Carnosine attenuates renal ischemia-reperfusion injury by inhibiting GPX4-mediated ferroptosis

Huaying Wang; Shanshan Guo; Bingdian Wang; Xueqi Liu; Li Gao; Chaoyi Chen; Yonggui Wu

doi:10.1016/j.intimp.2023.110850

Carnosine attenuates renal ischemia-reperfusion injury by inhibiting GPX4-mediated ferroptosis

Int Immunopharmacol. 2023 Nov;124(Pt A):110850. doi: 10.1016/j.intimp.2023.110850. Epub 2023 Aug 24.

Authors

Huaying Wang¹, Shanshan Guo¹, Bingdian Wang², Xueqi Liu¹, Li Gao¹, Chaoyi Chen¹, Yonggui Wu³

Affiliations

¹ Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, PR China.
² Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, PR China; School of Nursing, Anhui Medical University, Hefei, Anhui 230022, PR China.
³ Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, PR China; Center for Scientific Research of Anhui Medical University, Hefei, Anhui 230022, PR China. Electronic address: wuyonggui@medmail.com.cn.

PMID: 37633236
DOI: 10.1016/j.intimp.2023.110850

Abstract

Increasing evidence and our preliminary work have revealed the significant role of ferroptosis in acute kidney injury (AKI) induced by ischemia/reperfusion (IR). Carnosine (Car), a dipeptide consisting of β-alanine and L-histidine, has been shown to ameliorate HG-induced tubular epithelial cells inflammation. Whether Car exerts protective effects on AKI, and its molecular mechanism have not been clarified. Our in vivo and in vitro IR-AKI mouse models demonstrated that Car alleviates kidney injury, inflammation and ferroptosis. In hypoxia/reoxygenation (HR) induced human renal tubular epithelial cells (HK2), Car treatment reduced lipid peroxidation and iron accumulation, suppressed oxidative stress, and inhibited ferroptosis. Through cellular thermal shift assay (CETSA) and molecular docking, we identified GPX4 as a potential target that binds with Car. Further study showed that overexpressed GPX4 had a comparable protective effect on HK2 cells under HR conditions, similar to Car. Additionally, our findings demonstrated that Car exhibited similar anti-ferroptosis effects in both folic acid (FA)-induced AKI mouse models and Erastin induced HK2 cells. In conclusion, our results highlight that Car alleviate renal IR injury by inhibiting GPX4-mediated ferroptosis. Car shows promise as a potential therapeutic drug for IR-AKI and other diseases associated with ferroptosis.

Keywords: Acute kidney injury; Carnosine; Ferroptosis; GPX4; Ischemia/reperfusion; Oxidative stress.