Annexin A1 (Ac2-26)-dependent Fpr2 receptor alleviates sepsis-induced acute kidney injury by inhibiting inflammation and apoptosis in vivo and in vitro.

Excessive inflammatory responses and apoptosis are critical pathologies that contribute to sepsis-induced acute kidney injury (SI-AKI). Annexin A1 (ANXA1), a member of the calcium-dependent phospholipid-binding protein family, protects against SI-AKI through its anti-inflammatory and antiapoptotic effects, but the underlying mechanisms are still largely unknown. In vivo, SI-AKI mouse models were established via caecal ligation and puncture (CLP) and were then treated with the Ac2-26 peptide of ANXA1 (ANXA1 (Ac2-26)), WRW4 (Fpr2 antagonist) or both. In vitro, HK-2 cells were induced by lipopolysaccharide (LPS) and then treated with ANXA1 (Ac2-26), Fpr2-siRNA or both. In the present study, we found that the expression levels of ANXA1 were decreased, and the expression levels of TNF-α, IL-1β, IL-6, cleaved caspase-3, cleaved caspase-8 and Bax were significantly increased, accompanied by marked kidney tissue apoptosis in vivo. Moreover, we observed that ANXA1 (Ac2-26) significantly reduced the levels of TNF-α, IL-1β and IL-6 and cleaved caspase-3, cleaved caspase-8, FADD and Bax and inhibited apoptosis in kidney tissue and HK-2 cells, accompanied by pathological damage to kidney tissue. Seven-day survival, kidney function and cell viability were significantly improved in vivo and in vitro, respectively. Furthermore, the administration of ANXA1 (Ac2-26) inhibited the CLP- or LPS-induced phosphorylation of PI3K and AKT and downregulated the level of NF-κB in vivo and in vitro. Moreover, our data demonstrate that blocking the Fpr2 receptor by the administration of WRW4 or Fpr2-siRNA reversed the abovementioned regulatory role of ANXA1, accompanied by enhanced phosphorylation of PI3K and AKT and upregulation of the level of NF-κB in vivo and in vitro. Taken together, this study provides evidence that the protective effect of ANXA1 (Ac2-26) on SI-AKI largely depends on the negative regulation of inflammation and apoptosis via the Fpr2 receptor.

Zheng Y ，Li Y ，Li S ，Hu R ，Zhang L ... -  《-》

[Annexin A1 activates the G protein-coupled formyl peptide receptor type 2-dependent endothelial nitric oxide synthase pathway to alleviate sepsis associated acute lung injury].

Chen Y ，He Y ，Qin H ，Qin S ... -  《-》

Annexin A1 Mimetic Peptide AC2-26 Inhibits Sepsis-induced Cardiomyocyte Apoptosis through LXA4/PI3K/AKT Signaling Pathway.

Zhang L ，Zheng YL ，Hu RH ，Zhu L ，Hu CC ，Cheng F ，Li S ，Li JG ... -  《-》

Anti-inflammatory mechanisms of the annexin A1 protein and its mimetic peptide Ac2-26 in models of ocular inflammation in vivo and in vitro.

Girol AP ，Mimura KK ，Drewes CC ，Bolonheis SM ，Solito E ，Farsky SH ，Gil CD ，Oliani SM ... -  《-》

Annexin A1 protects against cerebral ischemia-reperfusion injury by modulating microglia/macrophage polarization via FPR2/ALX-dependent AMPK-mTOR pathway.

Xu X ，Gao W ，Li L ，Hao J ，Yang B ，Wang T ，Li L ，Bai X ，Li F ，Ren H ，Zhang M ，Zhang L ，Wang J ，Wang D ，Zhang J ，Jiao L ... -  《Journal of Neuroinflammation》