Advanced glycation end products increase endothelial permeability through the RAGE/Rho signaling pathway.
Although increased vascular permeability is known to be a major characteristic of diabetic vasculopathy, the precise mechanisms and relevance of advanced glycation end products (AGE) to hyperpermeability of vessels remains unclear. Here, we studied changes in cytoskeletal configuration and the signaling mechanism induced by AGE in human endothelial cells. AGE-BSA stimulation induced Rho activation, intercellular gap formation, prominent actin stress fiber and cell contraction without changing VE-cadherin, and subsequently transendothelial diffusion of FITC-labeled dextran. These processes induced by AGE-BSA were inhibited by either Rho-kinase inhibitor Y27632 or anti-RAGE antibody. We also showed that RhoA and RAGE spontaneously formed a complex. These findings suggest that activation of RAGE/Rho is involved in AGE-BSA-induced hyperpermeability through gap formation and actin reorganization in diabetes.
Hirose
Akiko
A
First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushyu, Japan.
Tanikawa
Takahisa
T
Mori
Hiroko
H
Okada
Yosuke
Y
Tanaka
Yoshiya
Y
D000199:Actins / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D002199:Capillary Permeability; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D011725:Pyridines / Q000494:pharmacology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000378:metabolism*; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000199:Actins; D000577:Amides; D017127:Glycation End Products, Advanced; D011725:Pyridines; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C081628:advanced glycation end products-bovine serum albumin; C066737:RHOA protein, human; C108830:Y 27632; D012710:Serum Albumin, Bovine; D020742:rhoA GTP-Binding Protein