Sepsis often leads to complications such as acute kidney injury (AKI) which is reported to range from 30 to 50% in critically ill patients. Dendritic (DCs) and neutrophils play a decisive role in the advancement of AKI through release of inflammatory cytokines and reactive oxygen species (ROS) respectively. Both of these processes are assumed to be controlled by spleen tyrosine kinase (Syk) signaling in DCs and neutrophils. However, the role of Syk signaling in these immune cells in sepsis-induced AKI has not been investigated. Therefore, the purpose of this study was to evaluate the effect of a Syk inhibitor, R406 on sepsis-induced AKI in a mouse model. Renal function (creatinine/blood urea nitrogen), inflammatory cytokines (IL-6/MCP-1) in CD11c + DCs and oxidant parameters in neutrophils [inducible nitric oxide synthase (iNOS), NADPH oxidase (NOX2), nitrotyrosine] were assessed. Our results showed elevated expression of Syk in neutrophils and CD11c + DC which was linked with increased IL-6/MCP-1 in CD11c + DCs, and iNOS, NOX2 and nitrotyrosine in neutrophils during sepsis-induced AKI. Inhibitor of Syk signaling, R406 led to improvement of sepsis-induced AKI as depicted by an attenuation of creatinine/blood urea nitrogen in serum, renal myeloperoxidase activity, and repair of tubular structures in kidney. Further, R406 led to a decrease in IL-6/MCP-1 in CD11c + DCs, and iNOS, NOX2 and nitrotyrosine in neutrophils during sepsis-induced AKI. In conclusion, our study proposes that Syk signaling in DCs and neutrophils plays a critical role during sepsis-induced AKI. Therefore, Syk inhibition in innate immune cells might serve as an effective strategy to limit inflammatory cascade during AKI.

脓毒症通常会导致并发症，例如急性肾损伤（AKI），据报道在重症患者中其占30％至50％。树突状细胞（DCs）和中性粒细胞分别通过释放炎性细胞因子和活性氧（ROS）在AKI的发展中起决定性作用。假定这两个过程均受DC和嗜中性粒细胞中脾酪氨酸激酶（Syk）信号的控制。但是，尚未研究脓毒症诱发的AKI中Syk信号在这些免疫细胞中的作用。因此，本研究的目的是评估小鼠模型中Syk抑制剂R406对败血症诱导的AKI的作用。肾功能（肌酐/血尿素氮），CD11c + DCs中的炎性细胞因子（IL-6 / MCP-1）和中性粒细胞中的氧化剂参数[诱导型一氧化氮合酶（iNOS），评估了NADPH氧化酶（NOX2），硝基酪氨酸]。我们的结果显示，败血症诱导的AKI期间中性粒细胞和CD11c + DC中Syk的表达升高，这与CD11c + DC中IL-6 / MCP-1的增加以及中性粒细胞中iNOS，NOX2和硝基酪氨酸的增加有关。Syk信号抑制剂R406导致败血症诱导的AKI改善，其表现为血清中肌酐/血液尿素氮的减少，肾髓过氧化物酶活性的降低以及肾小管结构的修复。此外，在败血症诱导的AKI期间，R406导致CD11c + DCs中IL-6 / MCP-1的降低，以及中性粒细胞中iNOS，NOX2和硝基酪氨酸的降低。总之，我们的研究提出DC和嗜中性粒细胞中的Syk信号在败血症诱导的AKI中起关键作用。所以，