{"title":"佩非替尼通过 JAK/STAT3 和生长因子免疫调节阻止急性肾损伤","authors":"","doi":"10.1016/j.ejphar.2024.177020","DOIUrl":null,"url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":null,"pages":null},"PeriodicalIF":4.2000,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Peficitinib halts acute kidney injury via JAK/STAT3 and growth factors immunomodulation\",\"authors\":\"\",\"doi\":\"10.1016/j.ejphar.2024.177020\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>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.</div></div>\",\"PeriodicalId\":12004,\"journal\":{\"name\":\"European journal of pharmacology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.2000,\"publicationDate\":\"2024-09-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European journal of pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0014299924007106\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European journal of pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0014299924007106","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
摘要
急性肾损伤(AKI)的特点是肾功能突然丧失,其治疗仍然是一项挑战。本研究对 Janus 激酶抑制剂(JAKi)peficitinib 的作用进行了研究,旨在早期阻止 AKI 的恶化。成年雄性小鼠单剂量(10 毫克/千克,静脉注射)注射马兜铃酸(AA)诱导 AKI。在注射马兜铃酸一小时后,以两种测试剂量之一(5或10毫克/千克,静注)注射培非替尼,并每天持续注射七天。组织病理学评估显示,培非替尼减轻了马兜铃酸诱导的坏死和透明铸模的形成。它还降低了血清肌酐和 AA 引起的肾损伤分子-1(KIM-1)升高。培非替尼还能通过调节肾组织中的总抗氧化能力(TAC)和还原型谷胱甘肽(GSH)水平,减轻马兜铃酸诱导的氧化应激。此外,从接受培非替尼治疗组分离的肾脏切片显示,血管内皮生长因子受体1间质表达和肾脏转化生长因子-β1(TGF-β1)水平有所下降。接受培非替尼治疗的小组显示,信号转导和转录激活因子(STAT3)的活性磷酸化形式有所减少。此外,培非替尼还能降低肾脏蛋白水平和促炎细胞因子(白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)和γ干扰素(IFN-γ))的基因表达。这些研究结果表明,peficitinib 通过调节 JAK/STAT3 依赖性炎症通路和参与肾小球正常功能的生长因子,有助于阻止 AKI 向慢性肾病发展。
Peficitinib halts acute kidney injury via JAK/STAT3 and growth factors immunomodulation
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.
期刊介绍:
The European Journal of Pharmacology publishes research papers covering all aspects of experimental pharmacology with focus on the mechanism of action of structurally identified compounds affecting biological systems.
The scope includes:
Behavioural pharmacology
Neuropharmacology and analgesia
Cardiovascular pharmacology
Pulmonary, gastrointestinal and urogenital pharmacology
Endocrine pharmacology
Immunopharmacology and inflammation
Molecular and cellular pharmacology
Regenerative pharmacology
Biologicals and biotherapeutics
Translational pharmacology
Nutriceutical pharmacology.