Fatty acid-binding protein 4 is a therapeutic target for septic acute kidney injury by regulating inflammatory response and cell apoptosis

• Main Authors: Cheng, L. (Author), Fu, P. (Author), Guo, F. (Author), Liang, Y. (Author), Ma, L. (Author), Ren, Q. (Author), Tan, Z. (Author), Wang, B. (Author), Xu, J. (Author), Yang, L. (Author)
• Format: Article
• Language: English
• Published: Springer Nature 2022
• Subjects: acute kidney failure; Acute Kidney Injury; animal; Animals; apoptosis; Apoptosis; fatty acid binding protein; Fatty Acid-Binding Proteins; genetics; inflammation; Inflammation; lipopolysaccharide; Lipopolysaccharides; metabolism; Mice; mouse; sepsis; Sepsis; toll like receptor 4; Toll-Like Receptor 4
• Online Access: View Fulltext in Publisher

 Sepsis is a systemic inflammatory state in response to infection, and concomitant acute kidney injury (AKI) significantly increases morbidity and mortality. Growing evidence suggests that fatty acid-binding protein 4 (FABP4) is critically involved in kidney diseases, while its role in septic AKI remains unknown. Here, FABP4 was mainly upregulated in renal tubular epithelial cells (RTECs) following cecal ligation and puncture (CLP)- or lipopolysaccharide (LPS)-induced septic AKI. FABP4 inhibition by genetic deletion or BMS309403 treatment both attenuated kidney dysfunction and pathological injury in CLP- or LPS-treated mice. Notably, RTEC-specific deletion of FABP4 also showed similar renoprotective effects. Moreover, FABP4 inhibition alleviated inflammation and apoptosis in CLP-injured kidneys and LPS-stimulated mouse tubular epithelial cells. Mechanistically, TLR4 blockage improved sepsis-induced kidney injury, as well as suppressed c-Jun phosphorylation and FABP4 expression, where c-Jun knockdown also inhibited LPS-stimulated FABP4 level. Meanwhile, FABP4 inhibition reduced the elevated phosphorylated c-Jun, while the levels of TLR4 and MyD88 were uninfluenced. Collectively, the increased FABP4 in RTECs is dependent on TLR4/c-Jun signaling activation and contributes to kidney injury, by forming a positive feedback loop with c-Jun to aggravate inflammation and apoptosis in septic AKI. Thus, FABP4 may be a therapeutic target for septic AKI. © 2022, The Author(s).