Polydatin Attenuates Cisplatin-Induced Acute Kidney Injury by Inhibiting Ferroptosis

Area of Science:

• Nephrology
• Pharmacology
• Biochemistry

Background:

• Cisplatin is a vital chemotherapy drug, but its use is limited by nephrotoxicity, leading to cisplatin-induced acute kidney injury (Cis-AKI).
• Currently, no effective treatments exist for Cis-AKI.
• Polydatin (PD) has shown prior nephroprotective effects via antioxidative stress, but its role in ferroptosis, a cell death pathway linked to oxidative stress, remained unclear.

Purpose of the Study:

• To investigate whether the nephroprotective effects of polydatin (PD) against cisplatin-induced acute kidney injury (Cis-AKI) are mediated by the inhibition of ferroptosis.
• To elucidate the underlying molecular mechanisms of PD's action in Cis-AKI.

Main Methods:

• In vitro studies using cisplatin-treated HK-2 cells and in vivo studies using a Cis-AKI mouse model.
• Assessment of ferroptosis markers including intracellular iron, reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and glutathione peroxidase-4 (GPx4) activity.
• Evaluation of PD's effect on erastin-induced cell death and comparison with known ferroptosis inhibitors (ferrostatin-1, deferoxamine).

Main Results:

• Polydatin (PD) inhibited ferroptosis in both cisplatin-treated HK-2 cells and a Cis-AKI mouse model.
• PD treatment reversed excessive intracellular iron accumulation and ROS generation, decreased MDA content, and mitigated GSH depletion while increasing GPx4 activity.
• PD dose-dependently alleviated erastin-induced cell death, with a 40 μM dose showing greater efficacy than classical ferroptosis inhibitors.

Conclusions:

• Polydatin (PD) demonstrates significant nephroprotection in cisplatin-induced acute kidney injury (Cis-AKI) by inhibiting ferroptosis.
• The mechanism involves maintaining the system Xc-GSH-GPx4 axis and regulating iron metabolism.
• PD represents a promising therapeutic agent for treating Cis-AKI.