p75NTR and Its Ligand ProNGF Activate Paracrine Mechanisms Etiological to the Vascular, Inflammatory, and Neurodegenerative Pathologies of Diabetic Retinopathy
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Título: | p75NTR and Its Ligand ProNGF Activate Paracrine Mechanisms Etiological to the Vascular, Inflammatory, and Neurodegenerative Pathologies of Diabetic Retinopathy |
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Autor/es: | Barcelona, Pablo F. | Sitaras, Nicholas | Galan, Alba | Esquiva, Gema | Jmaeff, Sean | Jian, Yifan | Sarunic, Marinko V. | Cuenca, Nicolás | Sapieha, Przemyslaw | Saragovi, H. Uri |
Grupo/s de investigación o GITE: | Neurobiología del Sistema Visual y Terapia de Enfermedades Neurodegenerativas (NEUROVIS) |
Centro, Departamento o Servicio: | Universidad de Alicante. Departamento de Fisiología, Genética y Microbiología |
Palabras clave: | Diabetes | Neurodegeneration | Neurotrophin | Pathophysiology | Receptor | Retina |
Área/s de conocimiento: | Biología Celular |
Fecha de publicación: | 24-ago-2016 |
Editor: | Society for Neuroscience |
Cita bibliográfica: | The Journal of Neuroscience. 2016, 36(34): 8826-8841. doi:10.1523/JNEUROSCI.4278-15.2016 |
Resumen: | In many diseases, expression and ligand-dependent activity of the p75NTR receptor can promote pericyte and vascular dysfunction, inflammation, glial activation, and neurodegeneration. Diabetic retinopathy (DR) is characterized by all of these pathological events. However, the mechanisms by which p75NTR may be implicated at each stage of DR pathology remain poorly understood. Using a streptozotocin mouse model of diabetic retinopathy, we report that p75NTR is upregulated very early in glia and in pericytes to mediate ligand-dependent induction of inflammatory cytokines, disruption of the neuro-glia-vascular unit, promotion of blood–retina barrier breakdown, edema, and neuronal death. In a mouse model of oxygen-induced retinopathy, mimicking proliferative DR, p75NTR-dependent inflammation leads to ischemia and pathological angiogenesis through Semaphorin 3A. The acute use of antagonists of p75NTR or antagonists of the ligand proNGF suppresses each distinct phase of pathology, ameliorate disease, and prevent disease progression. Thus, our study documents novel disease mechanisms and validates druggable targets for diabetic retinopathy. |
Patrocinador/es: | This work was supported by the Canadian Institutes of Health Research and the Foundation to Fight Blindness to H.U.S. and the Canadian Diabetes Association to P.S. |
URI: | http://hdl.handle.net/10045/57475 |
ISSN: | 0270-6474 (Print) | 1529-2401 (Online) |
DOI: | 10.1523/JNEUROSCI.4278-15.2016 |
Idioma: | eng |
Tipo: | info:eu-repo/semantics/article |
Derechos: | © 2016 the authors |
Revisión científica: | si |
Versión del editor: | http://dx.doi.org/10.1523/JNEUROSCI.4278-15.2016 |
Aparece en las colecciones: | INV - NEUROVIS - Artículos de Revistas |
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2016_Barcelona_etal_JNeurosci.pdf | 6,22 MB | Adobe PDF | Abrir Vista previa | |
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