Oxidative stress-induced signalling governing Müller cell reactivity

In recent times, oxidative stress has been identified as a major instigator of numerous conditions of aging and inflammation. The retina is subject to high levels of oxidative stress due to its high oxygen per weight requirements and perpetual exposure to light stress. Several diseases, such as macular degeneration and diabetic retinopathy are positively identified as having an oxidative stress pathophysiological component. These conditions are the leading causes of blindness in the first world adult population, thus representing significant morbidity to both economy and society. The retina has endogenous protection mechanisms that provide a degree of protection against common insults. One such mechanism involves induction of changes to the trans-retinal Müller cell. In response to certain physical or biological stimuli, the Müller cell becomes reactive, resulting in phenotypic changes such as increased release of growth factors, changes in extracellular fluid and ion uptake or proliferation that in certain contexts may limit retinal damage. However, in other contexts, such a response may be inappropriate, exacerbating retinal damage or disease. In order to understand and perhaps control Müller cell reactive expression, an unprecedented look at the early signalling cascades in response to prototypical oxidative stress agent, hydrogen peroxide, was undertaken. Conditions whereby hydrogen peroxide induced reactive Müller cell migration, proliferation and hypertrophy were optimized. Using these conditions, assay of the expression of select major signal transducing entities was performed in the presence and absence of inhibitors. This method identified hydrogen peroxide as enhancing ADAM-17 activity and tyrosine kinase receptors such as the epidermal growth factor receptor. Transduction of the hydrogen peroxide stimulated signal caused activation of ERK/MAPK and PI3K/Akt signalling pathways with subsequent induction of Egr1 expression and activity. Concomitantly, the ER