In vivo and molecular docking investigation of the novel anti-inflammatory and mitochondrial mechanisms underlying the renoprotective effects of resmetirom and curcumin in gentamicin-induced renal toxicity in rats

Gentamicin (GS) is a potent aminoglycoside antibiotic whose clinical use is limited by nephrotoxicity associated with oxidative stress, mitochondrial dysfunction, and inflammation. This study aimed to explore the renoprotective mechanisms of resmetirom (RES) and curcumin (CUR) against GS-induced renal injury in rats, emphasizing anti-inflammatory and mitochondrial pathways and supporting findings through molecular docking. Twenty-four adult male Wistar rats were randomly allocated into four groups (n = 6): control, GS (100 mg/kg, i.p.), GS + CUR (200 mg/kg, oral), and GS + RES (3 mg/kg, oral). Treatments were administered for seven days. Serum renal biomarkers (urea, creatinine) and tissue oxidative stress markers (MDA, NO, GSH) were quantified using spectrophotometric methods. Specific kidney damage indicators for kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) were evaluated. Gene expressions of dynamin-related protein 1 (DRP1) and AKT Serine/Threonine Kinase 1 (AKT1) were analyzed by quantitative RT-PCR, while mammalian target of rapamycin (mTOR) and forkhead box protein O1 (FOXO1) protein expression were assessed immunohistochemically. Histopathological and ultrastructural evaluations were conducted using light and electron microscopy. Molecular docking was performed using AutoDock Vina to assess binding affinities of CUR and RES with AKT1, DRP1, FOXO1, and mTOR. GS administration significantly elevated serum urea and creatinine and increased renal MDA levels while decreasing NO and GSH. These alterations were markedly attenuated by CUR and RES, with RES showing superior improvement in renal function and oxidative balance. qPCR analysis revealed significant GS-induced upregulation of AKT1 and DRP1, which was normalized by both CUR and RES. Immunohistochemistry demonstrated downregulation of mTOR and FOXO1 following GS exposure, with substantial restoration after CUR and RES treatments. Histopathological and ultrastructural analyses confirmed the protective effects of both compounds, showing preserved glomerular and tubular integrity. Resmetirom and CUR showed significant renoprotective benefits against GS-induced nephrotoxicity by alleviating oxidative stress, modulating mitochondrial dynamics, and restoring cellular signaling pathways involving AKT1, DRP1, mTOR, and FOXO1. The molecular docking results corroborate their direct interactions with these targets, highlighting RES as a promising therapeutic agent for nephroprotection.