Bruton's tyrosine kinase inhibition attenuates oxidative stress in systemic immune cells and renal compartment during sepsis-induced acute kidney injury in mice

Sepsis is a life-threatening condition which affects multiple organs including the kidney. Sepsis-induced acute kidney injury (AKI) is a major health burden throughout the globe. Pathogenesis of sepsis-induced AKI is complex; however, it involves both innate and adaptive immune cells such as B cells, T cells, dendritic cells (DCs), macrophages, and neutrophils. Bruton's tyrosine kinase (BTK) is reportedly involved in inflammatory and oxidative signaling in different immune cells, however its contribution with respect to sepsis-induced AKI has not been delineated. This study attempted to investigate the role of BTK and its inhibition on oxidizing enzymes NADPH oxidase (NOX-2) and inducible nitric oxide synthase (iNOS) in DCs, neutrophils, and B cells during AKI. Our data reveal that BTK is activated in DCs, neutrophils, and B cells which causes an increase in AKI associated biochemical markers such as serum creatinine/blood urea nitrogen, renal myeloperoxidase activity, and histopathological disturbances in renal tubular structures. Activation of BTK causes upregulation of NOX-2/iNOS/ nitrotyrosine in these immune cells and kidney. Treatment with BTK inhibitor, Ibrutinib causes attenuation in AKI associated dysfunction in biochemical parameters (serum creatinine/blood urea nitrogen, renal myeloperoxidase activity) and oxidative stress in immune cells and kidney (iNOS/NOX2/lipid peroxides/nitrotyrosine/ protein carbonyls). In summary, the current investigation reveals a compelling role of BTK signaling in sepsis induced AKI which is evident from amelioration of AKI associated renal dysfunction after its inhibition.

Automated summary

Sepsis-induced acute kidney injury (AKI) is a significant global health burden, involving complex pathogenesis with various immune cells. This study investigated the role of Bruton's tyrosine kinase (BTK) in different immune cells during AKI and found that its activation contributed to AKI associated biochemical markers. Inhibition of BTK with Ibrutinib attenuated AKI associated dysfunction and oxidative stress in immune cells and the kidney, highlighting the potential of BTK signaling as a therapeutic target for sepsis-induced AKI.