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Yun-Zheng Le, Meili Zhu; GDNF and BDNF are positive regulators for Müller cell viability through similar but divergent mechanisms. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1173.
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© ARVO (1962-2015); The Authors (2016-present)
To study Müller cell (MC)-mediated neuroprotection in diabetic retinopathy (DR) and hypoxic retinal diseases, we previously demonstrated that disrupting vascular endothelial growth factor receptor-2 (VEGFR2) in MCs caused accelerated MC loss and retinal degeneration in diabetes (Diabetes, 64: 3554). To determine the mechanism of VEGF signaling-mediated MC and neuronal viability in diabetes/hypoxia, we investigated the relationship among VEGF and its downstream neurotrophic factors, glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), in MC viability and neuroprotection.
Protein levels were quantified with immunoblotting and ELISA using a rat MC line and MC-specific VEGFR2 knockout (KO) mice. MC viability was measured by live cell quantification. Mechanistic analysis was performed with siRNA targeting.
BDNF and GDNF levels were significantly reduced in diabetic/hypoxic MC-specific VEGFR2 KO mice. VEGF, BDNF, and GDNF stimulated MC viability in a synergistic fashion under diabetic condition and CoCl2-induced hypoxia. To eliminate the possibility of non-hypoxic effect of CoCl2 in this observation, we confirmed that VEGF could stimulate MC viability in a dose-dependent manner in 2% oxygen. Analysis of the combined trophic effects of VEGF, GDNF, and BDNF on MC viability in 2% oxygen is in progress. Targeting the GDNF co-receptor RET with siRNA caused a significant reduction of activated form of AKT, pAKT, but not pERK, which resulted in a significant reduction of MC viability under normal and diabetic conditions. Targeting the main retinal BDNF receptor, TRK-B, with siRNA caused a significant reduction of both pAKT and pERK, which also resulted in a significant reduction in MC viability under the same conditions.
Our data suggest that GDNF and BDNF are positive regulators for MC viability through similar but divergent mechanisms, which in turn, supports MC-mediated trophic factor production for neurons in diabetic and hypoxic retina. Therefore, supporting MC viability with GDNF and BDNF may be a feasible strategy for neuroprotection in DR, AMD, and other hypoxic retinal diseases. As VEGF is a master regulator for GDNF and BDNF-mediated MC viability, GDNF and BDNF supplement may be particularly useful for neuroprotection during anti-VEGF treatment for these diseases.
This is a 2020 ARVO Annual Meeting abstract.
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