Liraglutide orchestrates ferroptosis defense against murine cisplatin acute kidney injury: NRF2 activation via both KEAP1-dependent and -independent mechanisms is essential for SLC7A11/GPX4 renoprotection

Abstract

Objective

Acute kidney injury (AKI) induced by oxidative stress, and recently associated with ferroptosis, represents a major complication of the chemotherapeutic cisplatin that often necessitates treatment cessation. The glucagon-like peptide 1 receptor (GLP1R) agonist liraglutide possesses reno-protective potential via its antioxidant character in different kidney injury settings while reducing iron overload in other models. Hence, we investigated the potential protective role of liraglutide in cisplatin-induced AKI targeting KEAP1-dependent and -independent ferroptosis pathways.

Methods

Rats were assigned to one of four groups: vehicle control, liraglutide control, cisplatin-induced AKI, and liraglutide-pretreated AKI. Renal function markers and histopathological changes were assessed. SLC7A11, NRF2, and KEAP1-canonical and non-canonical hubs were analyzed to elucidate the drug’s molecular mechanisms on ferroptosis.

Results

Liraglutide significantly improved renal function, evidenced by the reduction of serum cystatin C, creatinine, and BUN, along with renal histological improvements. In the kidney, liraglutide activated/phosphorylated AKT, mTOR, and P62 to reduce KEAP1 and inactivated GSK3β to enhance NRF2-mediated GPX4 and SLC7A11 formation, thus inhibiting cisplatin-ferroptosis-triggered renal injury.

Conclusion

Therefore, liraglutide is a promising treatment candidate for attenuating cisplatin-induced AKI by SLC7A11/GPX4 trajectory through upregulating the AKT/mTOR/P62/KEAP1/NRF2 and AKT/GSK3β/NRF2 signaling pathways to increase GPX4 alongside with SLC7A11. Indeed, the GLP1R-mediated AKT activation acts as a potential target for Liraglutide reno-protective actions; hence, the GLP1R can be considered a therapeutic entity in such a renal injurious paradigm.