Amelioration of sepsis-induced acute kidney injury through inhibition of inflammatory cytokines and oxidative stress in dendritic cells and neutrophils respectively in mice: Role of spleen tyrosine kinase signaling.
F1., Al-Harbi NO, Nadeem A, Ahmad SF, Alanazi MM, Aldossari AA, Alasmari . 2019
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.
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…
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