Inhaled gold nanoparticles cause cerebral edema and upregulate endothelial aquaporin 1 expression, involving caveolin 1 dependent repression of extracellular regulated protein kinase activity

Abstract

BackgroundGold 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.ResultsWe 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.ConclusionsThese data suggest that the subacute exposure of nanoparticles might induce cerebral edema, involving the Cav1 dependent accumulation on endothelial AQP1.

Gold nanoparticles alleviates the lipopolysaccharide-induced intestinal epithelial barrier dysfunction

“…Previous studies indicated that AuNPs alleviate inflammatory response and tight junction proteins via several signaling pathways including the NF-κB and ERK/JNK pathways [23,[39][40][41]. In detail, AuNPs protected against Aβ-induced neuroinflammation and neurodegeneration by targeting the NF-κB/JNK/glycogen synthase kinase 3β (GSK3β) signaling pathway [39].…”

Plasma TNFRSF11B as a New Predictive Inflammatory Marker of Sepsis–ARDS with Endothelial Dysfunction

“…Downregulation of AQP-1 expression leads to aggravation of edema, whereas upregulation of AQP-1 expression alleviates acute pulmonary edema . Chen et al demonstrated that gold nanoparticle-mediated AQP-1 induction is dependent on caveolin-1, but it requires the repression of ERK activity …”

“…9 Chen et al demonstrated that gold nanoparticle-mediated AQP-1 induction is dependent on caveolin-1, but it requires the repression of ERK activity. 10 Intercellular transport mediated by tight, adherent, and gap junctions is the main mechanism for endothelial intercellular permeability. Occludin, claudin-5, and zonula occludens 1 (ZO-1) are the key components of a tight junction; the downregulation of the tight-junction protein regulated inflammatory signal transduction and lung endothelial permeability during lung injury.…”

“… 9 Chen et al demonstrated that gold nanoparticle-mediated AQP-1 induction is dependent on caveolin-1, but it requires the repression of ERK activity. 10 …”

Neurotoxicity of Engineered Nanomaterials: Testing Considerations

“…Neurotoxicological studies with ENM in rodents have been performed with the most widely produced and used materials like Ag, SiO 2 , TiO 2 , CeO 2 , ZnO and carbon black. However, also less common materials have been studied like gold, quantum dots or iridium nanoparticles (11)(12)(13).…”