July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Endothelin Signaling in Glaucomatous Neurodegeneration
Author Affiliations & Notes
  • Olivia J Marola
    Ophthalmology, University of Rochester, Rochester, New York, United States
  • Stephanie B Syc-Mazurek
    Ophthalmology, University of Rochester, Rochester, New York, United States
  • Gareth R Howell
    The Jackson Laboratories, Bar Harbor, Maine, United States
  • Richard T Libby
    Ophthalmology, University of Rochester, Rochester, New York, United States
  • Footnotes
    Commercial Relationships   Olivia Marola, None; Stephanie Syc-Mazurek, None; Gareth Howell, None; Richard Libby, None
  • Footnotes
    Support  This work was supported by EY018606 (RTL), EY027701 (RTL), and Research to Prevent Blindness (an unrestricted grant to the Department of Ophthalmology at the University of Rochester Medical Center). 5 T32 EY 7125-28 (OJM), Diana Davis Foundation Chair for Glaucoma Research (GRH).
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 661. doi:
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    • Get Citation

      Olivia J Marola, Stephanie B Syc-Mazurek, Gareth R Howell, Richard T Libby; Endothelin Signaling in Glaucomatous Neurodegeneration. Invest. Ophthalmol. Vis. Sci. 2019;60(9):661.

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

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Purpose : The endothelin (EDN) system has been implicated in human glaucoma. EDN signaling has been shown to be an early, pathogenic event in animal models of glaucoma. In rodent ocular hypertensive models, pharmaceutical inhibition of EDN receptors significantly lessens glaucomatous neurodegeneration. Understanding the early signaling pathways that mediate EDN-induced retinal ganglion cell (RGC) death is critical for determining how EDN system activation contributes to the onset and progression of glaucoma. Here, we examine the neuronal response to EDN insult.

Methods : Eyes of 2-5 month old C57BL/6J mice were intravitreally injected with 2μL of 1000μM EDN1 or PBS. At various time points post-injection, eyes were harvested and assessed for RGCs (RPBMS) and dying cells (cleaved caspase 3; cCASP3). Furthermore, since JUN and DDIT3 have been implicated in RGC death after glaucoma- relevant injuries, retinas were examined for JUN activation (pJUN) and Ddit3 upregulation. Finally, EDN1 was then injected into Ddit3 and Jun deficient retinas to assess the importance of Ddit3 and Jun in EDN-induced RGC death.

Results : Caspase-3 was activated in RGCs 5 days after EDN1 insult (cCASP3+ RGCs per mm2±SEM; n per group: PBS, 0.4±0.2; EDN1, 38.7±17.7; n=9; p=0.030), and there is a significant reduction of RBPMS+ RGCs 28 days after intravitreal EDN1 [RGCs per mm2±SEM; n per group: PBS, 3477±155; EDN1, 2834±77; n=6; p=0.004]. JUN was activated in RGCs [pJUN+ RGCs per mm2±SEM; n per group: PBS, 4±1; EDN1: 351±115, n=12, p=0.005] and Ddit3 is upregulated [normalized fold change± SEM; n per group: PBS, 1.00±0.18, EDN1, 1.95±0.26, n=5, p=0.017] 3 days post-EDN1 insult. Preliminary experiments suggest Jun deletion attenuated caspase activation in RGCs 5 days post-EDN1 [cCASP3+RGCs/mm2±SEM, n per group: 2.9± 1.1, n=5, p=0.039] but Ddit3 does not seem to affect caspase activation after EDN1 [24.2±6.0, n=4, p=0.228].

Conclusions : Intravitreal injection of EDN1 caused a significant loss of RGCs in C57BL/6J mice. JUN was activated in RGCs and Ddit3 was upregulated after EDN1, suggesting that JUN and DDIT3 may have a role in EDN-induced RGC death. Furthermore, experiments using Jun and Ddit3 deficient mice suggested that JUN, but not DDIT3, may be important for endothelin-induced RGC death. It will be important to critically test the involvement of JUN in EDN-induced RGC death by assessing RGC survival post-EDN1 insult in Jun deficient retinas.

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


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