Gold Nanoparticles Increase Endothelial Paracellular Permeability by Altering Components of Endothelial Tight Junctions, and Increase Blood-Brain Barrier Permeability in Mice.
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.
*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.
Ching-Hao
CH
Li
Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan;
Ming-Kwang
MK
Shyu
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan;
Cheng
C
Jhan
School of Pharmacy, Taipei Medicine University, Taipei, Taiwan;
Yu-Wen
YW
Cheng
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan;
Chi-Hao
CH
Tsai
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan;
Chen-Wei
CW
Liu
Department of Microbiology and Immunology, School of Medicine, China Medicine University, Taichung, Taiwan;
Chen-Chen
CC
Lee
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.
Ruei-Ming
RM
Chen
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan; jjkang@ntu.edu.tw.
Jaw-Jou
JJ
Kang
D000818:Animals; D001812:Blood-Brain Barrier / Q000166:cytology / Q000187:drug effects*; D002199:Capillary Permeability / Q000187:drug effects*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004337:Drug Carriers; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006046:Gold / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D008297:Male; D053768:Metal Nanoparticles / Q000633:toxicity* / Q000648:ultrastructure; D008813:Mice, Inbred ICR; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010316:Particle Size; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D062725:Tight Junction Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects* / Q000378:metabolism; D066007:Toxicokinetics; D000099221:Protein Kinase C zeta
D004337:Drug Carriers; D006046:Gold; D009419:Nerve Tissue Proteins; D046988:Proteasome Endopeptidase Complex; D011493:Protein Kinase C; D062725:Tight Junction Proteins; D000099221:Protein Kinase C zeta
blood-brain barrier; endothelial barrier; paracellular permeability; protein kinase C zeta (PKCζ); tight junction