Treatment of diabetic retinopathy through neuropeptide Y-mediated enhancement of neurovascular microenvironment

Kepeng Ou, David A Copland, Sofia Theodoropoulou, Sonja Mertsch, Jian Liu, Youjian Li, Stefan Schrader, Lei Liu, Andrew David Dick*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

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Abstract

Diabetic retinopathy (DR) is one of the most severe clinical manifestations of diabetes mellitus and a major cause of blindness. DR is principally a microvascular disease, although the pathogenesis also involves metabolic reactive intermediates which induce neuronal and glial activation resulting in disruption of the neurovascular unit and regulation of the microvasculature. However, the impact of neural/glial activation in DR remains controversial, notwithstanding our understanding as to when neural/glial activation occurs in the course of disease. The objective of this study was to determine a potential protective role of neuropeptide Y (NPY) using an established model of DR permissive to N‐methyl‐D‐aspartate (NMDA)‐induced excitotoxic apoptosis of retinal ganglion cells (RGC) and vascular endothelial growth factor (VEGF)‐induced vascular leakage. In vitro evaluation using primary retinal endothelial cells demonstrates that NPY promotes vascular integrity, demonstrated by maintained tight junction protein expression and reduced permeability in response to VEGF treatment. Furthermore, ex vivo assessment of retinal tissue explants shows that NPY can protect RGC from excitotoxic‐induced apoptosis. In vivo clinical imaging and ex vivo tissue analysis in the diabetic model permitted assessment of NPY treatment in relation to neural and endothelial changes. The neuroprotective effects of NPY were confirmed by attenuating NMDA‐induced retinal neural apoptosis and able to maintain inner retinal vascular integrity. These findings could have important clinical implications and offer novel therapeutic approaches for the treatment in the early stages of DR.
Original languageEnglish
Number of pages13
JournalJournal of Cellular and Molecular Medicine
DOIs
Publication statusPublished - 6 Mar 2020

Keywords

  • Diabetic retinopathy
  • neurovascular unit
  • NPY
  • retinal ganglion cells
  • Vascular permeability
  • ZO-1

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