July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Mechanism of BDNF-mediated neuroprotection: critical role of Müller glia in diabetic retinopathy and age-related macular degeneration
Author Affiliations & Notes
  • Yun-Zheng Le
    Medicine/Endocrinology, Univ of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
    Cell Biology and Ophthalmology and Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Fangfang Qiu
    Medicine/Endocrinology, Univ of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Meili Zhu
    Medicine/Endocrinology, Univ of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Footnotes
    Commercial Relationships   Yun-Zheng Le, None; Fangfang Qiu, None; Meili Zhu, None
  • Footnotes
    Support  NIH grants R01EY026970, P30GM122744, and P30EY021725, grants from PHF and OCASCR, and endowments from Harold Hamm and Choctaw Nation.
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 4402. doi:
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      Yun-Zheng Le, Fangfang Qiu, Meili Zhu; Mechanism of BDNF-mediated neuroprotection: critical role of Müller glia in diabetic retinopathy and age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4402.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : The concept that the brain-derived neurotrophic factor (BDNF) is a major trophic factor for retinal neurons is well-established. However, the cellular and molecular mechanisms governing BNDF production and its neuroprotective effect remain largely unknown. To determine the role of BDNF in neuroprotection in diabetic retinopathy (DR) and age-related macular degeneration (AMD), we investigated the mechanism of BDNF production/secretion by Müller cells (MCs) and of BDNF-mediated MC viability under diabetic and hypoxic conditions using both in vivo and in vitro models.

Methods : BDNF production and expression were quantified with immunoblotting and ELISA analysis using a rat MC line (rMC1) and condtional gene knockout (KO) mice. MC viability was measured by live cell quantification. MG and neuronal density in mice was analyzed with immunohistochemistry and retinal morphology was examined with light microscopy.

Results : In high glucose media, MC secreted a high level of BDNF which was elevated significantly by the supplementation of recombinant vascular endothelial growth factor (rVEGF) in a dose-dependent manner. This result was supported by rVEGF upregulated BDNF synthesis in MCs and by reduced retinal BDNF in diabetic/hypoxic MG-specific VEGF receptor-2 (VEGFR2) KO mice, which demonstrated an accelerated loss of retinal MG 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.

Conclusions : BDNF is a significant stimulator for MG viability under diabetic/hypoxic condition, which provides a critical support for MG to produce trophic factors, such as BDNF. As a substantial portion (36%) of wet-AMD patients treated with anti-VEGF drugs for 5 years had very thin retinas (severe retinal cell/neuron loss), which bears striking resemblance to that in our diabetic/hypoxic MG-specific VEGFR2 KO mice, it is likely that blocking VEGF signaling in MG may cause unwanted retinal neuronal degeneration in AMD patients after long-term anti-VEGF treatment due to decrease of VEGF signaling-mediated BDNF/trophic factor production. In conclusion, supporting MG viability with BDNF may be a feasible strategy for neuroprotection during anti-VEGF treatment.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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