Ablation of macrophage transcriptional factor FoxO1 protects against ischemia-reperfusion injury-induced acute kidney injury.
10.1016/j.apsb.2025.04.009
- Author:
Yao HE
1
;
Xue YANG
1
;
Chenyu ZHANG
1
;
Min DENG
1
;
Bin TU
2
;
Qian LIU
1
;
Jiaying CAI
1
;
Ying ZHANG
1
;
Li SU
3
;
Zhiwen YANG
1
;
Hongfeng XU
1
;
Zhongyuan ZHENG
1
;
Qun MA
1
;
Xi WANG
1
;
Xuejun LI
1
;
Linlin LI
4
;
Long ZHANG
5
;
Yongzhuo HUANG
6
;
Lu TIE
1
Author Information
1. Department of Pharmacology, School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China.
2. Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Zhongshan 528400, China.
3. Medical and Health Science Analysis Center, Peking University, Beijing 100191, China.
4. Department of Pharmacology, Xinjiang Medical University, Xinjiang 830011, China.
5. Department of Wound Healing Center and Interventional Radiology and Vascular Surgery, Peking University Third Hospital, Beijing 100191, China.
6. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
- Publication Type:Journal Article
- Keywords:
AKI;
ARHGEF1;
Chemotaxis;
FoxO1;
I/R injury;
Inflammation;
Macrophage;
Migration
- From:
Acta Pharmaceutica Sinica B
2025;15(6):3107-3124
- CountryChina
- Language:English
-
Abstract:
Acute kidney injury (AKI) has high morbidity and mortality, but effective clinical drugs and management are lacking. Previous studies have suggested that macrophages play a crucial role in the inflammatory response to AKI and may serve as potential therapeutic targets. Emerging evidence has highlighted the importance of forkhead box protein O1 (FoxO1) in mediating macrophage activation and polarization in various diseases, but the specific mechanisms by which FoxO1 regulates macrophages during AKI remain unclear. The present study aimed to investigate the role of FoxO1 in macrophages in the pathogenesis of AKI. We observed a significant upregulation of FoxO1 in kidney macrophages following ischemia-reperfusion (I/R) injury. Additionally, our findings demonstrated that the administration of FoxO1 inhibitor AS1842856-encapsulated liposome (AS-Lipo), mainly acting on macrophages, effectively mitigated renal injury induced by I/R injury in mice. By generating myeloid-specific FoxO1-knockout mice, we further observed that the deficiency of FoxO1 in myeloid cells protected against I/R injury-induced AKI. Furthermore, our study provided evidence of FoxO1's pivotal role in macrophage chemotaxis, inflammation, and migration. Moreover, the impact of FoxO1 on the regulation of macrophage migration was mediated through RhoA guanine nucleotide exchange factor 1 (ARHGEF1), indicating that ARHGEF1 may serve as a potential intermediary between FoxO1 and the activity of the RhoA pathway. Consequently, our findings propose that FoxO1 plays a crucial role as a mediator and biomarker in the context of AKI. Targeting macrophage FoxO1 pharmacologically could potentially offer a promising therapeutic approach for AKI.
