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

British journal of pharmacology (2020-10-18)
Lianxia Guo, Tianpeng Zhang, Fei Wang, Xun Chen, Haiman Xu, Cui Zhou, Min Chen, Fangjun Yu, Shuai Wang, Deguang Yang, Baojian Wu
RESUMEN

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. AKI model was established by treating mice with folic acid. Regulatory effects of Rev-erb-α/β on AKI and ferroptosis were determined using single-gene knockout (Rev-erb-α-/- and Rev-erb-β-/- ) mice, incomplete double-knockout (icDKO, Rev-erb-α+/- Rev-erb-β-/- ) 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. 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. 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.

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Sigma-Aldrich
SR8278, ≥98% (HPLC)
Sigma-Aldrich
Monoclonal Anti-NR1D1 antibody produced in mouse, clone 4F6, purified immunoglobulin, buffered aqueous solution