Role of ITK signaling in acute kidney injury in mice: Amelioration of acute kidney injury associated clinical parameters and attenuation of inflammatory transcription factor signaling in CD4+T cells by ITK inhibition

Acute kidney injury (AKI) is a world-wide health problem and linked with increased risk of morbidity/mortality in hospitalized patients and its incidence has been on the rise in the last few decades. AKI is characterized by renal tubular injury which results from interactions between bacterial products and host immune responses which manifests as a rapid deterioration in renal function. Immune system dysfunction induced by sepsis plays a crucial role in AKI through activation of multiple immune cells of both innate and adaptive origin. These cells release pro-inflammatory cytokines such as IL-6, IL-17A, IFN-gamma, and reactive oxygen metabolites. Adaptive immune cells, especially T cells also participate in the amplification of renal inflammation through release of proinflammatory cytokines such as IL-17A, IFN-gamma, TNF-alpha, and IL-10. Non-receptor protein tyrosine kinases such as ITK play crucial role in T cell through modulation of key downstream molecules such as PLC gamma, STAT3, NFkB, NFATc1, and p-38MAPK. However, it has not been explored in CD4+ T cells during AKI. Therefore, this study investigated the effect of ITK inhibitor on AKI linked clinical parameters (serum BUN, creatinine and renal histopathology), downstream signaling molecules in CD4+ T cells (PLC gamma, STAT3, NFkB, and NFATc1), Th1/Th2/ Treg cell markers (IL-17A, TNF-alpha, and IL-10), and neutrophil-mediated oxidative inflammation (MPO/carbonyl/ nitrotyrosine formation) in mice. Our data exhibit elevated p-ITK levels in CD4+ T cells which is associated with renal dysfunction and elevated Th1/Th17/neutrophilic responses. Blockade of ITK signaling resulted in ameliorated of AKI associated biochemical; parameters through downregulation in transcription signaling in CD4+ T cells and Th1/Th17 immune responses. Therefore, this report suggests that ITK inhibition could be an effective strategy to halt renal dysfunction associated with AKI.

Automated summary

Acute kidney injury (AKI) is a global health issue with increasing incidence, mainly due to renal tubular injury causing rapid deterioration of renal function. Immune system dysfunction induced by sepsis plays a key role in AKI, releasing pro-inflammatory cytokines and leading to renal inflammation. Inhibition of ITK signaling may be an effective strategy to prevent renal dysfunction associated with AKI.