Advanced glycation end products induce actin rearrangement and subsequent hyperpermeability of endothelial cells
Guo XH, Huang QB, Chen B, Wang SY, Li Q, Zhu YJ, Hou FF, Fu N, Brunk UT, Zhao M. Advanced glycation end products induce actin rearrangement and subsequent hyperpermeability in endothelial cells. APMIS 2006;114:874–83.
This study aimed to determine the effects of advanced glycation end products (AGEs) on endothelial cytoskeleton morphology and permeability, and to detect the underlying signaling mechanisms involved in these responses. Cultured endothelial cells (ECs) were exposed to AGE-modified human serum albumin (AGE-HSA), and EC cytoskeletal changes were evaluated by observing fluorescence of F-actin following ligation with labeled antibodies. Endothelial permeability was detected by measuring the flux of TRITC-albumin across the EC monolayers. To explore the signaling pathways behind AGE-induced EC alteration, ECs were treated with either soluble anti-AGE receptor (RAGE) IgG, or the MAPK inhibitors PD98059 and SB203580 before AGE-HSA administration. To further elucidate possible involvement of the ERK and p38 pathways in AGE-induced EC changes, adenovirus-carried recombinant constitutive dominant-negative forms of upstream ERK and p38 kinases, namely MEK1(A) and MKK6b(A), were pre-infected into ECs 24 h prior to AGE-HSA exposure. AGE-HSA induced actin cytoskeleton rearrangement, as well as EC hyperpermeability, in a dose and time-dependent manner. The effects were attenuated in cells pretreated with anti-RAGE IgG, PD98059 or SB203580, respectively. EC pre-infection with MEK1(A) and MKK6b(A) also alleviated the effect of AGEs. Furthermore, adenovirus-mediated administration of activated forms of either MEK1 or MKK6b alone induced rearrangement of F-actin and hyperpermeability. The results indicate that ERK and p38 MAPK play important roles in the mediation of AGE-induced EC barrier dysfunction associated with morphological changes of the F-actin.
Advanced glycation end products (AGEs);
Document Type: Research Article
Nephrology (Nanfang Hospital),
Immunology, Southern Medical University, Guangzhou, P. R. China
Division of Pharmacology, Faculty of Health Sciences, Linkoping University, Linkoping,
Division of Medical Inflammation Research, Department of Cell and Molecular Biology, Lund University, Lund, Sweden
Publication date: December 1, 2006
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BRUNK, ULF T.