Neuronal Epac1 mediates retinal neurodegeneration in mouse models of ocular hypertension

Wei Liu, Yonju Ha, Fan Xia, Shuang Zhu, Yi Li, Shuizhen Shi, Fang C. Mei, Kevin Merkley, Gianmarco Vizzeri, Massoud Motamedi, Xiaodong Cheng, Hua Liu, Wenbo Zhang

Research output: Contribution to journalArticle

Abstract

Progressive loss of retinal ganglion cells (RGCs) leads to irreversible visual deficits in glaucoma. Here, we found that the level of cyclic AMP and the activity and expression of its mediator Epac1 were increased in retinas of two mouse models of ocular hypertension. Genetic depletion of Epac1 significantly attenuated ocular hypertension-induced detrimental effects in the retina, including vascular inflammation, neuronal apoptosis and necroptosis, thinning of ganglion cell complex layer, RGC loss, and retinal neuronal dysfunction. With bone marrow transplantation and various Epac1 conditional knockout mice, we further demonstrated that Epac1 in retinal neuronal cells (especially RGCs) was responsible for their death. Consistently, pharmacologic inhibition of Epac activity prevented RGC loss. Moreover, in vitro study on primary RGCs showed that Epac1 activation was sufficient to induce RGC death, which was mechanistically mediated by CaMKII activation. Taken together, these findings indicate that neuronal Epac1 plays a critical role in retinal neurodegeneration and suggest that Epac1 could be considered a target for neuroprotection in glaucoma.

Original languageEnglish (US)
JournalThe Journal of experimental medicine
Volume217
Issue number4
DOIs
StatePublished - Apr 6 2020

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Ocular Hypertension
Retinal Ganglion Cells
Glaucoma
Retina
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Bone Marrow Transplantation
Knockout Mice
Ganglia
Cyclic AMP
Blood Vessels
Cell Death
Apoptosis
Inflammation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Neuronal Epac1 mediates retinal neurodegeneration in mouse models of ocular hypertension. / Liu, Wei; Ha, Yonju; Xia, Fan; Zhu, Shuang; Li, Yi; Shi, Shuizhen; Mei, Fang C.; Merkley, Kevin; Vizzeri, Gianmarco; Motamedi, Massoud; Cheng, Xiaodong; Liu, Hua; Zhang, Wenbo.

In: The Journal of experimental medicine, Vol. 217, No. 4, 06.04.2020.

Research output: Contribution to journalArticle

Liu, Wei ; Ha, Yonju ; Xia, Fan ; Zhu, Shuang ; Li, Yi ; Shi, Shuizhen ; Mei, Fang C. ; Merkley, Kevin ; Vizzeri, Gianmarco ; Motamedi, Massoud ; Cheng, Xiaodong ; Liu, Hua ; Zhang, Wenbo. / Neuronal Epac1 mediates retinal neurodegeneration in mouse models of ocular hypertension. In: The Journal of experimental medicine. 2020 ; Vol. 217, No. 4.
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