Post-treatment With Irisin Attenuates Acute Kidney Injury in Sepsis Mice Through Anti-Ferroptosis via the SIRT1/Nrf2 Pathway

• Published in: Frontiers in pharmacology Vol. 13; p. 857067
• Main Authors: Qiongyue, Zhang, Xin, Yang, Meng, Peng, Sulin, Mi, Yanlin, Wang, Xinyi, Li, Xuemin, Song
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 17.03.2022
• Subjects: acute kidney injury; ferroptosis; irisin; Nrf2; Pharmacology; sepsis; SIRT1; acute kidney injury; ferroptosis; irisin; Nrf2; SIRT1; sepsis
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2022.857067

Kidney is one of the most vulnerable organs in sepsis, resulting in sepsis-associated acute kidney injury (SA-AKI), which brings about not only morbidity but also mortality of sepsis. Ferroptosis is a new kind of death type of cells elicited by iron-dependent lipid peroxidation, which participates in pathogenesis of sepsis. The aim of this study was to verify the occurrence of ferroptosis in the SA-AKI pathogenesis and demonstrate that post-treatment with irisin could restrain ferroptosis and alleviate SA-AKI activating the SIRT1/Nrf2 signaling pathway. We established a SA-AKI model by cecal ligation and puncture (CLP) operation and an model in LPS-induced HK2 cells, respectively. Our result exhibited that irisin inhibited the level of ferroptosis and ameliorated kidney injury in CLP mice, as evidenced by reducing the ROS production, iron content, and MDA level and increasing the GSH level, as well as the alteration of ferroptosis-related protein (GPX4 and ACSL4) expressions in renal, which was consistent with the ferroptosis inhibitor ferrostatin-1 (Fer-1). Additionally, we consistently observed that irisin inhibited ROS accumulation, iron production, and ameliorated mitochondrial dysfunction in LPS-stimulated HK-2 cells. Furthermore, our result also revealed that irisin could activate SIRT1/Nrf2 signaling pathways both and vitro. However, the beneficial effects of irisin were weakened by EX527 (an inhibitor of SIRT1) and by SIRT1 siRNA . In conclusion, irisin could protect against SA-AKI through ferroptotic resistance activating the SIRT1/Nrf2 signaling pathway.