Hesperidin attenuates gentamicin-induced nephrotoxicity: Association with SIRT3 and PAX2 expression, oxidative stress, and tubular injury.

Gentamicin (GEN) is an effective aminoglycoside antibiotic whose clinical use is limited by nephrotoxicity driven largely by oxidative stress, inflammation, mitochondrial dysfunction, and tubular injury. Although hesperidin (HES) has antioxidant and anti-inflammatory properties, its effects on SIRT3 and PAX2 expression and early renal injury biomarkers remain unclear. Twenty-eight male Wistar albino rats were randomly assigned to four groups (Control, GEN, HES, and GEN + HES; n = 7). Gentamicin (100 mg/kg/day, intraperitoneally) and hesperidin (100 mg/kg/day, orally) were administered for seven days. Renal function was assessed by serum creatinine and blood urea nitrogen (BUN). Oxidative stress markers, inflammatory cytokines, tubular injury biomarkers (KIM-1 and NGAL), and renal SIRT3 and PAX2 mRNA expression were evaluated. Histopathological changes and immunoreactivity for Caspase-3 and 8-hydroxy-2'-deoxyguanosine were also examined. Gentamicin significantly impaired renal function, increased relative kidney weight, oxidative stress, inflammatory cytokines, KIM-1 and NGAL levels, decreased SIRT3 mRNA expression, increased PAX2 mRNA expression, and aggravated histopathological damage and Caspase-3 and 8-OHdG immunoreactivity (all p < 0.05). Hesperidin significantly improved these alterations by restoring antioxidant defenses, reducing inflammation and tubular injury, increasing SIRT3 mRNA expression, attenuating PAX2 upregulation, and improving histopathological and immunohistochemical findings, although most parameters remained different from controls. Hesperidin attenuated gentamicin-induced renal injury across functional, oxidative, inflammatory, tubular, and histopathological endpoints. These protective effects were accompanied by partial restoration of SIRT3 mRNA expression and attenuation of injury-associated PAX2 upregulation, supporting an association of these molecular responses with the protective phenotype without establishing causality. These findings support the renoprotective potential of hesperidin under the experimental conditions evaluated.