July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Mechanisms of Müller glia-mediated neuroprotection in diabetic retinopathy and hypoxic retinal diseases
Author Affiliations & Notes
  • Yun-Zheng Le
    Medicine, Cell Biology, and Ophthalmology and Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Meili Zhu
    Medicine, Univ of Oklahoma Hlth Sci Ctr, Oklahoma City, Oklahoma, United States
  • Footnotes
    Commercial Relationships   Yun-Zheng Le, None; Meili Zhu, None
  • Footnotes
    Support  NIH grants R01EY026970, P30GM122744, and P30EY021725 (Core), grants from IRRF, OCASCR, OCAST, and RPB, and endowments from Harold Hamm and Choctaw Nation.
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 2505. doi:
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      Yun-Zheng Le, Meili Zhu; Mechanisms of Müller glia-mediated neuroprotection in diabetic retinopathy and hypoxic retinal diseases. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2505.

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

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Purpose : We previously showed that Vascular Endothelial Growth Factor (VEGF) signaling was required for MG survival in diabetic mice, which in turn, caused retinal degeneration, likely through the reduction of MG-derived neurotrophic factors, Glial cell line-Derived Neurotrophic Factor (GDNF) and Brain-Derived Neurotrophic Factor (BDNF)(Diabetes, 64: 3554). To develop Müller glia (MG)-mediated neuroprotection in DR and hypoxic retinal diseases, we investigated the relationship among VEGF, BDNF, and GDNF in promoting MG viability and its effect on neurons.

Methods : Interactions among trophic factors for MG viability and proliferation was analyzed with a rat cell line rMC1 and primary Müller cells (MCs) by quantitative analysis of live and BrdU+ cells. Hypoxia was generated with cobalt chloride. Retinal morphology was assessed in hematoxylin & eosin (H&E) stained sections. MG density was evaluated with immunohistochemistry. Protein concentration was analyzed with immunoblotting and ELISA.

Results : Under diabetes-like or hypoxic condition, BDNF, GDNF, or VEGF promoted MC viability, which was achieved through both survival and proliferation. These trophic factors appeared to work in an addictive or synergistic fashion in supporting MC viability. VEGF also had a stimulative effect on BDNF or GDNF production. MG-specific VEGF receptor-2 (VEGFR2) null mice had accelerated loss of MG and retinal neurons under hypoxia, which could be rescued partially by BDNF and GDNF supplement. Rescuing accelerated MG and neuronal degeneration in diabetic MG-specific VEGFR2 null mice is in progress.

Conclusions : VEGF is critical to the survival and proliferation of MG in diabetes and hypoxia. While VEGF may work in concert with BDNF and GDNF, it also stimulates the production of BDNF and GDNF by MG. As 1) DR shares a hypoxic retinal environment which is very similar to that in age-related macular degeneration (AMD) and 2) the very thin retina (loss of neurons in all retinal layers) in diabetic and hypoxic MG-specific VEGFR2 null mice resembles to that in a substantial portion of neovascular AMD patients treated with anti-VEGF drugs for 5+ years, protecting MG may provide additional support to retinal neurons in DR and AMD patients during anti-VEGF therapies. Finally, VEGF stimulated MG proliferation may also be critical to MG-mediated retinal regeneration de novo.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.


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