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V. Torbidoni, M. Iribarne, A. M. Suburo; Endothelinergic Receptors and the Stress-Activated Cascades in light Induced Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4414. doi: https://doi.org/.
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ET-1 and its receptors, ETR-A and ETR-B, are broadly expressed in murine retina. In light-induced retinal degeneration, blockade of endothelinergic receptors decreases apoptosis markers in photoreceptors and reduces gliosis. Since the A/P transcription factor and various MAPK pathways might be involved in photoreceptor apoptosis, we studied the effects of tezosentan, a dual endothelinergic blocker, on JNK (c-Jun N-terminal Kinase) pathway in retinas subjected to light damage.
Balb/c mice were exposed to continuous illumination (CI, 1,500 lux) during 1, 2 or 4 days. Control and CI animals were separated in two groups, one received daily saline injections whereas the other received tezosentan (sc, 10 mg/kg/day). We used immunohistochemistry and Western blot to evaluate localization and levels of activated JNK (pJNK) and c-Jun (pJun).
Control retinas injected with saline displayed pJNK immunoreactivity in the Inner Plexiform Layer (IPL). 1 day after CI, immunoreactivity appeared in Müller cell vitreous endfeet and in bodies of the Inner Nuclear Layer (INL), probably corresponding to Müller cells. An increase of pJNK immunoreactivity in Müller processes and bodies and in the IPL was observed in CI retinas treated with tezosentan. After tezosentan, pJNK immunoreactivity appeared in vitreal endfeet of Müller even in control retinas. pJNK immunoreactivity increased with longer illumination periods.In control animals, the layer of optic fibers displayed the strongest pJun immunoreactivity. The ganglion cell layer (GCL) and IPL also showed pJun immunoreactivity. Tezosentan did not modify basal levels and distribution of pJun immunoreactivity.1 day after CI, pJun immunoreactivity increased in nuclei of the GCL and appeared in nuclei of INL. pJun-immunoreactive photoreceptor nuclei appeared 2 and 4 days after CI. In controls, tezosentan increased the number of pJun-immunoreactive nuclei in the INL. Tezosentan treatment of animals subjected to CI increased intensity of pJun immunoreactivity. It also increased the proportion of INL and photoreceptor nuclei showing this immunoreactivity.Increases of pJNK and pJun induced by tezosentan and CI were also demonstrated in Western blots.
Our observations indicate that under control condition, the JNK pathway is activated in GCL. CI induces activation of this pathway in Müller cells and photoreceptors. Tezosentan increased JNK activation in the same cells. Modulation of stress-activated cascades by endothelinergic receptors could be involved in survival of photoreceptors under light injury.
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