Endothelin 1-induced retinal ganglion cell death is largely mediated by JUN activation
| Autor: | Stephanie B. Syc-Mazurek, Olivia J. Marola, Gareth R. Howell, Richard T. Libby |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Retinal Ganglion Cells Cancer Research genetic structures Immunology Apoptosis DNA damage-inducible transcript 3 Biology Retinal ganglion Article Retina 03 medical and health sciences Cellular and Molecular Neuroscience Mice 0302 clinical medicine Genes jun medicine Animals Humans lcsh:QH573-671 Neurodegeneration Cell Death Endothelin-1 lcsh:Cytology Glaucoma Cell Biology medicine.disease Endothelin 1 eye diseases Cell biology Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure Mechanisms of disease Retinal ganglion cell sense organs Muller glia 030217 neurology & neurosurgery |
| Zdroj: | Cell Death & Disease Cell Death and Disease, Vol 11, Iss 9, Pp 1-13 (2020) |
| ISSN: | 2041-4889 |
| Popis: | Glaucoma is a neurodegenerative disease characterized by loss of retinal ganglion cells (RGCs), the output neurons of the retina. Multiple lines of evidence show the endothelin (EDN, also known as ET) system is important in glaucomatous neurodegeneration. To date, the molecular mechanisms within RGCs driving EDN-induced RGC death have not been clarified. The pro-apoptotic transcription factor JUN (the canonical target of JNK signaling) and the endoplasmic reticulum stress effector and transcription factor DNA damage inducible transcript 3 (DDIT3, also known as CHOP) have been shown to act downstream of EDN receptors. Previous studies demonstrated that JUN and DDIT3 were important regulators of RGC death after glaucoma-relevant injures. Here, we characterized EDN insult in vivo and investigated the role of JUN and DDIT3 in EDN-induced RGC death. To accomplish this, EDN1 ligand was intravitreally injected into the eyes of wildtype, Six3-cre+Junfl/fl (Jun−/−), Ddit3 null (Ddit3−/−), and Ddit3−/−Jun−/− mice. Intravitreal EDN1 was sufficient to drive RGC death in vivo. EDN1 insult caused JUN activation in RGCs, and deletion of Jun from the neural retina attenuated RGC death after EDN insult. However, deletion of Ddit3 did not confer significant protection to RGCs after EDN1 insult. These results indicate that EDN caused RGC death via a JUN-dependent mechanism. In addition, EDN signaling is known to elicit potent vasoconstriction. JUN signaling was shown to drive neuronal death after ischemic insult. Therefore, the effects of intravitreal EDN1 on retinal vessel diameter and hypoxia were explored. Intravitreal EDN1 caused transient retinal vasoconstriction and regions of RGC and Müller glia hypoxia. Thus, it remains a possibility that EDN elicits a hypoxic insult to RGCs, causing apoptosis via JNK-JUN signaling. The importance of EDN-induced vasoconstriction and hypoxia in causing RGC death after EDN insult and in models of glaucoma requires further investigation. |
| Databáze: | OpenAIRE |
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