Oxidative Stress Induces Biphasic ERK1/2 Activation in the RPE with Distinct Effects on Cell Survival at Early and Late Activation. (August 2015)

• Record Type: Journal Article
• Authors: Koinzer, Stefan; Reinecke, Kirstin; Herdegen, Thomas; Roider, Johann; Klettner, Alexa
• Is Part Of: Current eye research. Volume 40:Number 8(2015:Aug.)
• Page Start: 853
• Page End: 857
• Publication Date: 2015-08
• Subjects: Ophthalmology -- Periodicals; Eye -- Diseases -- Periodicals; Ophthalmology -- Periodicals; 573.88
• DOI: 10.3109/02713683.2014.961613
• Languages: English
• ISSNs: 0271-3683

Abstract

<abstract> <title>Abstract</title> <p> <italic>Purpose</italic>: Oxidative stress is considered a major factor in the deterioration of retinal pigment epithelium (RPE) cells in dry age-related macular degeneration (AMD). The MAPK ERK1/2 can be activated by oxidative stress, may exert both pro- and anti-apoptotic functions, and has recently been proposed as a major factor in RPE degeneration in atrophic changes. Nrf2 is a master regulator of oxidative stress defense and ERK1/2 is an upstream activator of Nrf2. In this study, we investigate the participation of ERK1/2 in oxidative stress pathways in connection with Nrf2.</p> <p> <italic>Methods</italic>: Nrf2 knock-out and wild-type primary RPE cells were prepared from mouse eyes. Oxidative stress was induced by different concentrations of <italic>t</italic>-butylhydroperoxide. Mitogen-activated protein kinases (MAPKs) were blocked by commercially available inhibitors (SB203580, U0126, SP600125). Cell viability was determined by MTT assay. ERK1/2 expression and activation were assessed by Western blotting.</p> <p> <italic>Results</italic>: Oxidative stress induced concentration dependent cell death, which occurred at lower concentrations in Nrf2 knock-out RPE. Western blot analysis displayed a biphasic activation of ERK1/2 in murine wild-type RPE and the inhibition of late, but not early activation of ERK1/2 exerted protection in wild-type murine RPE cells. The biphasic activation of ERK1/2 is lost in Nrf2 knock-out mice, and inhibition of ERK1/2 was generally protective. The inhibition of MAPK JNK or p38 exerted no protection, irrespective of Nrf2.</p> <p> <italic>Conclusion</italic>: RPE cells display a biphasic activation of ERK1/2 after oxidative insult, of which the late activation is pro-apoptotic. The biphasic activation is lost in Nrf2 knock-outs, suggesting that early ERK1/2 activation may be connected to Nrf2 signaling. In addition, ERK1/2 activation in Nrf2 knock-outs mediates oxidative stress-induced cell death.</p> </abstract>