June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
GDNF and BDNF are positive regulators for Müller cell viability through similar but divergent mechanisms
Author Affiliations & Notes
  • Yun-Zheng Le
    Medicine (Endocrinology), Cell biology, and Ophthalmology , and Harold Hamm Diabetes Center, Univ of Oklahoma Hlth Sci Ctr, Oklahoma City, Oklahoma, United States
  • Meili Zhu
    Medicine (Endocrinology), Cell biology, and Ophthalmology , and Harold Hamm Diabetes Center, 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, PHF grant, and endowment from Mr. Harold Hamm.
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 1173. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      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.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : 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.

Methods : 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.

Results : 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.

Conclusions : 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.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×