July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
STAT3 directly regulates stress-induced expression of Edn2, to promote protection of photoreceptors through the activation of EdnrA
Author Affiliations & Notes
  • Marcus Hooper
    Ophthalmology, University of Florida, Gainesville, Florida, United States
  • Clayton Santiago
    Ophthalmology, University of Florida, Gainesville, Florida, United States
  • John D Ash
    Ophthalmology, University of Florida, Gainesville, Florida, United States
  • Footnotes
    Commercial Relationships   Marcus Hooper, None; Clayton Santiago, None; John Ash, None
  • Footnotes
    Support  Funding support to JDA includes NIH R01EY016459-12, Foundation Fighting Blindness, and an unrestricted departmental grant from Research to Prevent Blindness, Inc. Training support to MJH includes NIH T32EY007132
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 2508. doi:
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      Marcus Hooper, Clayton Santiago, John D Ash; STAT3 directly regulates stress-induced expression of Edn2, to promote protection of photoreceptors through the activation of EdnrA
      . Invest. Ophthalmol. Vis. Sci. 2018;59(9):2508.

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

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Abstract

Purpose : Retinal degeneration affects millions of people in the United States, and this number is expected to double by 2050. Photoreceptor degeneration is caused by many genes, thus there is a need to define pathways which protect photoreceptors in a broad-spectrum manner. Endothelin-2 (Edn2) is a cytokine that is induced under a wide range of retinal insults and disease states and has been suggested to be required for neuroprotection downstream of Leukemia inhibitory factor (LIF). Edn2 signals through endothelin receptors (EdnrA and EdnrB). We hypothesize that activation of EdnrB is required for the induction of endogenous protective pathways, downstream of LIF and STAT3. Endogenous neuroprotective pathways can be activated in mice by a process called preconditioning (PC), in which mice are exposed to cyclic bright light, preventing subsequent bright light-induced damage. We set out to determine the relationship between Edn2 and STAT3, and whether endothelin receptors are required for PC-induced protection from light damage.

Methods : PC was used to induce protective pathways for measuring gene expression and protection from light damage. For PC, mice were exposed to mild cyclic light (400 lux) for 6 days. Chx10-Cre was used to generate retina-specific knockout mice (rKO) for STAT3, EdnrA and EdnrB. Chromatin immunoprecipitation and qPCR were used to measure pSTAT3 binding to Edn2. qPCR was used to measure gene expression. Optical coherence tomography (OCT) and electroretinography (ERG) were used to measure photoreceptor survival and function.

Results : STAT3 rKO mice had reduced mRNA induction of Edn2, Fgf2 and Btc, but not Edn1 in PC. ChIP data show that pSTAT3 binds to regulatory regions in the Edn2 and Fgf2 genes in PC. EdnrA rKO mice had reduced ERG a-wave amplitudes and thinner photoreceptor layers following PC and light damage, while EdnrB rkO mice were protected. Interestingly, under non-stressed conditions, EdnrB rKO mice have reduced scotopic ERG a-wave amplitudes.

Conclusions : We conclude that STAT3 directly upregulates the transcription of downstream retinal protective genes, Edn2 and Fgf2. We determined that EdnrA is involved in endogenous neuroprotective pathways. Unexpectedly, EdnrB was found to not be required for PC-induced protection from light damage, but is required for normal a-wave amplitudes, though the observed reduction is small.

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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