Kininogen-1 modulates cGMP-PKG signaling to alleviate inflammatory neuronal injury in intracerebral hemorrhage

IF 4.5 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin Pub Date : 2026-02-01 Epub Date: 2026-01-19 DOI:10.1016/j.brainresbull.2026.111740

Yuan Wang , Jing Zhao , Kaijie Wang , Shuwei Wang , Jie Li , Chaopeng Xu , Haoyu Wang , Jianzhong Cui

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引用次数: 0

Abstract

Objective

Although the pathological mechanisms underlying intracerebral hemorrhage (ICH) have been widely explored, the contribution of kininogen-1 (Kng1) to inflammation-associated neuronal damage has not been fully elucidated. This study was designed to investigate the functional involvement of Kng1 and the cyclic guanosine monophosphate (cGMP)–protein kinase G (PKG) signaling cascade in inflammation-driven neuronal injury following cerebral hemorrhage.

Methods

Bioinformatics analyses based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were employed to identify Kng1 and the cGMP-PKG pathway as key candidates. An in vivo ICH model was generated by intracerebral injection of autologous blood, while an in vitro hemorrhagic injury model was established by treating neuronal cells with hemoglobin chloride. Levels of inflammatory mediators and gene expression were determined using enzyme-linked immunosorbent assay, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, and reverse transcription-quantitative polymerase chain reaction. Neurological impairment and cerebral edema were evaluated through behavioral deficit scoring and brain water content analysis, respectively.

Results

Kng1 protein levels were markedly increased in the serum of patients with ICH as well as in experimental hemorrhage models, and this elevation was closely associated with enhanced neuroinflammatory responses. Suppression of Kng1 expression significantly alleviated neurological dysfunction, reduced cerebral edema, mitigated inflammatory activation, and limited neuronal apoptosis in ICH rats. Further mechanistic investigations demonstrated that Kng1 modulates the cGMP-PKG signaling axis, as pharmacological stimulation of cGMP or PKG reversed the protective effects induced by Kng1 silencing. Consistent findings from both animal and cellular rescue experiments indicated that Kng1 aggravates neuronal injury after ICH by activating cGMP-PKG-dependent inflammatory signaling pathways.

Conclusion

Kng1 regulates the cGMP-PKG signaling pathway, influencing neuronal cell injury induced by the inflammatory response in ICH conditions. These findings suggest Kng1 as a potential therapeutic target for mitigating ICH-induced neuronal damage.

查看原文本刊更多论文

Kininogen-1调节cGMP-PKG信号减轻脑出血炎症性神经元损伤

目的：虽然脑出血（ICH）的病理机制已被广泛探讨，但kininogen-1 （kn1）在炎症相关神经元损伤中的作用尚未完全阐明。本研究旨在探讨kn1和环鸟苷单磷酸(cGMP)-蛋白激酶G （PKG）信号级联在脑出血后炎症驱动的神经元损伤中的功能参与。方法：基于基因本体和京都基因与基因组百科数据库进行生物信息学分析，确定Kng1和cGMP-PKG通路为关键候选者。采用脑内注射自体血建立脑内脑出血模型，用氯化血红蛋白处理神经元细胞建立体外出血性损伤模型。采用酶联免疫吸附法、末端脱氧核苷酸转移酶介导的dUTP镍端标记和逆转录-定量聚合酶链反应来测定炎症介质水平和基因表达。分别通过行为缺陷评分和脑含水量分析评估神经功能损害和脑水肿。结果：脑出血患者及实验性出血模型血清中kn1蛋白水平明显升高，且与神经炎症反应增强密切相关。抑制kn1表达可显著缓解脑出血大鼠神经功能障碍，减轻脑水肿，减轻炎症激活，限制神经元凋亡。进一步的机制研究表明，Kng1调节cGMP-PKG信号轴，因为cGMP或PKG的药理刺激逆转了Kng1沉默诱导的保护作用。动物和细胞救援实验的一致结果表明，kn1通过激活cgmp - pkg依赖性炎症信号通路加重脑出血后的神经元损伤。结论：Kng1调节cGMP-PKG信号通路，影响ICH炎症反应诱导的神经元细胞损伤。这些发现表明kn1是减轻ich诱导的神经元损伤的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Brain Research Bulletin 医学-神经科学

CiteScore

6.90

自引率

2.60%

发文量

253

审稿时长

67 days

期刊介绍： The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.