Resveratrol mitigates diclofenac‐induced hepatorenal toxicity in rats via modulation of miR‐144/Nrf2/GSH axis
Eman M. Elbaz, Kawkab A. Ahmed, Maha Abdelmonem
Abstract
Despite the extensive therapeutic uses of diclofenac, it may cause several adverse effects, including hepatorenal injury. The antioxidant and anti-inflammatory properties of resveratrol, a polyphenolic compound, make the agent effective in ameliorating a variety of drug-induced injuries. This study investigated the potential beneficial effects of resveratrol on diclofenac-induced hepatorenal toxicity and explored the role of miR-144 and its relationship to oxidative stress and inflammation triggered by diclofenac. Rats were divided into four groups: control; diclofenac group received diclofenac (10 mg/kg/day, intraperitoneal [ip]) for 7 days; prevention group received resveratrol concomitantly with diclofenac for 7 days; and the treatment group received diclofenac for 7 days followed by resveratrol (20 mg/kg/day, per oral) for another 7 days. Diclofenac administration induced a significant increase in serum hepatorenal biomarkers and histopathological aberrations. In addition, diclofenac upregulated miR-144 while reducing nuclear factor erythroid 2-related factor 2 (Nrf2) protein levels and glutathione (GSH) content. Moreover, diclofenac induced tissue inflammation and apoptosis as evidenced by increased protein expression of nuclear factor kappa B (NF-κB), tumor necrosis factor α (TNF-α), and caspase-3. Intriguingly, resveratrol prevention or treatment significantly mitigated the toxic effects of diclofenac as manifested by normalization of the hepatorenal functions and amelioration of the histopathological changes. Resveratrol also triggered miR-144 downregulation with Nrf2 upregulation. Consequently, resveratrol showed hepatorenal antioxidant, anti-inflammatory, and antiapoptotic activities as manifested by improvement in the antioxidant markers along with a decline in NF-κB, TNF-α, and caspase-3 expressions. In conclusion, this study demonstrates a potential therapeutic role of resveratrol in mitigating diclofenac-induced hepatorenal insult, possibly via modulating miR-144/Nrf2/GSH axis.