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

Riyaz Mohamed, Ahmed Y Shanab, Azza B El Remessy

Research output: Contribution to journalArticlepeer-review

Abstract

Diabetic retinopathy is characterized by early stage of retinal neuro-inflammation that triggers development of acellular capillaries and a late stage of pathological neovascularization. Due to limited treatment options, there is a pressing need to develop new therapeutics. Our group discovered that diabetes-impaired processing of the nerve growth factor precursor (proNGF) resulting in its accumulation and its receptor p75NTR. Here, we examine the protective effects of modulating p75NTR in experimental model of diabetic retinopathy. Diabetes was induced using streptozotocin in both wild type (WT) and p75NTR knockout (p75KO) mice. Retinal inflammation and microvascular dysfunction were assessed. Western blot analysis was performed to assess expression of apoptotic and inflammatory markers and levels of the neurotrophin, p75NTR and ephrin-B2. Deletion of p75NTR did not alter body weight or diabetes status compared to WT mice. In WT-mice, diabetes triggered retinal inflammation, significant decrease in pericyte count and marked increase in development of occluded (acellular) capillary formation after 24-weeks. Deletion of p75NTR prevented acellular capillary, restored pericyte count, and inhibited the retinal Ephrin-B2, activation of the stress-kinase JNK and apoptotic marker cleaved caspase-3 in the diabetic retina. Deletion of p75NTR reduced retinal inflammation, and proNGF expression. These effects coincided with increased NGF level and TrkA activation in the diabetic retina. Targeting p75NTR using genetic approach protected the retina from the impact of long-term diabetes in mediating microvascular degeneration and maintains the balance of NGF/proNGF level. Together, these results provide rationale that targeting p75NTR may offer novel and effective therapeutic strategy to combat diabetic retinopathy.

Original languageEnglish (US)
JournalJournal of diabetes, metabolic disorders & control
Volume4
Issue number6
DOIs
StatePublished - 2017
Externally publishedYes

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