Targeted inhibition of Rev‐erb‐α/β limits ferroptosis to ameliorate folic acid‐induced acute kidney injury
Lianxia Guo, Tianpeng Zhang, Fei Wang, Xun Chen, Haiman Xu, Cui Zhou, Min Chen, Fangjun Yu, Shuai Wang, Deguang Yang, Baojian Wu
Abstract
BACKGROUND AND PURPOSE: Acute kidney injury (AKI) is a common and critical illness, resulting in severe morbidity and a high mortality. There is a considerable interest in identifying novel molecular targets for management of AKI. We investigated the potential role of the circadian clock components Rev-erb-α/β in regulation of ferroptosis and AKI. EXPERIMENTAL APPROACH: ) mice and cells with erastin-induced ferroptosis. Targeted antagonism of Rev-erb-α/β to alleviate AKI and ferroptosis was assessed using the small-molecule antagonist SR8278. Transcriptional gene regulation was investigated using luciferase reporter, mobility shift and chromatin immunoprecipitation assays. KEY RESULTS: Loss of Rev-erb-α or Rev-erb-β reduced the sensitivity of mice to folic acid-induced AKI and eliminated the circadian time dependency in disease severity. This coincided with less extensive ferroptosis, a main cause of folic acid-induced AKI. Moreover, icDKO mice were more resistant to folic acid-induced AKI and ferroptosis as compared with single-gene knockout mice. Supporting this, targeting Rev-erb-α/β by SR8278 attenuated ferroptosis to ameliorate folic acid-induced AKI in mice. Rev-erb-α/β promoted ferroptosis by repressing the transcription of Slc7a11 and HO1 (two ferroptosis-inhibitory genes) via direct binding to a RORE cis-element. CONCLUSION AND IMPLICATIONS: Targeted inhibition of Rev-erb-α/β limits ferroptosis to ameliorate folic acid-induced AKI in mice. The findings may have implications for improved understanding of circadian clock-controlled ferroptosis and for formulating new strategies to treat AKI.