2. Academic Validation
  3. Macrophage AMPK activated by oxidative stress drives profibrotic crosstalk with tubular cells to accelerate renal fibrosis after ischemic and reperfusion injury

Macrophage AMPK activated by oxidative stress drives profibrotic crosstalk with tubular cells to accelerate renal fibrosis after ischemic and reperfusion injury

  • Redox Biol. 2026 Mar:90:104002. doi: 10.1016/j.redox.2025.104002.
Yuandong Tao 1,  Min Zhang 2,  Lei Chen 3,  Hongshuai Jia 1,  Yunjie Yang 4,  Yangyang Wu 1,  Pin Li 1,  Zhuyuan Wen 1,  Xiaowei Zhang 1,  Xiangmei Chen 5,  Xizhao Chen 6,  Xiubin Li 7,  Huixia Zhou 8
Affiliations

Affiliations

  • 1 Senior Department of Pediatrics, Chinese PLA General Hospital, Beijing, China.
  • 2 Senior Department of Nephrology, Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China.
  • 3 Department of Critical Care Nephrology and Blood Purification, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 4 The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China; Department of Pediatric Surgery, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, China.
  • 5 Senior Department of Nephrology, Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China. Electronic address: [email protected].
  • 6 Senior Department of Nephrology, Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China. Electronic address: [email protected].
  • 7 Senior Department of Urology, Chinese PLA General Hospital, Beijing, China. Electronic address: [email protected].
  • 8 Senior Department of Pediatrics, Chinese PLA General Hospital, Beijing, China. Electronic address: [email protected].
PMID: 41621245 DOI: 10.1016/j.redox.2025.104002
Abstract

Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) that significantly increases the risk of progression to chronic kidney disease (CKD). Although oxidative stress has been implicated in this transition, the precise mechanisms through which it orchestrates inflammation and fibrosis during IRI-induced AKI-CKD progression remain poorly understood. In this study, we observed sustained Reactive Oxygen Species (ROS) production in post-IRI kidneys. ROS were found to activate AMP-activated protein kinase (AMPK) in macrophages in a calcium-dependent manner. Conditional knockout of AMPKα1 in macrophages (Lyz2-Cre; Prkaa1-fl/fl mice) significantly attenuated renal fibrosis following IRI. Single-cell RNA Sequencing analysis further revealed that AMPKα1 deletion reduced the accumulation of Arg1+ MMP12+ macrophages and diminished a profibrotic tubular epithelial cell (TEC) subpopulation marked by persistent expression of PDGFB and VCAM1. These macrophages were shown to interact with PDGFB+ VCAM1+ TECs. Mechanistically, macrophage-derived TWEAK signaling through its receptor Fn14 promoted PDGFB production in TECs, driving maladaptive changes and a fibrogenic phenotype. Importantly, TWEAK neutralization effectively mitigated the AKI-to-CKD transition. Together, our results identify macrophage AMPK as a key redox sensor that, upon activation by oxidative stress, initiates maladaptive macrophage-TEC crosstalk, ultimately promoting renal fibrosis and CKD progression.

Keywords

AKI-CKD transition; AMPK; Ischemia-reperfusion injury; Macrophage; Tubular epithelial cells.

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