Cilastatin attenuates vancomycin- induced nephrotoxicity via P-glycoprotein
- Authors
- Im, Dai Sig; Shin, Hye Jin; Yang, Keum Jin; Jung, So Young; Song, Ho Yeon; Hwang, Hyeon Seok; Gil, Hyo-Wook
- Issue Date
- Aug-2017
- Publisher
- Elsevier BV
- Keywords
- Vancomycin; Cilastatin; Proximal tubule cells; Acute kidney injury
- Citation
- Toxicology Letters, v.277, pp 9 - 17
- Pages
- 9
- Journal Title
- Toxicology Letters
- Volume
- 277
- Start Page
- 9
- End Page
- 17
- URI
- https://scholarworks.bwise.kr/sch/handle/2021.sw.sch/7348
- DOI
- 10.1016/j.toxlet.2017.05.023
- ISSN
- 0378-4274
1879-3169
- Abstract
- Background: Oxidative stress is one of the main pathogenic mechanisms in vancomycin-induced nephrotoxicity (VIN). Some studies suggest proximal renal tubular cell necrosis by vancomycin accumulation as a mechanism of nephrotoxicity, and other studies demonstrate that cilastatin has protective effects against drug-induced nephrotoxicity. We investigated whether cilastatin regulates p-gp expression and whether cilastation prevents VIN. Materials and methods: We conducted an in vitro study using an immortalized proximal tubule epithelial cell line from a normal adult human kidney (HK-2) and an in vivo study using male C57BL/6J mice. Results: Vancomycin showed dose-dependent toxicity in the HK-2 cells, and cilastatin attenuated VIN. Vancomycin provoked the reactive oxygen species in a dose-dependent pattern on DCF-DA. Caspase 3/7 activity showed a dose-dependent increase at 6 h. We confirmed apoptosis by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay at 24 h (vancomcyin 2 mM). Cilastatin attenuated vancomycin-induced ROS production and apoptosis, and it also attenuated vancomycin-induced P-gp suppression. In vivo, vancomycin (400 mg/kg, 600 mg/kg IP, 7 days) induced acute kidney injury, as demonstrated by elevated blood urea nitrogen and creatinine. Histological examination of the sections indicated greater tubular damage in the vancomycin-treated kidney compared with the control. TUNEL-positive cells decreased significantly in the mouse kidney with cilastatin and vancomycin. Bax/Bcl-2 ratio were significantly increased in the vancomycin-treated kidney. Cilastatin 300 mg/kg treatment significantly decreased the vancomycin concentrations in the blood and kidney. Conclusion: Our study showed that mechanism of VIN might be involved, at least in part, in suppressing P-gp function, and cilastatin attenuated VIN.
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Collections - College of Medicine > Department of Internal Medicine > 1. Journal Articles
- College of Medicine > Department of Microbiology > 1. Journal Articles
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