The Receptor for Advanced Glycation End-Products (RAGE) Is Only Present in Mammals, and Belongs to a Family of Cell Adhesion Molecules (CAMs)

Parasitic helminths can reside in humans owing to their ability to disrupt host protective immunity. Receptor for advanced glycation end products (RAGE), which is highly expressed in host skin, mediates inflammatory responses by regulating the expression of pro-inflammatory cytokines and endothelial adhesion molecules. In this study, we evaluated the effects of venestatin, an EF-hand Ca2+-binding protein secreted by the parasitic helminth Strongyloides venezuelensis, on RAGE activity and immune responses. Our results demonstrated that venestatin bound to RAGE and downregulated the host immune response. Recombinant venestatin predominantly bound to the RAGE C1 domain in a Ca2+-dependent manner. Recombinant venestatin effectively alleviated RAGE-mediated inflammation, including footpad edema in mice, and pneumonia induced by an exogenous RAGE ligand. Infection experiments using S. venezuelensis larvae and venestatin silencing via RNA interference revealed that endogenous venestatin promoted larval migration from the skin to the lungs in a RAGE-dependent manner. Moreover, endogenous venestatin suppressed macrophage and neutrophil accumulation around larvae. Although the invasion of larvae upregulated the abundance of RAGE ligands in host skin tissues, mRNA expression levels of tumor necrosis factor-α, cyclooxygenase-2, endothelial adhesion molecules vascular cell adhesion protein-1, intracellular adhesion molecule-1, and E-selectin were suppressed by endogenous venestatin. Taken together, our results indicate that venestatin suppressed RAGE-mediated immune responses in host skin induced by helminthic infection, thereby promoting larval migration. The anti-inflammatory mechanism of venestatin may be targeted for the development of anthelminthics and immunosuppressive agents for the treatment of RAGE-mediated inflammatory diseases.

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Relationship between vascular cell adhesion molecule-1 (VCAM-1), soluble receptor for advanced glycation end products (sRAGE) and functional hemodynamic parameters of arteriovenous fistula

The Journal of Vascular Access ◽

10.1177/1129729820976264 ◽

2020 ◽

pp. 112972982097626

Author(s):

Maria Ticala ◽

Crina Claudia Rusu ◽

Diana Moldovan ◽

Alina Ramona Potra ◽

Dacian Calin Tirinescu ◽

...

Keyword(s):

Cell Adhesion ◽

Arteriovenous Fistula ◽

Advanced Glycation End Products ◽

Cell Adhesion Molecule ◽

Soluble Receptor ◽

Vascular Cell Adhesion ◽

Advanced Glycation ◽

Vascular Cell ◽

Glycation End Products ◽

End Products

Background: The preferred vascular access for hemodialysis is represented by arteriovenous fistula (AVF) due to fewer complications and more prolonged survival. Considerable efforts have been made to identify biomarkers associated with AVF dysfunction, but results are conflicting. Vascular cell adhesion molecule (VCAM-1) and advanced glycation end products are involved in atherogenesis, vascular calcification, peripheral artery disease, and neointimal hyperplasia in renal and non-renal patients. The objective of this study was to evaluate whether there is an association between VCAM-1, soluble receptor for advanced glycation end products (sRAGE), NcarboxymethylLysine (CML), and arteriovenous fistula dysfunction (AVF). Methods: VCAM-1, sRAGE, and CML were performed using the ELISA technique in 88 HD patients. Ultrasound assessment of AVF reports brachial artery blood flow (Qa), brachial resistivity index (RI), presence of calcification, and the diameter. AVF dysfunction was defined as a brachial artery Qa ⩽ 500 ml/min or RI ⩾ 0.5. Results: The median level of VCAM-1 [2676.5(2206.8–4203.9) versus 2613.2(1885.7–3161.8), p 0.026] was significantly higher in patients with AVF dysfunction compared to the rest of the patients. sRAGE and CML were higher in this group but without statistical significance. In patients with AVF dysfunction, significant positive correlations were found between VCAM-1and sRAGE ( r = 0.417, p = 0.001), RI ( r = 0.313, p = 0.046), dialysis vintage ( r = 0.540, p < 0.001), AVF vintage ( r = 0.336, p = 0.032), intima-media thickness ( r = 0.423, p = 0.006) and C-reactive protein ( r = 0.315, p = 0.045). VCAM-1 correlated inversely with cholesterol ( r = −0.312, p = 0.047), triglycerides ( r = −0.358, p = 0.021), body mass index ( r = −0.388, p = 0.012). In multivariate regression analysis, VCAM-1 ( p = 0.013) and sRAGE ( p = 0.01) remained significant predictors of RI and Qa. Logistic regression disclosed calcification, VCAM-1, as risks factors for AVF dysfunction. Conclusion: The results we obtained showed that patients with AVF dysfunction had a significantly higher level of VCAM-l. A positive correlation between VCAM-1 and sRAGE was identified in this group.

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Inhibition of Homophilic Interactions and Ligand Binding of the Receptor for Advanced Glycation End Products by Heparin and Heparin-Related Carbohydrate Structures

Medicines ◽

10.3390/medicines5030079 ◽

2018 ◽

Vol 5 (3) ◽

pp. 79 ◽

Cited By ~ 1

Author(s):

Ari Rouhiainen ◽

Niko-Petteri Nykänen ◽

Juha Kuja-Panula ◽

Päivi Vanttola ◽

Henri Huttunen ◽

...

Keyword(s):

Cell Adhesion ◽

Cell Surface ◽

Ligand Binding ◽

Advanced Glycation End Products ◽

Living Cell ◽

Cell Protein ◽

Adhesion Assay ◽

Advanced Glycation ◽

Glycation End Products ◽

End Products

Background: Heparin and heparin-related sulphated carbohydrates inhibit ligand binding of the receptor for advanced glycation end products (RAGE). Here, we have studied the ability of heparin to inhibit homophilic interactions of RAGE in living cells and studied how heparin related structures interfere with RAGE–ligand interactions. Methods: Homophilic interactions of RAGE were studied with bead aggregation and living cell protein-fragment complementation assays. Ligand binding was analyzed with microwell binding and chromatographic assays. Cell surface advanced glycation end product binding to RAGE was studied using PC3 cell adhesion assay. Results: Homophilic binding of RAGE was mediated by V1- and modulated by C2-domain in bead aggregation assay. Dimerisation of RAGE on the living cell surface was inhibited by heparin. Sulphated K5 carbohydrate fragments inhibited RAGE binding to amyloid β-peptide and HMGB1. The inhibition was dependent on the level of sulfation and the length of the carbohydrate backbone. α-d-Glucopyranosiduronic acid (glycyrrhizin) inhibited RAGE binding to advanced glycation end products in PC3 cell adhesion and protein binding assays. Further, glycyrrhizin inhibited HMGB1 and HMGB1 A-box binding to heparin. Conclusions: Our results show that K5 polysaccharides and glycyrrhizin are promising candidates for RAGE targeting drug development.

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