Ameliorative effects of hesperidin against iohexol-induced acute kidney injury.

Ameliorative effects of hesperidin against iohexol-induced acute kidney injury: Modulating the levels of NF-κB/TNF-α/IL-1β, JAK2/STAT3, and Wnt3a/Dvl-2 signaling pathways.

Fatih Mehmet Mutlu, Hasan Huseyin Mutlu, Özge Kandemir, Nurhan Akaras, Hasan Şimşek, Cuneyt Caglayan, F M Kandemir

Tissue Cell

Sep 27, 2025

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Abstract

Iohexol is a non-ionic contrast agent widely used in diagnostic imaging and angiographic procedures; however, its administration carries the risk of contrast-induced nephropathy. This study was conducted to investigate the ameliorative effects of hesperidin use against iohexol-induced acute kidney injury (AKI) in rats. Male wistar albino rats were randomly assigned into five groups: i) control, ii) hesperidin (100 mg/kg/day orally), iii) iohexol (3 g/kg, i.p), iv) iohexol (3 g/kg) and hesperidin (100 mg/kg) and v) iohexol (3 g/kg) and hesperidin (200 mg/kg). The induction of AKI was performed by dehydration and the administration of contrast media (iohexol) and inhibitors of prostaglandin (indomethacin) and nitric oxide synthesis (L-NAME: N-nitro L-arginine methyl ester). Hesperidin was administered for two weeks before the induction of AKI. Results showed that iohexol induced significant histopathological kidney damage and increased serum urea and creatinine levels. Molecular analyses revealed that iohexol suppressed AQP1 and AQP2 expression, while upregulating KIM-1 and inflammatory markers such as MAPK14, JAK2/STAT3, TRAF6/ACT1/IL-17A, and NFκB/TNF-α/IL-1βat the gene expression level. Furthermore, iohexol decreased the measured activity of antioxidant enzymes (SOD, CAT and GPx) and the GSH content, and significantly increased MDA levels. Additionally, iohexol promoted apoptosis mediated by Caspase-3, Bax, and Bcl-2, and suppressed gene expression of Wnt3a/Dvl-2 and Cyclin D1, which are involved in cell cycle regulation and development. This is the first study to link hesperidin with modulation of Wnt3a/Dvl-2 signaling in iohexol-induced AKI. Hesperidin treatment significantly modulated these parameters, demonstrating a nephroprotective effect. Thus, it was supported that hesperidin could be a potential nephroprotective agent.