Cilastatin attenuates vancomycin- induced nephrotoxicity via P-glycoprotein
- 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.
- All Author(s)
- D. S. Im
; H. J. Shin
; K. J. Yang
; S. Y. Jung
; H. Y. Song
; H. S. Hwang
; H. W. Gil
- Issued Date
- 2017
- Type
- Article
- Keyword
- Acute kidney injury; Cilastatin; Proximal tubule cells; Vancomycin
- Publisher
- Elsevier
- ISSN
- 0378-4274
; 1879-3169
- Citation Title
- Toxicology Letters
- Citation Volume
- 277
- Citation Start Page
- 9
- Citation End Page
- 17
- Language(ISO)
- eng
- DOI
- 10.1016/j.toxlet.2017.05.023
- URI
- http://schca-ir.schmc.ac.kr/handle/2022.oak/1920
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