Abstract
To develop neuroprotective strategy for diabetic retinopathy (DR) and age-related macular degeneration (AMD), we studied the mechanism of trophic factor production/secretion by Müller cell (MC) and of MC viability in vivo and in vitro models under diabetic and hypoxic conditions. MC secreted a high level of brain-derived neurotrophic factor (BDNF) in high glucose media, which was elevated significantly by adding recombinant vascular endothelial growth factor (rVEGF) in a dose-dependent manner. This result was supported by VEGF upregulated BDNF synthesis in MCs and by reduced retinal BDNF in diabetic/hypoxic MC-specific VEGF receptor-2 (VEGFR2) knockout (KO) mice, which appeared to have an accelerated loss of retinal MCs and neurons. In addition, rBDNF and rVEGF promoted MC viability in a synergistic fashion. Targeting the main retinal BDNF receptor, tropomyosin receptor kinase B (TRK-B), with siRNA caused a significant reduction of activated ERK and MC viability. Parallel analyses for glial cell line-derived neurotrophic factor (GDNF) demonstrated a similar effect in GDNF production, MC protection, and survival pathway activation. In conclusion, neurotrophins are capable of elevating MC viability under diabetic/hypoxic condition, which provide a critical support for MC to produce themselves and other trophic factors for neuroprotection. As a substantial portion of patients treated with anti-VEGF drugs for 5 years appeared to have very thin retinas (presumably severe retinal cell/neuron loss), which bears striking resemblance to that in our diabetic/hypoxic MC-specific VEGFR2 KO mice, it is likely that blocking VEGF signaling in MC may cause unwanted retinal neuronal degeneration in AMD patients subjected to long-term anti-VEGF treatment due to blocking VEGF signaling-mediated reduction of neurotrophin and other trophic factor production. Therefore, supporting MC viability with neurotrophins may be a feasible strategy for neuroprotection during anti-VEGF treatment. Disclosure Y. Le: None. F. Qiu: None. M. Zhu: None.
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