Takigawa Masaki, Masutomi Hirofumi, Shimazaki Yoshitomo, Arai Tomio, Lee Jaewon, Ishii Toshihiro, Mori Yoshiko, Ishigami Akihito
Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.
Department of Pharmacy, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.
J Toxicol Pathol. 2019 Jan;32(1):57-66. doi: 10.1293/tox.2018-0036. Epub 2018 Dec 10.
Vancomycin hydrochloride (VCM) is a glycopeptide antibiotic that is commonly used to eradicate methicillin-resistant gram-positive cocci, despite its nephrotoxic side effects. Elderly people are particularly susceptible to developing VCM-induced nephrotoxicity. However, the precise mechanism by which VCM induces nephrotoxicity in elderly people is not completely understood. Therefore, we investigated VCM-induced nephrotoxicity in mice of different ages. VCM was injected intraperitoneally into mice at 1, 3, 6, 12, and 24 months of age at a dosage of 400 mg/kg body weight for 3 and 14 days. Twenty-four hours after the last injection, we examined plasma creatinine levels and histopathological alterations in the kidneys. VCM administration increased plasma creatinine levels, and these values gradually increased to higher levels with aging. The histological examination revealed renal tubular degeneration, such as brush-border atrophy, apoptosis/necrosis of the tubular epithelium, and epithelial desquamation, that gradually became more severe with aging. Furthermore, immunohistochemical staining with anti-CD10 and anti-single-stranded DNA antibodies revealed damaged renal proximal tubules with marked dilatation, as well as numerous apoptotic cells, and these features increased in severity in 12- and 24-month-old mice receiving VCM. Based on these results, aged mice were highly susceptible to kidney damage induced by VCM administration. In addition, proximal tubular epithelial cells likely underwent apoptosis after the administration of VCM. This report is the first to document VCM-induced nephrotoxicity in mice of different ages. Thus, this mouse model could be useful for understanding the mechanisms of VCM-induced nephrotoxicity in the elderly.
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，但常用于根除耐甲氧西林革兰氏阳性球菌。老年人尤其容易发生VCM诱导的肾毒性。然而，VCM在老年人中诱导肾毒性的确切机制尚未完全明确。因此，我们研究了不同年龄小鼠中VCM诱导的肾毒性。将VCM以400mg/kg体重的剂量腹腔注射到1、3、6、12和24月龄的小鼠体内，持续3天和14天。最后一次注射后24小时，我们检测了血浆肌酐水平和肾脏的组织病理学改变。给予VCM后血浆肌酐水平升高，且这些值随年龄增长逐渐升高至更高水平。组织学检查显示肾小管变性，如刷状缘萎缩、肾小管上皮细胞凋亡/坏死和上皮脱落，且随年龄增长逐渐加重。此外，用抗CD10和抗单链DNA抗体进行免疫组化染色显示，接受VCM的12月龄和24月龄小鼠的肾近端小管受损，伴有明显扩张以及大量凋亡细胞，且这些特征的严重程度增加。基于这些结果，老年小鼠对VCM给药诱导的肾损伤高度敏感。此外，给予VCM后近端肾小管上皮细胞可能发生凋亡。本报告首次记录了不同年龄小鼠中VCM诱导的肾毒性。因此，该小鼠模型可能有助于理解老年人中VCM诱导肾毒性的机制。
