Cannabidiol interacts with the FXR/Nrf2 pathway and changes the CB1/CB2 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 6 groups (n=7), including: (1)  Control, (2) Vehicle, (3) Gentamicin-treated group (100 mg/kg/day) for 10 days (GM), (4-6) 3 Gentamicin-CBD-treated groups (2.5, 5, and 10 mg/kg/day) for 10 days (GM+CBD2.5, GM+CBD5, GM+CBD10). 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 0.001), down-regulation of FXR (P 0.001), SOD (P 0.05) and up-regulation of CB1 receptor mRNA (P 0.01). Compared to the control group, CBD at 5 decreased (P 0.05) and at 10 mg/kg/day increased the expression of FXR (P 0.05). Nrf2 expression in CBD groups was increased (P 0.001 vs. GM). The expression of TNF-α compared to the control and GM groups, was significantly increased in CBD2.5 (P 0.01) and CBD10 (P 0.05). Compared to the control, CBD at 2.5 (P 0.01), 5 (P 0.001) and 10 (P 0.001) mg/kg/day significantly increased the expression of CB1R. Up-regulation of CB1R in the GM+CBD5, was significantly higher (P 0.05) than the GM group. Compared to the control group, the most significant increase in CB2 receptor expression was observed at CBD10 (P 0.05).  Conclusion: CBD particularly at 10 mg/kg/day might be of significant therapeutic benefit against such renal complications. Activating the FXR/Nrf2 pathway and counteracting the deleterious effects of CB1 receptors via CB2 receptors scale-up could be part of the protective mechanisms of CBD.