title: Negatively charged silver nanoparticles cause retinal vascular permeability by activating plasma contact system and disrupting adherens junction.
abstract: Silver nanoparticles (AgNPs) have been extensively used as antibacterial component in numerous healthcare, biomedical and consumer products. Therefore, their adverse effects to biological systems have become a major concern. AgNPs have been shown to be absorbed into circulation and redistributed into various organs. It is thus of great importance to understand how these nanoparticles affect vascular permeability and uncover the underlying molecular mechanisms. A negatively charged mecaptoundeonic acid-capped silver nanoparticle (MUA@AgNP) was investigated in this work. Ex vivo experiments in mouse plasma revealed that MUA@AgNPs caused plasma prekallikrein cleavage, while positively charged or neutral AgNPs, as well as Ag ions had no effect. In vitro tests revealed that MUA@AgNPs activated the plasma kallikrein-kinin system (KKS) by triggering Hageman factor autoactivation. By using specific inhibitors aprotinin and HOE 140, we demonstrated that KKS activation caused the release of bradykinin, which activated B2 receptors and induced the shedding of adherens junction protein, VE-cadherin. These biological perturbations eventually resulted in endothelial paracellular permeability in mouse retina after intravitreal injection of MUA@AgNPs. The findings from this work provided key insights for toxicity modulation and biomedical applications of AgNPs.
authors.affiliation: a State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing , China .|b Institute of Environment and Health, Jianghan University , Wuhan , China .
authors.forename: Yan-Min
authors.initials: YM
authors.lastname: Long
authors.affiliation: a State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing , China .
authors.forename: Xing-Chen
authors.initials: XC
authors.lastname: Zhao
authors.affiliation: c Joslin Diabetes Center, Harvard Medical School , Boston , MA , USA , and.
authors.forename: Allen C
authors.initials: AC
authors.lastname: Clermont
authors.affiliation: a State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing , China .
authors.forename: Qun-Fang
authors.initials: QF
authors.lastname: Zhou
authors.affiliation: a State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing , China .
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: c Joslin Diabetes Center, Harvard Medical School , Boston , MA , USA , and.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Feener
authors.affiliation: d School of Chemistry and Chemical Engineering, Shandong University , Jinan , China.
authors.forename: Bing
authors.initials: B
authors.lastname: Yan
authors.affiliation: a State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing , China .
authors.forename: Gui-Bin
authors.initials: GB
authors.lastname: Jiang
mesh_terms: D022005:Adherens Junctions / Q000187:drug effects*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D007611:Aprotinin / Q000494:pharmacology; D001920:Bradykinin / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005174:Factor XII / Q000378:metabolism; D058449:Intravitreal Injections; D007610:Kallikreins / Q000097:blood; D008297:Male; D053768:Metal Nanoparticles / Q000008:administration & dosage / Q000737:chemistry* / Q000633:toxicity*; D051379:Mice; D010949:Plasma / Q000378:metabolism*; D011288:Prekallikrein / Q000378:metabolism; D012171:Retinal Vessels / Q000187:drug effects*; D012834:Silver / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D007611:Aprotinin; D001920:Bradykinin; D015820:Cadherins; D005174:Factor XII; D007610:Kallikreins; D011288:Prekallikrein; D012834:Silver; D000099152:Cadherin 5; C065679:icatibant
keywords: Cell junction; kallikrein-kinin system; retinal endothelial cell; silver NP; vascular permeability