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.

• Cell junction
• kallikrein-kinin system
• retinal endothelial cell
• silver NP
• vascular permeability

Declaration of interest

This study was jointly supported by the National Basic Research Program of China (2011CB936001), National Natural Science Foundation of China (21137002, 21477153, 21307151) and the China Postdoctoral Science Foundation (2013M541055). The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.

Supplementary material available online

Supplementary Figures S1-S5.