title: p75NTR and Its Ligand ProNGF Activate Paracrine Mechanisms Etiological to the Vascular, Inflammatory, and Neurodegenerative Pathologies of Diabetic Retinopathy.
abstract: In many diseases, expression and ligand-dependent activity of the p75(NTR) 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 p75(NTR) may be implicated at each stage of DR pathology remain poorly understood. Using a streptozotocin mouse model of diabetic retinopathy, we report that p75(NTR) 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, p75(NTR)-dependent inflammation leads to ischemia and pathological angiogenesis through Semaphorin 3A. The acute use of antagonists of p75(NTR) 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.
  
  
  
  Diabetic retinopathy (DR) affects an estimated 250 million people and has no effective treatment. Stages of progression comprise pericyte/vascular dysfunction, inflammation, glial activation, and neurodegeneration. The pathophysiology of each stage remains unclear. We postulated that the activity of p75NTR may be implicated. We show that p75NTR in glia and in pericytes mediate ligand-dependent induction of inflammatory cytokines, disruption of the neuro-glia-vascular unit, promotion of blood-retina barrier breakdown, edema, and neuronal death. p75NTR-promoted inflammation leads to ischemia and angiogenesis through Semaphorin 3A. Antagonists of p75NTR or antagonists of proNGF suppress each distinct phase of pathology, ameliorate disease, and prevent disease progression. Our study documents novel mechanisms in a pervasive disease and validates druggable targets for treatment.
authors: Lady Davis Institute-Jewish General Hospital, Center for Translational Research, McGill University, Montreal, Quebec H3T 1E2, Canada, Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors: Pablo F
authors: PF
authors: Barcelona
authors: Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, Quebec H1T 2M4, Canada.
authors: Nicholas
authors: 0000-0002-5920-2008
authors: N
authors: Sitaras
authors: Lady Davis Institute-Jewish General Hospital, Center for Translational Research, McGill University, Montreal, Quebec H3T 1E2, Canada.
authors: Alba
authors: A
authors: Galan
authors: Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante CP 03690, Spain.
authors: Gema
authors: 0000-0002-3951-6464
authors: G
authors: Esquiva
authors: Lady Davis Institute-Jewish General Hospital, Center for Translational Research, McGill University, Montreal, Quebec H3T 1E2, Canada, Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors: Sean
authors: S
authors: Jmaeff
authors: School of Engineering Science, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
authors: Yifan
authors: Y
authors: Jian
authors: School of Engineering Science, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
authors: Marinko V
authors: MV
authors: Sarunic
authors: Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante CP 03690, Spain.
authors: Nicolas
authors: 0000-0002-6767-5710
authors: N
authors: Cuenca
authors: Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, Quebec H1T 2M4, Canada, Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, Quebec H1T 2M4, Canada, Department of Neurology-Neurosurgery, McGill University, Montreal, Quebec H3A 2B4, Canada, and.
authors: Przemyslaw
authors: P
authors: Sapieha
authors: Lady Davis Institute-Jewish General Hospital, Center for Translational Research, McGill University, Montreal, Quebec H3T 1E2, Canada, Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada, McGill Cancer Center, McGill University, Montreal, Quebec H3A 1A3, Canada uri.saragovi@mcgill.ca.
authors: H Uri
authors: HU
authors: Saragovi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D001253:Astrocytes / Q000737:chemistry; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000139:chemically induced / Q000150:complications*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020932:Nerve Growth Factor / Q000276:immunology / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000209:etiology*; D011498:Protein Precursors / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D017475:Receptors, Nerve Growth Factor / Q000276:immunology / Q000378:metabolism*; D012160:Retina / Q000473:pathology; D013311:Streptozocin / Q000633:toxicity; D041623:Tomography, Optical Coherence; D014652:Vascular Diseases / Q000209:etiology*; D014795:Visual Pathways / Q000473:pathology
chemical_list: D000906:Antibodies; D017077:Culture Media, Conditioned; D016207:Cytokines; D011498:Protein Precursors; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; C489226:pro-nerve growth factor, mouse; D013311:Streptozocin; D020932:Nerve Growth Factor
keywords: diabetes; neurodegeneration; neurotrophin; pathophysiology; receptor; retina