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Toxicol Sci. 2015 Nov;148(1):192-203. doi: 10.1093/toxsci/kfv176. Epub 2015 Aug 13.

Gold Nanoparticles Increase Endothelial Paracellular Permeability by Altering Components of Endothelial Tight Junctions, and Increase Blood-Brain Barrier Permeability in Mice.

Author information

1
*Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; jjkang@ntu.edu.tw.
2
Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan;
3
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan;
4
School of Pharmacy, Taipei Medicine University, Taipei, Taiwan;
5
Department of Microbiology and Immunology, School of Medicine, China Medicine University, Taichung, Taiwan;
6
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Cell Physiology and Molecular Image Research Center, Taipei Medical University's Wan-Fang Hospital, Taipei, Taiwan; and Anesthetics Toxicology Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
7
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan; jjkang@ntu.edu.tw.

Abstract

Gold nanoparticles (Au-NPs) are being increasingly used as constituents in cosmetics, biosensors, bioimaging, photothermal therapy, and targeted drug delivery. This elevated exposure to Au-NPs poses systemic risks in humans, particularly risks associated with the biodistribution of Au-NPs and their potent interaction with biological barriers. We treated human umbilical vein endothelial cells with Au-NPs and comprehensively examined the expression levels of tight junction (TJ) proteins such as occludin, claudin-5, junctional adhesion molecules, and zonula occludens-1 (ZO-1), as well as endothelial paracellular permeability and the intracellular signaling required for TJ organization. Moreover, we validated the effects of Au-NPs on the integrity of TJs in mouse brain microvascular endothelial cells in vitro and obtained direct evidence of their influence on blood-brain barrier (BBB) permeability in vivo. Treatment with Au-NPs caused a pronounced reduction of PKCζ-dependent threonine phosphorylation of occludin and ZO-1, which resulted in the instability of endothelial TJs and led to proteasome-mediated degradation of TJ components. This impairment in the assembly of TJs between endothelial cells increased the permeability of the transendothelial paracellular passage and the BBB. Au-NPs increased endothelial paracellular permeability in vitro and elevated BBB permeability in vivo. Future studies must investigate the direct and indirect toxicity caused by Au-NP-induced endothelial TJ opening and thereby address the double-edged-sword effect of Au-NPs.

KEYWORDS:

blood-brain barrier; endothelial barrier; paracellular permeability; protein kinase C zeta (PKCζ); tight junction

PMID:
26272951
DOI:
10.1093/toxsci/kfv176
[Indexed for MEDLINE]

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