18β-glycyrrhetinic acid ameliorates ifosfamide-induced nephrotoxicity by suppressing Wnt3a/IL-17A-driven inflammatory signaling, ER stress, and apoptosis while preserving ZO-1 integrity.

Abstract

Ifosfamide (IFO) is an effective chemotherapeutic agent, but its clinical use is limited by dose-dependent nephrotoxicity. This study investigated the protective effects of 18β-glycyrrhetinic acid (18β-GA) against IFO-induced acute renal injury and explored the underlying molecular mechanisms. Twenty-eight male Wistar albino rats were divided into four groups: Control, 18β-GA, IFO, and IFO+18β-GA. 18β-GA was administered orally at 100 mg/kg/day for two consecutive days, while nephrotoxicity was induced by a single intraperitoneal injection of IFO at 500 mg/kg. Renal function markers, oxidative stress parameters, inflammatory and apoptotic gene expression, Wnt3a/IL-17 A/ACT1/TRAF6 and Notch/HES1 signaling pathways, histopathological alterations, ZO-1 integrity, and CHOP expression were evaluated. IFO markedly impaired renal function, increased serum urea and creatinine levels, enhanced lipid peroxidation, depleted antioxidant defenses, and induced severe histopathological damage. IFO also upregulated NF-κB, TNF-α, Bax, Caspase-3, Wnt3a, IL-17 A, ACT1, TRAF6, Notch, and HES1 expression, while reducing Bcl-2 expression. In addition, IFO increased CHOP immunoreactivity and disrupted ZO-1 expression in tubular epithelial cells. Co-treatment with 18β-GA significantly improved renal function, restored antioxidant capacity, and was associated with the suppression of inflammatory and apoptotic signaling, downregulation of Wnt3a/IL-17 A/ACT1/TRAF6 and Notch/HES1 activation, reduced CHOP expression, preserved ZO-1 immunoreactivity, and ameliorated renal histological injury. These findings suggest that 18β-GA exerts potential multi-target renoprotective effects against IFO-induced nephrotoxicity by modulating oxidative stress, inflammation, ER stress, apoptosis, developmental signaling, and epithelial junctional integrity.