Abstract: TH-OR005
Circadian Bmal1/Rev-erbα/CSF-1 Axis in Proximal Tubules Modulates Macrophage-Driven Diurnal Variation in Renal Ischemia-Reperfusion Injury
Session Information
- AKI Progression and Resolution: Cellular and Molecular Insights
November 06, 2025 | Location: Room 320A, Convention Center
Abstract Time: 05:10 PM - 05:20 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Chen, Lihong, East China Normal University, Shanghai, China
- Li, Shuyao, East China Normal University, Shanghai, China
- Yang, Guangrui, Shanghai University of Medicine and Health Sciences, Shanghai, China
Background
Renal ischemia-reperfusion injury (RIRI), a leading cause of acute kidney injury, exhibits time-of-day–dependent severity, implicating the circadian clock in disease progression. However, the underlying mechanisms remain poorly understood. Here we aimed to investigate the role of the core circadian gene Bmal1 in the diurnal variation of RIRI and to elucidate the molecular mechanisms involved.
Methods
The impact of ischemia/reperfusion (I/R) timing (ZT0 vs. ZT12, corresponding to high or low Bmal1 expression, respectively) on renal damage and inflammation were assessed in proximal tubule-specific Bmal1 knockout (Bmal1flox/flox/KAPCre+, ptKO) and the littermate Bmal1flox/flox mice. Multiple molecular and cell-based assays were conducted to delineate the regulatory axis downstream of Bmal1
Results
Initiating I/R operations at ZT12 resulted in significantly more severe renal injury and greater inflammatory cell infiltration in wild-type mice compared to ZT0. Deletion of the proximal tubule Bmal1 mitigated the time-dependent effects of surgery and displayed exaggerated renal injury at ZT0. Macrophage depletion via clodronate liposomes similarly eliminated the diurnal variation of RIRI and significantly attenuated renal damage specifically at ZT12. Mechanistically, proximal tubular Bmal1 deficiency increased renal expression of colony stimulating factor-1 (CSF-1) and enhanced recruitment of CSF-1R+ macrophages into the kidney. Csf-1 transcription was suppressed by REV-ERBα, and both genetic overexpression and pharmacologic activation of REV-ERBα reduced CSF-1 expression and rescued Bmal1 deficiency-induced renal injury. Moreover, pharmacological inhibition of CSF-1R abrogated the time-dependent differences in RIRI and alleviated renal injury at ZT12.
Conclusion
Our findings reveal a circadian Bmal1–Rev-erbα–CSF-1 axis in proximal tubules that governs the rhythmic infiltration of macrophages and drives diurnal variation in RIRI severity. Targeting this pathway may offer novel chronotherapeutic strategies for the prevention and treatment of RIRI.