7-hydroxycoumarin modulates Nrf2/HO-1 and microRNA-34a/SIRT1 signaling and prevents cisplatin-induced oxidative stress, inflammation, and kidney injury in rats

The kidneys are vulnerable to toxicity and acute kidney injury (AKI) is the main adverse effect associated with the clinical use of the chemotherapeutic agent cisplatin (CIS). Oxidative stress and inflammation are implicated in CIS nephrotoxicity. In this study, the effect of the antioxidant 7-hydroxycoumarin (7-HC) against CIS-induced renal intoxication was evaluated. Rats received 7-HC (25, 50, and 100 mg/kg) orally for 14 days and CIS (7 mg/ kg) at day 15, and samples were collected 3 days after CIS administration. CIS increased serum urea, creatinine and kidney injury molecule (Kim)-1, caused multiple histopathological changes and increased renal reactive oxygen species (ROS), malondialdehyde (MDA), nitric oxide (NO), NF-& UKappa;B p65, iNOS, and pro-inflammatory cytokines. 7-HC dose-dependently prevented kidney dysfunction and tissue injury and suppressed ROS and in-flammatory mediators. 7-HC boosted renal antioxidants and Bcl-2 while decreased Bax and caspase-3 expression in CIS-administered rats. In addition, 7-HC downregulated Keap-1 and microRNA-34a and upregulated Nrf2, NQO-1, HO-1, and SIRT1. Molecular docking revealed the binding affinity of 7-HC towards NF-& UKappa;B, Keap-1, and SIRT1. In Conclusion, 7-HC prevented CIS nephrotoxicity by attenuating tissue injury, oxidative stress, inflam-mation, and apoptotic cell death. The protective efficacy of 7-HC was associated with inhibiting NF-& UKappa;B and Keap-1, and modulating Nrf2/HO-1 and microRNA34a/Sirt1 signaling.

Automated summary

In this study, the protective effect of the antioxidant 7-hydroxycoumarin (7-HC) against cisplatin-induced acute kidney injury was investigated. Results showed that 7-HC prevented kidney dysfunction and tissue injury, suppressed oxidative stress and inflammation, and modulated several signaling pathways. Molecular docking revealed the potential binding of 7-HC to specific proteins involved in these pathways.