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Targeted inhibition of Rev-erbα/β limits ferroptosis to ameliorate folic acid-induced acute kidney injury.
British Journal of Pharmacology 2020 October 18
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. Here, we investigated the potential role of the circadian clock components Rev-erbα/β in regulation of ferroptosis and AKI.
EXPERIMENTAL APPROACH: AKI model was established by treating mice with folic acid (FA). Regulatory effects of Rev-erbα/β on AKI and ferroptosis were determined using single gene knockout (Rev-erbα-/- and Rev-erbβ-/- ) mice, incomplete double knockout (icDKO, Rev-erbα+/- Rev-erbβ-/- ) mice, and cells with erastin-induced ferroptosis. Targeted antagonism of Rev-erbα/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-erbα or Rev-erbβ reduced the sensitivity of mice to FA-induced AKI and eliminated the circadian time-dependency in disease severity. This coincided with less extensive ferroptosis, a main cause of FA-induced AKI. Moreover, icDKO mice were more resistant to FA-induced AKI and ferroptosis as compared to single gene knockout mice. Supporting this, targeting Rev-erbα/β by SR8278 attenuated ferroptosis to ameliorate FA-induced AKI in mice. Mechanistically, Rev-erbα/β promoted ferroptosis by repressing the transcription of Slc7a11 and HO-1 (two ferroptosis-inhibitory genes) via direct binding to a RORE cis-element.
CONCLUSION AND IMPLICATIONS: Targeted inhibition of Rev-erbα/β limits ferroptosis to ameliorate FA-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.
EXPERIMENTAL APPROACH: AKI model was established by treating mice with folic acid (FA). Regulatory effects of Rev-erbα/β on AKI and ferroptosis were determined using single gene knockout (Rev-erbα-/- and Rev-erbβ-/- ) mice, incomplete double knockout (icDKO, Rev-erbα+/- Rev-erbβ-/- ) mice, and cells with erastin-induced ferroptosis. Targeted antagonism of Rev-erbα/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-erbα or Rev-erbβ reduced the sensitivity of mice to FA-induced AKI and eliminated the circadian time-dependency in disease severity. This coincided with less extensive ferroptosis, a main cause of FA-induced AKI. Moreover, icDKO mice were more resistant to FA-induced AKI and ferroptosis as compared to single gene knockout mice. Supporting this, targeting Rev-erbα/β by SR8278 attenuated ferroptosis to ameliorate FA-induced AKI in mice. Mechanistically, Rev-erbα/β promoted ferroptosis by repressing the transcription of Slc7a11 and HO-1 (two ferroptosis-inhibitory genes) via direct binding to a RORE cis-element.
CONCLUSION AND IMPLICATIONS: Targeted inhibition of Rev-erbα/β limits ferroptosis to ameliorate FA-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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