Nephroprotective effects of hesperidin on ifosfamide-induced acute nephrotoxicity in rats: Role of NF-κB/TNF-α/ IL-1β, p53/caspase-3/Bax/Bcl-2, and ATF6/IRE1/PERK/GRP78 signaling pathways

This study explored the protective effects of hesperidin (HES) against ifosfamide (IFA)-induced nephrotoxicity in rats using biochemical, histopathological, and immunohistochemical techniques. The rats were administered IFA at a dose of 500 mg/kg body weight, followed by oral HES treatment at doses of 200 and 300 mg/kg body weight. The results demonstrated that HES significantly reduced IFA-induced increases in urea and creatinine levels, indicating improved kidney function. HES was shown to mitigate IFA-induced lipid peroxidation, likely due to its antioxidant properties, and to enhance the activities of key antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx), as well as elevate glutathione (GSH) levels. Biochemical and immunohistochemical analyses further revealed that HES exhibited anti-inflammatory, antiapoptotic and anti-endoplasmic reticulum stress effects, suppressing the elevated levels of nuclear factor kappa-B (NF-κB), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), Caspase-3, 6, 9, Bax, Apaf1, p53, serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1α (IRE1α), glucose-regulated protein 78 (GRP78), activating transcription factor 6 (ATF-6), and protein kinase R-like ER kinase (PERK), CHOP and alleviating level of Bcl-2 in IFA-exposed kidney tissue. Additionally, the immunohistochemical staining results for TIM-1 in rat kidney tissues showed minimal expression in the control and HES groups. However, the IFA-treated group exhibited a significant increase in TIM-1 expression. Co-administration of IFA with HES at 200 or 300 mg/kg resulted in a significant reduction in TIM-1 expression. In conclusion, these results demonstrate that HES efficiently alleviated kidney toxicity induced by IFA.