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

Abstract

Objectives 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. Methods 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. Results 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. Conclusions 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.

Formyl Peptide Receptor Type 2 Deficiency in Myeloid Cells Amplifies Sepsis-Induced Cardiac Dysfunction

“…Apart from cardioprotective effects, the protection afforded by FPR2 activation is also evident in other organ injuries. In settings of sepsis, AnxA1 peptide Ac2-26 improved kidney function by reducing the levels of NF-κB, TNF-03B1;, IL-103B2;, IL-6, and cleaved caspase −3 and −8 in kidney tissue, while the protective role of Ac2-26 is abolished by the administration of FPR2 antagonist WRW4 or Fpr2-siRNA [43] . In the brain, Ac2-26 mitigated LPS-induced leukocyte adhesion in cerebral venules in WT mouse; however, Ac2-26 loses its effect in Fpr2 global KO mice [21] .…”

Research Progress of Macromolecules in the Prevention and Treatment of Sepsis

“…Ac2-26 is an N-terminal active peptide of Annexin A1 that targets formyl peptide receptor-2 receptors and inhibits PI3K and AKT phosphorylation. Ac2-26 downregulates the level of NF-κB, reduces the expression of inflammatory cytokines and pro-apoptotic proteins in septic mice, inhibits inflammation and apoptosis, improves renal injury, and increases the 7-day survival rate of CLP mice (>40%) [ 40 ].…”