Abstract
Drug-related factors represent a primary cause of acute kidney injury. Gentamicin (GM), while being one of the most effective and commonly used clinical agents against Gram-negative bacteria, frequently induces nephrotoxicity and triggers acute kidney injury during treatment. Melatonin, a natural antioxidant produced by the pineal gland, has been shown in recent studies to mitigate drug-induced nephrotoxicity. This study aimed to delineate the dose-dependent effects and underlying mechanisms of GM-induced acute kidney injury, along with the protective role of melatonin. Results demonstrated that GM administration elicited dose-dependent nephrotoxicity in rats, significantly elevating urinary biomarkers of tubular injury (KIM-1 and NGAL) and serum markers of renal dysfunction (BUN and SCr) at doses ≥50 mg/kg. Histopathological analysis revealed progressive renal damage including brush border loss, epithelial necrosis, basement membrane disruption, and interstitial inflammation. GM further exacerbated renal oxidative stress, depleting SOD and GSH while elevating MDA levels. Mechanistically, GM dose-dependently upregulated Keap1 and downregulated NRF2 expressions, consequently suppressing downstream antioxidants (GPX1, NQO1, HO-1). However, melatonin treatment significantly ameliorated high-dose GM-induced acute kidney injury by normalizing biochemical markers of renal impairment, attenuating histopathological damage, restoring antioxidant capacity, and reactivating the KEAP1/NRF2 pathway through suppression of Keap1 while enhancing NRF2 and its target proteins (GPX1/NQO1/HO-1) to nearly double of GM-H group levels, confirming its renoprotective role against GM-induced oxidative injury.