The role of receptor for advanced glycation end products (RAGE) in neuronal differentiation
Department of Anatomy with Radiology, Centre for Brain Research, Faculty of Medical and Health Science, University of Auckland, Auckland, New Zealand. Journal of Neuroscience Research
(Impact Factor: 2.59).
06/2012; 90(6):1136-47. DOI: 10.1002/jnr.23014
The receptor for advanced glycation end products (RAGE) is a multiligand receptor protein thought to play an important role in neuronal differentiation. RAGE can bind a number of ligands and activate a variety of signalling pathways that lead to diverse downstream effects. Amphoterin and S100B are endogenous ligands, the interaction of which with RAGE is known to be involved in defined physiological processes. The present study investigated the spatiotemporal pattern of the expression for RAGE and its ligands, amphoterin and S100B, during neuronal differentiation of NT2/D1 cells. In this study, all three proteins were shown to increase with progression of neuronal differentiation as determined by Western blotting, raising the possibility that both amphoterin and S100B may interact with RAGE and have important functions during the process of cell differentiation. Moreover, blocking the activation of RAGE with neutralizing antibody in the presence of retinoic acid disrupted the progression of normal neuronal differentiation. Immunocytochemistry (ICC) studies showed that amphoterin partially colocalized with RAGE within differentiating NT2 cells, whereas S100B showed a high degree of colocalization. This result suggests that S100B is more likely to be the principal ligand for RAGE during the differentiation process and that RAGE and amphoterin might have both independent and combined roles. Moreover, RAGE was expressed only in cells that were committed to a neuronal phenotype, suggesting direct involvement of RAGE in mediating cellular changes within differentiating neuronal cells. Further detailed studies are now required to characterize fully the role of RAGE during the neuronal differentiation period.
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Available from: Lori Tessler
- "In multiple cell types ligand-induced RAGE activation triggers numerous intracellular signaling pathways with binding of mDia-1 to the cytoplasmic C-terminal region being a common mediator of subsequent signal transduction events (Hudson et al., 2008; Ramasamy et al., 2011; Xu et al., 2010). RAGE signaling also mediates normal neuronal processes including enhancement of neurite outgrowth, neuronal differentiation and cell migration (Huttunen et al., 1999, 2000; Kim et al., 2012; Rauvala et al., 2000; Sbai et al., 2010). The endogenous ligands for RAGE include amphoterin (or high mobility group protein 1 (HMGB1)) and S100 calcium binding protein (S100B). "
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ABSTRACT: The receptor for advanced glycation end-products (RAGE) is implicated in neuronal differentiation during embryogenesis and in regulation of peripheral nerve regeneration. However, the role of RAGE ligands and the signaling pathways utilized by activated RAGE in mediating axon regeneration in adult neurons remain unknown. We tested the hypothesis that RAGE signaling modulated neurotrophin-induced neurite outgrowth in cultured adult sensory neurons.
Dorsal root ganglia (DRG) neurons from adult rats in vitro were exposed to specific RAGE ligands, signal transduction inhibitors and function blocking anti-RAGE IgG to assess their impact on neurite outgrowth. RAGE ligands including human glycated albumin (HGA), S100 calcium binding protein (S100B) and high mobility group 1 protein (HMGB1; alternatively termed amphoterin) in the presence of neurotrophins elevated neurite outgrowth 2-fold (p<0.05). shRNA to RAGE or anti-RAGE IgG blockade of RAGE inhibited neurite outgrowth by 40-90% (p<0.05). Western blotting and gene reporter analysis showed RAGE ligands activated NF-κB, JAK-STAT and ERK pathways. RAGE ligand induction of neurite outgrowth was blocked by inhibition of NF-κB, JAK-STAT or ERK pathways revealing the necessity for combined activation for optimal growth. RAGE ligands rapidly elevated NF-κB p65 expression in the cytoplasm while triggering translocation of NF-κB p50 to the nucleus. shRNA blockade of p50 demonstrated that translocation of p50 to the nucleus was implicated in driving axonal outgrowth.
