p75NTR and its ligand ProNGF activate paracrine mechanisms etiological to the vascular, inflammatory, and neurodegenerative pathologies of diabetic retinopathy

Pablo F. Barcelona, Nicholas Sitaras, Alba Galan, Gema Esquiva, Sean Jmaeff, Yifan Jian, Marinko V. Sarunic, Nicolas Cuenca, Przemyslaw Sapieha, H. Uri Saragovi

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8826-8841
Number of pages16
JournalJournal of Neuroscience
Volume36
Issue number34
DOIs
StatePublished - Aug 24 2016
Externally publishedYes

Fingerprint

Diabetic Retinopathy
Blood Vessels
Pathology
Ligands
Neuroglia
Pericytes
Semaphorin-3A
Pathologic Neovascularization
Inflammation
Streptozocin
Disease Progression
Edema
Ischemia
Cytokines
Oxygen

Keywords

  • Diabetes
  • Neurodegeneration
  • Neurotrophin
  • Pathophysiology
  • Receptor
  • Retina

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

p75NTR and its ligand ProNGF activate paracrine mechanisms etiological to the vascular, inflammatory, and neurodegenerative pathologies of diabetic retinopathy. / Barcelona, Pablo F.; Sitaras, Nicholas; Galan, Alba; Esquiva, Gema; Jmaeff, Sean; Jian, Yifan; Sarunic, Marinko V.; Cuenca, Nicolas; Sapieha, Przemyslaw; Saragovi, H. Uri.

In: Journal of Neuroscience, Vol. 36, No. 34, 24.08.2016, p. 8826-8841.

Research output: Contribution to journalArticle

Barcelona, Pablo F. ; Sitaras, Nicholas ; Galan, Alba ; Esquiva, Gema ; Jmaeff, Sean ; Jian, Yifan ; Sarunic, Marinko V. ; Cuenca, Nicolas ; Sapieha, Przemyslaw ; Saragovi, H. Uri. / p75NTR and its ligand ProNGF activate paracrine mechanisms etiological to the vascular, inflammatory, and neurodegenerative pathologies of diabetic retinopathy. In: Journal of Neuroscience. 2016 ; Vol. 36, No. 34. pp. 8826-8841.
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AU - Esquiva, Gema

AU - Jmaeff, Sean

AU - Jian, Yifan

AU - Sarunic, Marinko V.

AU - Cuenca, Nicolas

AU - Sapieha, Przemyslaw

AU - Saragovi, H. Uri

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