Circadian Clock Molecule REV-ERBα Deficiency in Tubular Cells Regulates Renal Fibrosis Through Increasing Lipid Accumulation

Background: The dysregulation of lipid metabolism in renal tubular cells is closely associated with renal interstitial fibrosis. As a key circadian clock regulator, REV-ERBα plays a central role in lipid homeostasis. However, its role and underlying mechanisms in renal fibrogenesis remain poorly understood. In this study, we investigated the functional significance of REV-ERBα in kidney fibrosis. Methods: Unilateral ureteral obstruction (UUO) was employed to induce renal fibrogenesis. Renal proximal tubule-specific Rev-ERBα knockout mice were generated, and Rev-ERBα agonist (SR9009) administration was used to evaluate its therapeutic effects. The downstream targets of REV-ERBα were detected by chromatin immunoprecipitation. Results: 1. UUO induced a significant reduction in REV-ERBα abundance in obstructed kidneys. 2. Rev-ERBα deletion exacerbated extracellular matrix deposition and lipid accumulation in renal tubules compared to wild-type mice. 3. SR9009 administration alleviated renal fibrosis and normalized lipid metabolism in UUO mice. 4. REV-ERBα regulated fatty acid translocase CD36 via directly suppressing NFIL3. Conclusion: Our data demonstrate that REV-ERBα deficiency promotes renal fibrosis through lipid metabolic dysfunction, while pharmacological activation of REV-ERBα exerts protective effects. These findings highlight the therapeutic potential of REV-ERBα agonists in fibrotic kidney diseases.