Gold nanoparticles (Au-NPs) have extensive applications in electronics and biomedicine, resulting in increased exposure and prompting safety concerns for human health. After absorption, nanoparticles enter circulation and effect endothelial cells. We previously showed that exposure to Au-NPs (40–50 nm) collapsed endothelial tight junctions and increased their paracellular permeability. Inhaled nanoparticles have gained significant attention due to their biodistribution in the brain; however, little is known regarding their role in cerebral edema. The present study investigated the expression of aquaporin 1 (AQP1) in the cerebral endothelial cell line, bEnd.3, stimulated by Au-NPs. We found that treatment with Au-NPs induced AQP1 expression and increased endothelial permeability to water. Au-NP exposure rapidly boosted the phosphorylation levels of focal adhesion kinase (FAK) and AKT, increased the accumulation of caveolin 1 (Cav1), and reduced the activity of extracellular regulated protein kinases (ERK). The inhibition of AKT (GDC-0068) or FAK (PF-573228) not only rescued ERK activity but also prevented AQP1 induction, whereas Au-NP-mediated Cav1 accumulation remained unaltered. Neither these signaling molecules nor AQP1 expression responded to Au-NPs while Cav1 was silenced. Inhibition of ERK activity (U0126) remarkably enhanced Cav1 and AQP1 expression in bEnd.3 cells. These data demonstrate that Au-NP-mediated AQP1 induction is Cav1 dependent, but requires the repression on ERK activity. Mice receiving intranasally administered Au-NPs displayed cerebral edema, significantly augmented AQP1 protein levels; furthermore, mild focal lesions were observed in the cerebral parenchyma. These data suggest that the subacute exposure of nanoparticles might induce cerebral edema, involving the Cav1 dependent accumulation on endothelial AQP1.

中文翻译：

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吸入的金纳米颗粒引起脑水肿并上调内皮水通道蛋白1的表达，涉及小窝蛋白1依赖性的细胞外调节蛋白激酶活性的抑制。

金纳米颗粒（Au-NPs）在电子和生物医学中具有广泛的应用，导致暴露量增加并引发对人类健康的安全隐患。吸收后，纳米颗粒进入循环并影响内皮细胞。我们以前的研究表明，暴露于Au-NPs（40–50 nm）会使内皮紧密连接塌陷并增加其细胞旁通透性。吸入的纳米颗粒由于其在大脑中的生物分布而备受关注。然而，关于它们在脑水肿中的作用鲜为人知。本研究调查了水通道蛋白1（AQP1）在Au-NPs刺激的脑内皮细胞系bEnd.3中的表达。我们发现用Au-NPs处理可诱导AQP1表达并增加内皮对水的通透性。Au-NP暴露迅速提高了粘着斑激酶（FAK）和AKT的磷酸化水平，增加了小窝蛋白1（Cav1）的积累，并降低了细胞外调节蛋白激酶（ERK）的活性。抑制AKT（GDC-0068）或FAK（PF-573228）不仅可以挽救ERK活性，而且可以阻止AQP1诱导，而Au-NP介导的Cav1积累仍然没有改变。当Cav1沉默时，这些信号分子和AQP1表达均未响应Au-NP。抑制ERK活性（U0126）显着增强bEnd.3细胞中Cav1和AQP1的表达。这些数据表明Au-NP介导的AQP1诱导是Cav1依赖性的，但需要抑制ERK活性。接受鼻内给药的Au-NPs的小鼠表现出脑水肿，显着增加了AQP1蛋白水平。此外，在脑实质中观察到轻度局灶性病变。这些数据表明，纳米粒子的亚急性暴露可能诱发脑水肿，涉及内皮AQP1上Cav1依赖性积累。