The role of receptor for advanced glycation end products (RAGE) in neuronal differentiation.
ABSTRACT 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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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.Experimental Neurology 09/2013; · 4.65 Impact Factor
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ABSTRACT: Blockade of advanced glycation end-products (AGE) is able to reduce diabetic complications and control periodontitis. This study aimed to determine whether the application of aminoguanidine (AG), an AGE inhibitor, or N-phenacylthiazolium bromide (PTB), an AGE breaker, facilitates the healing of an osseous wound in non-diabetic animals. 2.6 mm diameter full-thickness osseous wounds were created bilaterally in 54 healthy Sprague-Dawley rats. Rats received daily normal saline, AG, or PTB injections respectively and were euthanized after 7 days, 14 days, or 28 days (n = 6). The wound healing pattern was assessed by micro-computed tomography, histology, histochemistry for the fiber arrangement, and the gene expression levels of AGE receptor, tumor necrosis factor-α, type I collagen, and fibronectin. Under the AG and PTB administration, osteogenesis was apparently promoted in the early stages of healing, but the union of the osseous wound and the fibril re-arrangement was apparently retarded. No significant difference was found in any of the micro-computed tomography parameters as compared to the control in the first 14 days, whereas the relative bone volume was significantly higher in the control at Day 28. AGE receptor and tumor necrosis factor-α were depressed in the PTB group, but only temporarily at Day 14 in the AG group. Therefore, at Day 14, type I collagen was significantly upregulated in the PTB group, and fibronectin was significantly increased in the AG group. Anti-AGE agents reduced inflammation but did not apparently facilitate osteogenesis during the osseous wound repair.Journal of the Formosan Medical Association 01/2014; · 1.00 Impact Factor
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ABSTRACT: Astrocytes are major components of the adult neurogenic niche and play a crucial role in regulating neural stem cell proliferation and differentiation. Following brain injury, astrocytes become reactive and release high-mobility group box 1 (HMGB1), which plays a crucial role in the inflammatory process. However, although it has been reported that HMGB1 promotes neural stem/progenitor cell (NS/PC) proliferation in the developing brain, whether HMGB1 released by reactive astrocytes regulates NS/PC proliferation remains unknown. In this study, we aimed to investigate whether HMGB1 released from reactive astrocytes enhances NS/PC proliferation and to elucidate the possible mechanisms involved in this process. To evaluate the effects of HMGB1 on NS/PC proliferation, NS/PCs were cultured in HMGB1 culture medium and astrocyte-conditioned medium with or without reactive astrocyte-derived HMGB1 by RNA interference (RNAi). To explore the possible mechanisms, the HMGB1 receptor for advanced glycation endproducts (RAGE) in the NS/PCs was blocked with anti-RAGE antibody, and c-Jun N-terminal protein kinase (JNK) in the NS/PCs was inhibited using the potent JNK inhibitor, SP600125. Our results suggested that HMGB1 released from reactive astrocytes promoted NS/PC proliferation in vitro, and the blockade of RAGE or the inhibition of the JNK signaling pathway in the NS/PCs prevented the HMGB1-induced NS/PC proliferation. Our findings demonstrated that HMGB1 released by reactive astrocytes promoted NS/PC proliferation by binding RAGE and enhancing the phosphorylation of the JNK signaling pathway. These findings support a previously described mechanism of a crosstalk between astrocytes and NS/PCs, and suggest that reactive astrocyte-derived HMGB1 plays an important role in the repair of the central nervous system following brain injury.International Journal of Molecular Medicine 06/2014; · 1.96 Impact Factor