Modulation Of ProNGF/p75^NTR Pathway Prevents Microvascular Degeneration In Diabetic Retinopathy

Abstract

Purpose : Diabetic retinopathy is characterized by early stage of retinal neuro-inflammation that triggers development of acellular capillaries and retinal ischemia 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 p75^NTR. Here, we examine the long term outcome of anti-proNGF treatment or genetic deletion of its receptor, p75^NTR in experimental model of diabetic retinopathy.

Methods : Diabetes was induced using streptozotocin in both wild type (WT) and p75^NTR knockout (p75KO) mice. A group of diabetic WT received intravitreal injection of crude anti-proNGF 3µg/eye (McGill University) every 6-weeks. Mice were sacrificed after 24-weeks of diabetes. Acellular capillary formation and pericyte number were counted in trypsin digested diabetic retina. Western blot analysis was performed to assess expression of apoptotic markers and levels of the neurotrophins.

Results : Deletion of p75^NTR or treatment with anti-proNGF did not alter body weight or diabetes status. In WT-mice, diabetes caused significant decrease in pericyte count and increase in acellular capillary formation, hallmark of retinal ischemia. Deletion of p75^NTR prevented acellular capillary and restored pericyte count in the diabetic retina. Treatment with anti-proNGF or deletion of p75^NTR reduced the increase in expression of proNGF and its receptor p75^NTR, activation of the stress-kinase JNK and apoptotic marker cleaved caspase-3. These effects coincided with increased NGF and TrkA level in the diabetic retina.

Conclusions : The proNGF and p75^NTR axis plays major role in retinal vascular dysfunction during diabetes. Deletion of p75^NTR and anti-proNGF treatment protects the retina from long term diabetes induced microvascular degeneration and maintains the balance of NGF/proNGF level. Therefore, targeting proNGF or p75^NTR may offer novel and effective therapeutic strategy to combat diabetic retinopathy

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.