18-Glycyrrhetinic acid protects against methotrexate-induced kidney injury by up-regulating the Nrf2/ARE/HO-1 pathway and endogenous antioxidants

Objectives: 18-glycyrrhetinic acid (18-GA) has multiple beneficial and therapeutic effects. However, its protective roles on methotrexate (MTX)-induced renal injury are not well defined. In the present study, we investigated the possible protective effects of 18-GA against MTX-induced nephrotoxicity in rats.Materials: 18-GA (50 and 100mg/kg) was administered for 7 days either before or after MTX. The rats were decapitated and kidney and serum samples were collected.Results: MTX-induced renal injury in rats was evidenced by the significant (p<0.001) increase in circulating kidney function markers and tumor necrosis factor alpha (TNF-), as well as the histopathological alterations. MTX-induced rats exhibited significantly increased lipid peroxidation (p<0.05) and nitric oxide (p<0.001) levels, with concomitant marked (p<0.001) decline in the antioxidant defenses. 18-GA, administered either before or after MTX, produced a significant amelioration of circulating kidney function markers, TNF-, kidney lipid peroxidation, nitric oxide, and antioxidant defenses. In addition, 18-GA supplementation significantly up-regulated the mRNA abundance of both nuclear factor-erythroid 2-related factor 2 (Nrf2) and hemoxygenase 1 (HO-1) in the kidney of MTX-induced rats.Conclusions: These results indicate that 18-GA has a protective effect on MTX-induced nephrotoxicity with possible mechanisms of attenuating oxidative stress and inflammation through up-regulating the Nrf2/ARE signaling. These findings make 18-GA candidate as a potent agent in preventing MTX-induced kidney injury.