Pharmacology and Toxicology Department, Faculty of Pharmacy, Mansoura University, Mansoura, 33516, Egypt; Pharmacist at Urology and Nephrology Center, Mansoura University, Mansoura, 33516, Egypt.
Pharmacology and Toxicology Department, Faculty of Pharmacy, Mansoura University, Mansoura, 33516, Egypt.
Eur J Pharmacol. 2024 Dec 5;984:177020. doi: 10.1016/j.ejphar.2024.177020. Epub 2024 Sep 28.
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.
急性肾损伤（AKI）的特征是肾功能突然丧失，其治疗仍然是一个挑战。在这项研究中，研究了一种 Janus 激酶抑制剂（JAKi）——培非替尼，旨在在损伤早期阻止 AKI 的进展。成年雄性小鼠单次腹腔注射马兜铃酸（AA，10mg/kg）诱导 AKI。培非替尼以两种测试剂量（5 或 10mg/kg，腹腔注射）中的一种在 AA 注射后 1 小时注射，并持续 7 天。组织病理学评估表明，培非替尼减轻了马兜铃酸诱导的坏死和透明样铸型形成。它降低了血清肌酐和 AA 升高的肾损伤分子-1（KIM-1）。培非替尼还通过调节组织中的总抗氧化能力（TAC）和还原型谷胱甘肽（GSH）水平来减轻 AA 诱导的氧化应激。此外，从接受培非替尼治疗的组中分离出的肾切片显示血管内皮生长因子受体 1 间质表达和转化生长因子-β1（TGF-β1）肾水平降低。培非替尼治疗组的信号转导和转录激活因子（STAT3）的活性磷酸化形式减少。此外，培非替尼降低了肾组织中促炎细胞因子白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）和干扰素-γ（IFN-γ）的蛋白水平和基因表达。这些发现表明，培非替尼通过调节 JAK/STAT3 依赖性炎症途径和参与正常肾小球功能的生长因子，有助于阻止 AKI 进展为慢性肾脏病。
