کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5562163 | 1562596 | 2017 | 9 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Cilastatin attenuates vancomycin-induced nephrotoxicity via P-glycoprotein Cilastatin attenuates vancomycin-induced nephrotoxicity via P-glycoprotein](/preview/png/5562163.png)
- Vancomcyin induced nephrotoxicity is involved with suppression of P-gp.
- Cilastatin attenuated vancomcyin induced nephrotoxicity by decreasing apoptosis.
- The effect of cilastatin on vancomcyin induced nephrotoxicity could be related, at least in part, reduction of vancomycin concentration in kidney via P-gp.
- P-gp in kidney translocated to cellular membrane by cilastatin.
- Cilastatin could be a therapeutic approach to prevent VIN.
BackgroundOxidative 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 methodsWe 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.ResultsVancomycin 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 6Â h. We confirmed apoptosis by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay at 24Â h (vancomcyin 2Â mM). Cilastatin attenuated vancomycin-induced ROS production and apoptosis, and it also attenuated vancomycin-induced P-gp suppression. In vivo, vancomycin (400Â mg/kg, 600Â mg/kg IP, 7Â 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 300Â mg/kg treatment significantly decreased the vancomycin concentrations in the blood and kidney.ConclusionOur study showed that mechanism of VIN might be involved, at least in part, in suppressing P-gp function, and cilastatin attenuated VIN.
Journal: Toxicology Letters - Volume 277, 5 August 2017, Pages 9-17