RAGE signaling is a complex mediator of neurotrophin-dependent neurite outgrowth, operating through divergent but partly inter-dependent pathways.
Available from: Paul R Reynolds
- "Altered cellular differentiation has not sufficiently been characterized in the distal lung of COPD patients; however, new research has emerged demonstrating that human ciliated cells can respond to cigarette smoke by promoting GDF15, a factor capable of driving Muc5A expression in goblet cells (Wu et al., 2011). RAGE and RAGE ligands have been implicated in altered cellular differentiation of several cell types including smooth muscle cells, skeletal myocytes and developing neural tissue (Suga et al., 2011; Kim et al., 2012; Riuzzi et al., 2012). Thyroid transcription factor 1 (TTF-1; also known as Nkx2.1) is a key regulator of pulmonary development and present in distal lung epithelium that can negatively regulate RAGE expression (Reynolds et al., 2008) and SP-1 positively regulates the active promoter region of TTF-1 in surfactant producing cells (Das et al., 2011). "
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ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a progressive condition characterized by chronic airway inflammation and airspace remodeling, leading to airflow limitation that is not completely reversible. Smoking is the leading risk factor for compromised lung function stemming from COPD pathogenesis. First- and second-hand cigarette smoke contain thousands of constituents, including several carcinogens and cytotoxic chemicals that orchestrate chronic lung inflammation and destructive alveolar remodeling. Receptors for advanced glycation end-products (RAGE) are multi-ligand cell surface receptors primarily expressed by diverse lung cells. RAGE expression increases following cigarette smoke exposure and expression is elevated in the lungs of patients with COPD. RAGE is responsible in part for inducing pro-inflammatory signaling pathways that culminate in expression and secretion of several cytokines, chemokines, enzymes, and other mediators. In the current review, new transgenic mouse models that conditionally over-express RAGE in pulmonary epithelium are discussed. When RAGE is over-expressed throughout embryogenesis, apoptosis in the peripheral lung causes severe lung hypoplasia. Interestingly, apoptosis in RAGE transgenic mice occurs via conserved apoptotic pathways also known to function in advanced stages of COPD. RAGE over-expression in the adult lung models features of COPD including pronounced inflammation and loss of parenchymal tissue. Understanding the biological contributions of RAGE during cigarette smoke-induced inflammation may provide critically important insight into the pathology of COPD.
Available from: jbc.org
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ABSTRACT: The impaired adipogenic potential of senescent preadipocytes is a hallmark of adipose aging and aging-related adipose dysfunction.
Although advanced glycation end products (AGEs) derived from both foods and endogenous nonenzymatic glycation and AGE-associated
signaling pathways are known to play a key role in aging and its related diseases, the role of AGEs in adipose aging remains
elusive. We show a novel pro-adipogenic function of AGEs in replicative senescent preadipocytes and mouse embryonic fibroblasts,
as well as primary preadipocytes isolated from aged mice. Using glycated bovine serum albumin (BSA) as a model protein of
AGEs, we found that glycated BSA restores the impaired adipogenic potential of senescent preadipocytes in vitro and ex vivo. However, glycated BSA showed no effect on adipogenesis in nonsenescent preadipocytes. The AGE-induced receptor for AGE (RAGE)
expression is required for the pro-adipogenic function of AGEs in senescent preadipocytes. RAGE is required for impairment
of p53 expression and p53 function in regulating p21 expression in senescent preadipocytes. We also observed a direct binding between RAGE and p53 in senescent preadipocytes.
Taken together, our findings reveal a novel pro-adipogenic function of the AGE-RAGE axis in p53-regulated adipogenesis of
senescent preadipocytes, providing new insights into aging-dependent adiposity by diet-driven and/or endogenous glycated proteins.
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