Endothelin-1 (ET-1) causes death of retinal neurons through activation of nitric oxide synthase (NOS) and production of superoxide anion

Oku, Hidehiro; Fukuhara, Masayuki; Komori, Asako; Okuno, Takashi; Sugiyama, Tetsuya; Ikeda, Tsunehiko

doi:10.1016/j.exer.2007.10.001

Cited by 15 publications

(11 citation statements)

References 71 publications

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“…Different retinal injuries upregulate both EDNRA and EDNRB, as well as EDN1 and EDN2 [3], and a growing body of data suggests roles in retinal pathogenesis including diabetic retinopathy and glaucoma [11]. EDN1 is elevated in aqueous humor of some glaucoma patients [12–14] and EDN1 has been shown to cause retinal ganglion cell death in experimental models for glaucoma [15, 16]. Opposed to the adverse effects seen by EDN1 in several injury models, EDN2 has displayed neuroprotective properties for photoreceptors.…”

Section: Introductionmentioning

confidence: 99%

Endothelin B Receptors on Primary Chicken Müller Cells and the Human MIO-M1 Müller Cell Line Activate ERK Signaling via Transactivation of Epidermal Growth Factor Receptors

et al. 2016

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Injury to the eye or retina triggers Müller cells, the major glia cell of the retina, to dedifferentiate and proliferate. In some species they attain retinal progenitor properties and have the capacity to generate new neurons. The epidermal growth factor receptor (EGFR) system and extracellular signal-regulated kinase (ERK) signaling are key regulators of these processes in Müller cells. The extracellular signals that modulate and control these processes are not fully understood. In this work we studied whether endothelin receptor signaling can activate EGFR and ERK signaling in Müller cells. Endothelin expression is robustly upregulated at retinal injury and endothelin receptors have been shown to transactivate EGFRs in other cell types. We analyzed the endothelin signaling system in chicken retina and cultured primary chicken Müller cells as well as the human Müller cell line MIO-M1. The Müller cells were stimulated with receptor agonists and treated with specific blockers to key enzymes in the signaling pathway or with siRNAs. We focused on endothelin receptor mediated transactivation of EGFRs by using western blot analysis, quantitative reverse transcriptase PCR and immunocytochemistry. The results showed that chicken Müller cells and the human Müller cell line MIO-M1 express endothelin receptor B. Stimulation by the endothelin receptor B agonist IRL1620 triggered phosphorylation of ERK1/2 and autophosphorylation of (Y1173) EGFR. The effects could be blocked by Src-kinase inhibitors (PP1, PP2), EGFR-inhibitor (AG1478), EGFR-siRNA and by inhibitors to extracellular matrix metalloproteinases (GM6001), consistent with a Src-kinase mediated endothelin receptor response that engage ligand-dependent and ligand-independent EGFR activation. Our data suggest a mechanism for how injury-induced endothelins, produced in the retina, may modulate the Müller cell responses by Src-mediated transactivation of EGFRs. The data give support to a view in which endothelins among several other functions, serve as an injury-signal that regulate the gliotic response of Müller cells.

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Section: Introductionmentioning

confidence: 99%

Endothelin B Receptors on Primary Chicken Müller Cells and the Human MIO-M1 Müller Cell Line Activate ERK Signaling via Transactivation of Epidermal Growth Factor Receptors

et al. 2016

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“…On the other hand, we suggested that ET-1 may act synergistically with glutamate to damage retinal neurons under hypoxic conditions through ETA receptors [41] . In addition, we verified that ET-1 caused the death of retinal neurons through activation of nitric oxide synthase and production of superoxide anions, which were upregulated by ETA receptor-mediated activation of NADPH oxidase [42,43] . Furthermore, Wang et al demonstrated the immunoreactivity of ETB receptor in GON and its association with astrocytes, suggesting that the glia-ET system may be involved in the pathologic mechanisms of neuronal degeneration in glaucoma [44] .…”

Section: Et Receptors and Gon In Ntgmentioning

confidence: 82%

Involvement of Endothelin-1 in the Pathophysiology of Normal-Tension Glaucoma

Sugiyama¹

2015

International Journal of Ophthalmic Research

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“…In addition, it is also known that NO may be one of the agents that contributes to the excessive production of ROS/RNS [5,43]. However, until recently there was no evidence that ET-1 could contribute to the formation of ROS/RNS (possibly via interaction with NADPH oxidases) [26,27,38]. It was also shown that ET-1 may induce oxidative stress in the cardiovascular system by increased free radical production via NADPH oxidases [10].…”

Section: Discussionmentioning

confidence: 96%

Reversal of Postischemic Hypoperfusion by Tempol: Endothelial Signal Transduction Mechanism

et al. 2011

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This report entails in vivo and in vitro studies concerned with free radical species involved in brain ischemia. The participation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the early manifestation of cerebral ischemia/reperfusion was investigated in gerbils exposed to transient global ischemia using 4-OH-2,2,6,6-tetramethylpiperidine-1-oxyl (TPL), a well-known antioxidant. TPL treatment reversed cerebral postischemic hypoperfusion and tissue edema in these animals. The findings are consistent with ROS/RNS participation in tissue injury and the reduction of cerebromicrovascular blood flow (CBF) during postischemic recirculation. The activation/deactivation of signal transduction pathway by oxidation/antioxidation [i.e., using hydrogen peroxide (H₂O₂)/TPL] was evaluated in cultured human brain endothelial cells (HBEC) to assess the involvement of endothelial-dependent mechanisms. The data showed that H₂O₂ activates various "stress" kinases and vasodilalator-stimulated phosphoprotein (VASP); activation of this pathway was reduced by inhibitors of Rho- or IP-3 kinases, as well as TPL. H₂O₂ also induced cytoskeleton (actin) rearrangements in HBEC; this effect was prevented by inhibitors of Rho/IP3 kinase or TPL. The observed activation/deactivation of H₂O₂-induced "stress" kinase is in agreement with the reported capacity of ROS/RNS to stimulate the oxidative signal transduction pathway. The noted TPL reduction of H₂O₂-induced phosphorylation of kinase strongly suggests that the beneficial effect of TPL implicates the stress signal transduction pathway. This may represent a mechanism for the cerebral postischemic manifestations observed by in vivo experiments.

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Endothelin-1 (ET-1) causes death of retinal neurons through activation of nitric oxide synthase (NOS) and production of superoxide anion

Cited by 15 publications

References 71 publications

Endothelin B Receptors on Primary Chicken Müller Cells and the Human MIO-M1 Müller Cell Line Activate ERK Signaling via Transactivation of Epidermal Growth Factor Receptors

Endothelin B Receptors on Primary Chicken Müller Cells and the Human MIO-M1 Müller Cell Line Activate ERK Signaling via Transactivation of Epidermal Growth Factor Receptors

Involvement of Endothelin-1 in the Pathophysiology of Normal-Tension Glaucoma

Reversal of Postischemic Hypoperfusion by Tempol: Endothelial Signal Transduction Mechanism

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