Gold nanoparticles increase endothelial paracellular permeability by altering components of endothelial tight junctions, and increase blood-brain barrier permeability in mice

Ching Hao Li, Ming Kwang Shyu, Cheng Jhan, Yu Wen Cheng, Chi Hao Tsai, Chen Wei Liu, Chen Chen Lee, Ruei Ming Chen, Jaw Jou Kang

Research output: Contribution to journalArticle

38 Citations (Scopus)

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 PKζ-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.

Original languageEnglish
Article numberkfv176
Pages (from-to)192-203
Number of pages12
JournalToxicological Sciences
Volume148
Issue number1
DOIs
Publication statusPublished - Nov 1 2015

Keywords

  • blood-brain barrier
  • Endothelial barrier
  • paracellular permeability
  • protein kinase C zeta (PKCζ)
  • tight junction

ASJC Scopus subject areas

  • Toxicology

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