Ergothioneine mitigates cisplatin-evoked nephrotoxicity via targeting Nrf2, NF-κB, and apoptotic signaling and inhibiting γ-glutamyl transpeptidase

• Published in: Life sciences (1973) Vol. 278; p. 119572
• Main Authors: Salama, Samir A., Abd-Allah, Gamil M., Mohamadin, Ahmed M., Elshafey, Mostafa M., Gad, Hesham S.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.08.2021; Elsevier BV
• Subjects: Antioxidants; Apoptosis; Biotransformation; Blood; Chemical compounds; Cisplatin; Creatinine; Cytokines; DNA fragmentation; Dosage; Downstream effects; Ergothioneine; GGT; IL-1β; Inflammation; Metabolites; Molecular modelling; Nephrotoxicity; NF-κB protein; Nuclear factor kappa B; Oxidative stress; p53 Protein; Pharmacology; Renal function; Signaling; Spectrophotometry; Transcription factors; Tumor necrosis factor-α; Urea; Western blotting; γ-Glutamyltransferase; Ergothioneine; GGT; Nephrotoxicity; Cisplatin; DNA fragmentation; Nuclear factor kappa B
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2021.119572

Cisplatin is a potent chemotherapeutic agent whose therapeutic application is hindered by the associated nephrotoxicity. Cisplatin-evoked nephrotoxicity has been largely attributed to the induction of oxidative stress and inflammatory responses. The current study aimed at investigating the ability of ergothioneine to mitigate cisplatin-evoked nephrotoxicity and to elucidate the underlining molecular mechanisms. Wistar rats were treated with a daily dose of ergothioneine (70 mg/kg, po) for fourteen days and a single dose of cisplatin (5 mg/kg, ip) on day ten. On day fifteen, kidneys and blood specimens were collected and subjected to Western blotting, ELISA, histopathological, and spectrophotometric analysis. Ergothioneine significantly enhanced renal function in cisplatin-treated rats as manifested by increased GFR and decreased serum creatinine and blood urea nitrogen. Ergothioneine effectively reduced the cisplatin-induced oxidative stress and mitigated apoptosis and the histopathological changes. Mechanistically, ergothioneine induced the expression of the antioxidant transcription factor Nrf2 and up-regulated its downstream targets NQO1 and HO-1. Equally important, ergothioneine inhibited γ-glutamyl transpeptidase that plays crucial roles in biotransformation of cisplatin into a toxic metabolite. Additionally, it reduced the pro-apoptotic protein p53 and the inflammatory transcription factor NF-κB along with its downstream pro-inflammatory cytokines TNF-α and IL-1β. The results of the current work shed the light on the ameliorating effect of ergothioneine on cisplatin-evoked nephrotoxicity that is potentially mediated through modulation of Nrf2, p53, and NF-κB signaling and inhibition of γ-glutamyl transpeptidase. This findings support the potential application of ergothioneine in controlling cisplatin-associated nephrotoxicity although clinical investigations are warranted. •Ergothioneine improves renal function in the cisplatin-treated rats.•Ergothioneine suppresses cisplatin-induced up-regulation of NF-κB and p53.•Ergothioneine activates Nrf2 signaling in the cisplatin-treated rats.•Ergothioneine down-regulates GGT activity in the cisplatin-treated rats.•Ergothioneine suppresses cisplatin-induced oxidative stress in renal tissues.