2. Academic Validation
  3. ACE2/Ang(1-7)/MasR axis exerts protective effects on lung ischemia/reperfusion injury via NF-κB-dependent mitochondrial adaptation and epithelial cell pyroptosis

ACE2/Ang(1-7)/MasR axis exerts protective effects on lung ischemia/reperfusion injury via NF-κB-dependent mitochondrial adaptation and epithelial cell pyroptosis

  • Int Immunopharmacol. 2025 Aug 11:164:115325. doi: 10.1016/j.intimp.2025.115325.
Yin Chen 1,  Liang Guo 2,  Juan Shen 3,  Wenzhuo Zhu 1,  Yu Zhuang 4
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.100 Haining Road, Shanghai 200080, China.
  • 2 Department of Thoracic Surgery, Shanghai Pulmonary Hospital,Tongji University School of Medicine, No.507 Zhengmin Road, Shanghai 200433, China.
  • 3 Department of Pathology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.100 Haining Road, Shanghai 200080, China.
  • 4 Department of Cardiovascular Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.100 Haining Road, Shanghai 200080, China. Electronic address: yu.zhuang@shgh.cn.
PMID: 40795499 DOI: 10.1016/j.intimp.2025.115325
Abstract

Aim: Mitochondrial dysfunction and Pyroptosis of epithelial cells are main contributors to the pathological process of lung ischemia/reperfusion (I/R) injury. Angiotensin-converting enzyme 2 (ACE2) has been implicated in suppressing lung injury. Accordingly, this study investigated whether ACE2 could attenuate mitochondrial dysfunction and Pyroptosis after lung I/R injury.

Methods: A lung I/R injury model was developed in rats by clamping the lung hilum after thoracotomy. The blood gas analysis was performed on arterial blood in the left ventricle of rats using a blood gas analyzer. The wet-to-dry weight ratio (W/D) of rat lung tissues was calculated to evaluate edema. H&E staining, transmission electron microscopy, and ELISA assessed rat lung tissue injury. An in vitro lung I/R injury model was generated by oxygen-glucose deprivation/reoxygenation (OGD/R) induction. The ACE2-MasR axis, NF-κB/NLRP3, and pyroptosis-related protein expression, cell death, mitochondrial related functions, and calcium ion levels were assessed by Western blot, LDH kit, flow cytometry, assay kits, and immunofluorescence.

Results: In the lung I/RI rat model, the ACE2 activator (DIZE) treatment reduced ACE2/Ang(1-7)/MasR imbalance, alleviated lung tissue damage, inhibited inflammation-related factor levels (TNF-a, IL-1β, IL-6), alleviating lung inflammation and injury. OGD/R inhibited ACE2/MasR axis activation in lung epithelial cells and induced NLRP3-mediated cell Pyroptosis. ACE2/MasR activation regulated OGD/R-induced lung epithelial cell Pyroptosis through NF-κB. ACE2/MasR improved mitochondrial functional integrity in OGD/R-induced lung epithelial cells. ACE2/MasR reduced the accumulation of calcium ions and alleviated OGD/R-induced lung epithelial cell Pyroptosis.

Conclusions: The ACE2/Ang(1-7)/MasR axis protects the lung against I/R injury by regulating mitochondrial adaptation and cell Pyroptosis.

Keywords

ACE2; ACE2/Ang(1–7)/MasR axis; Lung ischemia/reperfusion injury; Mitochondrial adaptation; NF-κB; NLRP3; Pyroptosis.

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