端小管就出现明显扩张，并有大量凋亡细胞。症状的严重程度一直持续到第15天。这些结果表明，VCM诱导的肾损伤和早期肾衰竭在治疗开始后不久就开始，并逐渐恶化。这是第一份描述VCM诱导的小鼠肾毒性的时间依赖性并描绘阐明这种组织损伤机制的模型的报告。
