Cannabidiol interacts with the FXR/Nrf۲ pathway and changes the CB۱/CB۲ receptors ratio in gentamicin-induced kidney injury in rats

Objective(s): Gentamicin-induced nephrotoxicity was used as an experimental model of kidney disease. The present study was performed to assess the therapeutic role of cannabidiol (CBD) against gentamicin-induced renal damage. Materials and Methods: Forty two male Wistar rats were randomly allocated into ۶ groups (n=۷), including: (۱)  Control, (۲) Vehicle, (۳) Gentamicin-treated group (۱۰۰ mg/kg/day) for ۱۰ days (GM), (۴-۶) ۳ Gentamicin-CBD-treated groups (۲.۵, ۵, and ۱۰ mg/kg/day) for ۱۰ days (GM+CBD۲.۵, GM+CBD۵, GM+CBD۱۰). Serum levels of BUN and Cr, renal histology as well as real-time qRT-PCR were used to investigate the pattern of changes at different levels.Results: Gentamicin increased serum BUN and Cr (P<۰.۰۰۱), down-regulation of FXR (P<۰.۰۰۱), SOD (P<۰.۰۵) and up-regulation of CB۱ receptor mRNA (P<۰.۰۱). Compared to the control group, CBD at ۵ decreased (P<۰.۰۵) and at ۱۰ mg/kg/day increased the expression of FXR (P<۰.۰۵). Nrf۲ expression in CBD groups was increased (P<۰.۰۰۱ vs. GM). The expression of TNF-α compared to the control and GM groups, was significantly increased in CBD۲.۵ (P<۰.۰۱) and CBD۱۰ (P<۰.۰۵). Compared to the control, CBD at ۲.۵ (P<۰.۰۱), ۵ (P<۰.۰۰۱) and ۱۰ (P<۰.۰۰۱) mg/kg/day significantly increased the expression of CB۱R. Up-regulation of CB۱R in the GM+CBD۵, was significantly higher (P<۰.۰۵) than the GM group. Compared to the control group, the most significant increase in CB۲ receptor expression was observed at CBD۱۰ (P<۰.۰۵). Conclusion: CBD particularly at ۱۰ mg/kg/day might be of significant therapeutic benefit against such renal complications. Activating the FXR/Nrf۲ pathway and counteracting the deleterious effects of CB۱ receptors via CB۲ receptors scale-up could be part of the protective mechanisms of CBD.