Brain-derived neurotrophic factor in retinal integrity under diabetic and hypoxic conditions

Abstract

Purpose : To examine the mechanism of vascular endothelial growth factor (VEGF)-mediated neuronal viability in diabetes and hypoxia, we previously showed that the loss of VEGF receptor-2 (VEGFR2) signaling in Müller cells (MCs) in diabetic mice caused a) an accelerated degeneration of all retinal neurons and b) an accelerated reduction of retinal brain-derived neurotrophic factor (BDNF), a major retinal neurotrophin (Diabetes, 64:3554). These observations support a potential role for VEGF to act as a neuroprotectant through its downstream neurotrophins. We thus explored a neuroprotective strategy for diabetic and hypoxic retinal disorders through the action of BDNF, which should bypass the pathogenic effects of VEGF on blood-retina barriers.

Methods : Recombinant VEGF (rVEGF)-stimulated BDNF production was examined in vitro and in vivo with Western blot and ELISA analysis. Mouse primary MCs and rMC1 cells were used in investigating MC viability and BDNF production. The mechanism of BDNF-mediated MC viability was examined by targeting BNDF receptor TRK-B with siRNA knockdown approach. The effect of BDNF on retinal neuronal integrity was investigated in hypoxic mice with intravitreal rBDNF injection.

Results : Under diabetic condition, recombinant VEGF (rVEGF) stimulated BDNF production and rBDNF supported MC viability in a dose-dependent manner. siRNA targeting BDNF receptor TRK-B substantially downregulated the activated AKT and ERK, the classical survival and proliferation mediators. Although the photoreceptor outer nuclear layer (ONL) was slightly thinner in mice subjected to hypoxia (8% oxygen) for five days, intravitreal BDNF supplement did not appear to improve ONL thickness. Instead, the retina was disorganized and formed rosette-like morphology.

Conclusions : Our data suggest that BDNF stimulates MC viability through survival and proliferation. However, BDNF may not be suitable to serve as a neuroprotectant in hypoxia. As BDNF is downregulated in diabetic/hypoxic retinas and is considered as biomarker for diabetic retinopathy, it is of great importance to address a) the biological significance of BDNF-mediated MC viability, b) the mechanism and biological significance of BDNF downregulation under diabetic/hypoxic condition, and c) the suitability of BDNF and its family neurotrophins in neuroprotection in diabetic and hypoxic retinal disorders, which is a major focus in our laboratory now.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.