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Advanced glycation endproducts link inflammatory cues to upregulation of galectin-1 in diabetic retinopathy.

ABSTRACT: Diabetic retinopathy (DR) is an inflammatory and progressive vaso-occlusive disease resulting in angiogenesis. Galectin-1 is a hypoxia-induced angiogenic factor associated with cancer and proliferative DR. Here we reveal a significant upregulation of galectin-1 in eyes of DR patients along with progression of clinical stages beginning from the pre-ischemic, inflammatory stage with diabetic macular edema, but not in eyes with non-diabetic retinal vascular occlusions. As for its regulatory mechanism unrelated to hypoxia but selective to DR, in vitro galectin-1/LGALS1 expression was shown to increase after application to Müller glial cells with interleukin (IL)-1β, which was induced in monocyte-derived macrophages and microglial cells via toll-like receptor (TLR) 4 signaling stimulated by advanced glycation endproducts (AGE). In vivo inhibition of AGE generation with aminoguanidine, macrophage depletion with clodronate liposomes, and antibody-based blockade of Il-1β and Tlr4 attenuated diabetes-induced retinal Lgals1 expression in mice. Fibrovascular tissues from proliferative DR eyes were immunoreactive for AGE, TRL4 and IL-1β in macrophages, and IL-1β receptor-positive glial cells expressed galectin-1. Therefore, diabetes-induced retinal AGE accumulation was suggested to activate IL-1β-related inflammatory cues in macrophages followed by Müller cells, linking to galectin-1 upregulation in human DR with time. Our data highlight AGE-triggered inflammation as the DR-selective inducer of galectin-1.

SUBMITTER: Kanda A

PROVIDER: S-EPMC5700925 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Dietary Advanced Glycation Endproducts Induce an Inflammatory Response in Human Macrophages in Vitro.

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Project description: Not available

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Effect of benfotiamine on advanced glycation endproducts and markers of endothelial dysfunction and inflammation in diabetic nephropathy.

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| S-EPMC3391239 | biostudies-literature

Methylglyoxal-Derived Advanced Glycation Endproducts Accumulate in Multiple Sclerosis Lesions.

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The receptor for advanced glycation endproducts (RAGE) modulates T cell signaling.

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Beneficial effects of C36, a novel breaker of advanced glycation endproducts cross-links, on the cardiovascular system of diabetic rats.

Project description:Background and purposeAdvanced glycation endproducts (AGE) have been implicated in the pathogenesis of diabetic complications, including diabetic cardiovascular dysfunctions. 3-benzyloxycarbonylmethyl-4-methyl-thiazol-3-ium bromide (C36), a novel AGE breaker, was investigated for its beneficial effects on the cardiovascular system of diabetic rats.Experimental approachThe in vitro breaking abilities of C36 on AGE cross-links formed in vitro and in vivo were assessed. After 4 weeks' treatment with C36, cardiovascular and left ventricular functions in diabetic (streptozotocin-induced) rats were evaluated by haemodynamic studies. Effects of C36 on AGE accumulation, collagen distribution, and fibrosis-associated gene expression were also investigated by biochemical and morphological methods and reverse transcription-PCR, respectively.Key resultsIn vitro, C36 released bovine serum albumin (BSA) from preformed AGE-BSA-collagen complexes and decreased the IgG cross-linked to red blood cell surface (RBC-IgG). In vivo, C36 treatment of diabetic rats resulted in a significant increase in left ventricular systolic pressure and the maximal rate of left ventricular pressure rise and pressure fall, induction in cardiac output and systemic arterial compliance, decrease of total peripheral resistance, reduction of diabetes-induced RBC-IgG content, increase of myocardial and tail tendon collagen solubility, and normalization of collagen type III/I ratio in diabetic rats. In addition, C36 treatment attenuated mRNA levels of diabetes-induced genes, including receptors for AGE, transforming growth factor beta1, connective tissue growth factor, and collagen III.Conclusions and implicationsC36 was an effective breaker of AGE cross-links and had beneficial effects on the cardiovascular system of diabetic rats.

| S-EPMC2189992 | biostudies-literature

Targeting the Receptor for Advanced Glycation Endproducts (RAGE): A Medicinal Chemistry Perspective.

Project description:The receptor for advanced glycation endproducts (RAGE) is an ubiquitous, transmembrane, immunoglobulin-like receptor that exists in multiple isoforms and binds to a diverse range of endogenous extracellular ligands and intracellular effectors. Ligand binding at the extracellular domain of RAGE initiates a complex intracellular signaling cascade, resulting in the production of reactive oxygen species (ROS), immunoinflammatory effects, cellular proliferation, or apoptosis with concomitant upregulation of RAGE itself. To date, research has mainly focused on the correlation between RAGE activity and pathological conditions, such as cancer, diabetes, cardiovascular diseases, and neurodegeneration. Because RAGE plays a role in many pathological disorders, it has become an attractive target for the development of inhibitors at the extracellular and intracellular domains. This review describes the role of endogenous RAGE ligands/effectors in normo- and pathophysiological processes, summarizes the current status of exogenous small-molecule inhibitors of RAGE and concludes by identifying key strategies for future therapeutic intervention.

| S-EPMC5601361 | biostudies-literature

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