1. Academic Validation
  2. Liraglutide alleviates ferroptosis in renal ischemia reperfusion injury via inhibiting macrophage extracellular trap formation

Liraglutide alleviates ferroptosis in renal ischemia reperfusion injury via inhibiting macrophage extracellular trap formation

  • Int Immunopharmacol. 2024 Dec 5;142(Pt B):113258. doi: 10.1016/j.intimp.2024.113258.
Zejia Sun 1 Feilong Zhang 1 Zihao Gao 1 Jiyue Wu 1 Qing Bi 1 Xiang Zheng 1 Jiandong Zhang 2 Peng Cao 3 Wei Wang 4
Affiliations

Affiliations

  • 1 Department of Urology, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China; Institute of Urology, Capital Medical University, Beijing 100020, China.
  • 2 Department of Urology, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China; Institute of Urology, Capital Medical University, Beijing 100020, China. Electronic address: yjs2010zjd@126.com.
  • 3 Department of Urology, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China; Institute of Urology, Capital Medical University, Beijing 100020, China. Electronic address: petercao0103@163.com.
  • 4 Department of Urology, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China; Institute of Urology, Capital Medical University, Beijing 100020, China. Electronic address: weiwang0920@163.com.
Abstract

Background and purpose: Renal transplantation and other conditions with transiently reduced blood flow is major cause of renal ischemia/reperfusion injury (RIRI), a therapeutic challenge clinically. This study investigated the role of liraglutide in ferroptosis-associated RIRI via macrophage extracellular traps (METs).

Methods: Animal model with RIRI was established in C57BL/6J mice. A total of 72 C57BL/6J mice were used with 8 mice per group. Primary tubular epithelium was co-culture with RAW264.7 under hypoxia/reoxygenation (H/R) condition to mimic in vitro. Liraglutide was administrated into mice and cells. Extracellular DNA, neutrophil Elastase and myeloperoxidase in serum and supernatant of cell medium were collected for measuring METs. F4/80 and citH3 were labeled to show METs.

Results: Liraglutide relieved RIRI and Ferroptosis in vivo, and inhibited renal I/R-induced METs both in vivo and in vitro. F4/80 and citrullinated histone H3 (citH3) were highly co-localized after RIRI. Liraglutide attenuated the co-localization of citH3 and F4/80. Expressions of M2 markers were enhanced whereas these of M1 markers suppressed during liraglutide treatment in RIRI. Phosphorylation of signal transducer and activator of transcription (STAT)1, 3 and 6 were increased in RIRI mice and H/R-induced RAW264.7. However, liraglutide decreased phosphorylation of STAT1 and increased phosphorylation of STAT3 and STAT6. STAT3/6 inhibition reversed liraglutide-inhibited M1 polarization, extracellular traps and Ferroptosis.

Conclusion: Liraglutide inhibited ferroptosis-induced renal dysfunction since it skewed macrophage polarization into M2 phenotype that interfered the formation of extracellular traps based on STAT3/6 pathway during RIRI. Liraglutide was proposed to be used for RIRI clinical treatment.

Keywords

Ferroptosis; Liraglutide; M1/M2 polarization; Macrophage extracellular traps; Renal ischemia reperfusion injury.

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