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: AKI model was established by treating mice with folic acid. Regulatory effects of Rev-erb-α/β on AKI and ferroptosis were determined using singlegene 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. 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.

Deficiency of intestinal Bmal1 prevents obesity induced by high-fat feeding

“…was used to evaluate lipid droplets in the intestine 51,53 . In brief, proximal jejunum samples were fixed in 2.5% glutaraldehyde, post-fixed in 1% OsO 4 , dehydrated in graded ethanol and embedded in epoxy resin.…”

Folic acid‐induced animal model of kidney disease

“…19,21,47,48 However, this article will focus on a very popular kidney disease animal model, the folic acid (FA)-induced rodent model involving the use of both mouse and rat. [49][50][51][52][53] A comparison of the FA model with other chemically induced kidney injury animal models is given in Table 1.…”

Molecular regulations of circadian rhythm and implications for physiology and diseases

“…–Increase in renal GSH and Gpx4 levels. Wild-type C57BL/6 mice treated with folic acid Acute kidney injury 152 ARN5187 Dual inhibitory activity toward both REV-ERBs and autophagy –Disruption of lysosomal function, blockade of autophagy at the late stage, and reduction of cancer cell viability. –Inhibition of REV-ERB mediated transcriptional regulation.…”