p75^NTR 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 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 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 NTRdependent 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.

Deletion of the Neurotrophin Receptor p75NTR Prevents Diabetes-Induced Retinal Acellular Capillaries in Streptozotocin-Induced Mouse Diabetic Model

“…Our results are in consistence with previous work that diabetes induced p75 NTR activate NF k B in endothelial cell and activated NF k B act on pericyte through transferring micro particles containing microRNA-503 resulting in decreased VEGF and Ephrin-B2 expression [19]. Our results are also in agreement with a recent report showing that p75 NTR is mediating pericytes loss and diabetes-induced BRB breakdown [16]. …”

“…Consistent with our previous report, genetic deletion of p75 NTR suppressed long-term diabetes-induced IL-1β inflammation (Figure 2). We and others have shown that modulating p75 NTR expression or activity significantly reduced TNF-α expression by inhibiting NF k B activation in retina of short term diabetic animals [10,11,16] and in response to stable proNGF over expression [11,30]. …”

“…The imbalance of proNGF/NGF during diabetes was associated with alteration and expression of TrkA and p75 NTR receptors (reviewed in [9–14]). The impaired TrkA activity was associated with upregulation of p75 NTR receptor, resulting in favoring activation of cell death pathway, neuro degeneration and BRB breakdown in the diabetic retina [11,15,16]. Genetic deletion of p75 NTR prevented diabetes-induced short-term neurodegeneration, inflammation and BRB breakdown [11].…”

“…Prior studies using stable over expression of proNGF showed that upregulated p75 NTR expression coincided with endothelial cell death [17] and pericyte cell death [18]. Other reports showed that short-term diabetes triggered p75 NTR and pericyte death [16,19]. However, the effects of modulating p75 NTR expression on the long term effects of diabetes-induced retinal microvascular degeneration remain unknown.…”

Subconjunctival Delivery of p75NTR Antagonists Reduces the Inflammatory, Vascular, and Neurodegenerative Pathologies of Diabetic Retinopathy

“…The receptor p75 NTR is a novel therapeutic target implicated in many retinal degenerative diseases such as DR, 17 experimental glaucoma, 18 and optic nerve damage. 19 Specifically, studies using a streptozotocin (STZ) mouse model of type I diabetes demonstrated p75 NTR -dependent induction of proinflammatory agents TNFa and a2M, disruption of the neuroglia vascular unit, blood-retina barrier (BRB) breakdown, edema, and ganglion cell neuronal death.…”