scholarly journals Advanced glycation end products induce endothelial hyperpermeability via β‐catenin phosphorylation and subsequent up‐regulation of ADAM10

2021 ◽  
Author(s):  
Jie Weng ◽  
Zhenfeng Chen ◽  
Jieyu Li ◽  
Qi He ◽  
Deshu Chen ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products ◽  
Endothelial Hyperpermeability

scholarly journals Mdia1 is Crucial for Advanced Glycation End Product-Induced Endothelial Hyperpermeability

2018 ◽  
Vol 45 (4) ◽  
pp. 1717-1730 ◽  
Author(s):  
Xiaoyan Zhou ◽  
Jie Weng ◽  
Jing Xu ◽  
Qiulin Xu ◽  
Weiju Wang ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
Recombinant Adenovirus ◽  
Umbilical Vein ◽  
Critical Role ◽  
Cell Permeability ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products ◽  
Endothelial Hyperpermeability

Background/Aims: Disruption of endothelial barrier integrity in response to advanced glycation end products (AEGs) stimulation contributes to vasculopathy associated with diabetes mellitus. Mammalian diaphanous-related formin (mDia1) has been reported to bind to the cytoplasmic domain of the receptor for advanced glycation end products (RAGE), which induces a series of cellular processes. This study directly evaluated the participation of mDia1 in AGE-induced hyperpermeability and revealed the precise intracellular signal transductions of this pathological process. Methods: Human umbilical vein endothelial cells (HUVECs) were used in the in vitro studies. Trans-endothelial electric resistance and permeability coefficient for dextran (Pd) were measured to analyze cell permeability. Western blotting, immunofluorescence staining and flow cytometry assay were performed to investigate the underlying mechanism. Dextran flux across the mesentery in mice was monitored to investigate in vivo microvascular permeability. Results: we found that AGEs evoked Nox4 membrane translocation, reactive oxygen species production, phosphorylation of Src and VE-cadherin, dissociation of adherens junctions and eventual endothelial hyperpermeability through RAGE-mDia1 binding. Cells overexpressing mDia1 by recombinant adenovirus infection showed stronger cellular responses induced by AGEs. Down-regulation of mDia1 by infection with an adenovirus encoding siRNA or blockade of RAGE-mDia1 binding by transfection with RAGE mutant plasmids into HUVECs abolished these AGE-induced effects. Furthermore, knockdown of mDia1 using an adenovirus or genetical knockout of RAGE in C57 mice rescued AGE-evoked microvascular hyperpermeability. Conclusion: Our study revealed that mDia1 plays a critical role in AGE-induced microvascular hyperpermeability through binding to RAGE.

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