期刊
FASEB JOURNAL
卷 34, 期 11, 页码 15029-15046出版社
WILEY
DOI: 10.1096/fj.202000261RRR
关键词
AKI; BAY61-3606; macrophage; Mincle; Syk
资金
- Luzhou-Southwest Medical University Joint Project [2017LZXNYD-P01, 2018LZXNYD-PT03, 2017LZXNYD-Z03]
- Southwest Medical University [2018XYLH-013]
- The Scientific Research Program of Health Commission of Sichuan Province [19PJ154, 19PJ152]
- The Luzhou Municipal Southwest Medical University Joint Special Grant for the Introduction of High-level Talents
- Affiliated Traditional Medicine Hospital [2018XYLH-013]
Acute kidney injury (AKI) is a highly prevalent clinical syndrome with high mortality and morbidity. Previous studies indicated that inflammation promotes tubular damage and plays a key role in AKI progress. Spleen tyrosine kinase (Syk) has been linked to macrophage-related inflammation in AKI. Up to date, however, no Syk-targeted therapy for AKI has been reported. In this study, we employed both cell model of LPS-induced bone marrow-derived macrophage (BMDM) and mouse model of ischemia/reperfusion injury (IRI)-induced AKI to evaluate the effects of a Syk inhibitor, BAY61-3606 (BAY), on macrophage inflammation in vitro and protection of kidney from AKI in vivo. The expression and secretion of inflammatory cytokines, both in vitro and in vivo, were significantly inhibited even back to normal levels by BAY. The upregulated serum creatinine and blood urea nitrogen levels in the AKI mice were significantly reduced after administration of BAY, implicating a protective effect of BAY on kidneys against IRI. Further analyses from Western blot, immunofluorescence staining and flow cytometry revealed that BAY inhibited the Mincle/Syk/NF-kappa B signaling circuit and reduced the inflammatory response. BAY also inhibited the reactive oxygen species (ROS), which further decreased the formation of inflammasome and suppressed the mature of IL-1 beta and IL-18. Notably, these inhibitory effects of BAY on inflammation and inflammasome in BMDM were significantly reversed by Mincle ligand, trehalose-6,6-dibehenate. In summary, these findings provided compelling evidence that BAY may be an efficient inhibitor of the Mincle/Syk/NF-kappa B signaling circuit and ROS-induced inflammasome, which may help to develop Syk-inhibitors as novel therapeutic agents for AKI.
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