Peficitinib halts acute kidney injury via JAK/STAT3 and growth factors immunomodulation

• Published in: European journal of pharmacology 2024-12, Vol.984, p.177020, Article 177020
• Main Authors: Ibrahim, Hassnaa, Sharawy, Maha H., Hamed, Mohamed F., Abu-Elsaad, Nashwa
• Format: Article
• Language: English
• Subjects: Acute kidney injury; Acute Kidney Injury - chemically induced; Acute Kidney Injury - drug therapy; Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Animals; Cytokines - metabolism; Immunomodulation - drug effects; Intercellular Signaling Peptides and Proteins - metabolism; JAK/STAT; Janus kinase; Janus Kinase Inhibitors - pharmacology; Janus Kinase Inhibitors - therapeutic use; Janus Kinases - metabolism; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Male; Mice; Niacinamide - pharmacology; Oxidative Stress - drug effects; Peficitinib; pSTAT3; Signal Transduction - drug effects; STAT3 Transcription Factor - metabolism; VEGF
• ISSN: 0014-2999; 1879-0712; 1879-0712
• DOI: 10.1016/j.ejphar.2024.177020

Acute Kidney Injury (AKI) is characterized by a sudden loss of kidney function and its management continues to be a challenge. In this study the effect of peficitinib, a Janus kinase inhibitor (JAKi), was studied in an aim to stop the progression of AKI at an early point of injury. Adult male mice were injected with aristolochic acid (AA) a single dose (10 mg/kg, i.p) to induce AKI. Peficitinib was injected in one of the two tested doses (5 or 10 mg/kg, i.p) 1 h after AA injection and was continued daily for seven days. Histopathological evaluation showed that peficitinib alleviated necrosis and hyaline cast formation induced by aristolochic acid. It decreased serum creatinine and the kidney injury molecule-1 (KIM-1) elevated by AA. Peficitinib also mitigated AA induced oxidative stress through regulating total antioxidant capacity (TAC) and reduced glutathione (GSH) level in renal tissue. Additionally, renal sections isolated from groups that received peficitinib revealed a decrease in vascular endothelial growth factor receptor 1 interstitial expression and transforming growth factor-beta 1 (TGF-β1) renal level. Peficitinib received groups showed a decrease in the active phosphorylated form of signal transducers and activators of transcription (STAT3). Moreover, peficitinib decreased renal protein levels and gene expression of the pro-inflammatory cytokines; interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and interferon gamma (IFN-γ). These findings suggest that peficitinib is helpful in halting AKI progression into chronic kidney disease through modulating JAK/STAT3 dependent inflammatory pathways and growth factors involved in normal glomerular function. •Peficitinib improves AKI outcomes by abating oxidative stress.•Peficitinib regulates TGF-β1 and VEGFR1 mediated normal glomerular function.•Peficitinib immunomodulates JAK/STAT dependent inflammatory cytokines cascade.