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.

Abstract

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-γ, and reactive oxygen metabolites. Adaptive immune cells, especially T cells also participate in the amplification of renal inflammation through release of pro-inflammatory cytokines such as IL-17A, IFN-γ, TNF-α, 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 PLCγ, 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 (PLCγ, STAT3, NFkB, and NFATc1), Th1/Th2/Treg cell markers (IL-17A, TNF-α, 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.

• Authors: Ahmed Nadeem, Sheikh F Ahmad, Naif O Al-Harbi, Khalid E Ibrahim, Wedad Sarawi, Sabry M Attia, Abdullah F Alasmari, Saleh A Alqarni, Ali S Alfradan, Saleh A Bakheet, Mohammad M Al-Harbi
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 99 Pg. 108028 (Oct 2021) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 34365077 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• Protein-Tyrosine Kinases
• emt protein-tyrosine kinase

Topics

• Acute Kidney Injury (immunology, prevention & control)
• Animals
• CD4-Positive T-Lymphocytes (drug effects, immunology, metabolism)
• Disease Models, Animal
• Humans
• Male
• Mice
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Sepsis (complications, drug therapy, immunology)
• Signal Transduction (drug effects, immunology)
• Th1 Cells (drug effects, immunology, metabolism)
• Th17 Cells (drug effects, immunology, metabolism)