Melatonin Attenuates Diclofenac Induced Renal Injury in Aged Rats via Modulating mRNA Expression of miR-34a, Nrf2/HO-1, ENaC and Suppressing NLRP3 Inflammasome Activation

Abstract Background High doses of diclofenac (DF) might induce acute kidney injury (AKI), particularly in elderly, a known vulnerable population. Melatonin was found to afford a beneficial effect in various kidney diseases. Aim To investigate the possible nephroprotective effect of melatonin in aged rats subjected to AKI by DF, and to highlight the implicated mechanisms. Design Experimental study Methods Thirty male Wister rats, aged 22-24 month, were equally divided into: control group, DF treated group (DF-group), and melatonin and DF treated group (Mel-DF-group). Results Melatonin significantly attenuated plasma creatinine, and urea along with decreased renal malondialdehyde and NADPH-oxidase-4 in Mel-DF-group versus DF-group. This was associated with a significant decrease in renal levels NLRP3 (NLR family-pyrin domain containing-3) inflammasome, Toll-like receptor-4, nuclear factor kappa (NF-κB), caspase-1, renal mRNA expression of microRNA-34a (miR-34a), and renal expression of tumor necrosis factor-alpha. The renal reduced glutathione (GSH), nuclear factor erythroid-2-related factor-2 (Nrf2), and hemoxygenase-1 (HO-1) were significantly increased in Mel-DF-group versus DF- group. Also, melatonin significantly reduced DF-induced hypernatremia together with significant decrease in renal epithelial sodium channels (ENaC) expression. Histopathological examination showed a significant decrease in vascular congestion, mononuclear cells infiltration, glomerular and tubular damage scores in Mel-DF-group-versus DF-group, besides a significant decrease in area % of collagen fibers deposition. Conclusions Melatonin provides a nephroprotective effect against DF-induced AKI in aged rats via attenuating renal oxidative stress, miR-34a, and NLRP3 inflammasome activation, which further increased renal Nrf2/HO-1 and GSH and inhibited fibrosis. Also, melatonin alleviated DF-induced hypernatremia via decreasing the ENaC renal expression.