Targeted inhibition of Rev‐erb‐α/β limits ferroptosis to ameliorate folic acid‐induced acute kidney injury

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.