Abstract
Astrocytes are macroglial cells that have a crucial role in development of the retinal vasculature and maintenance of the blood-retina-barrier (BRB). Diabetes affects the physiology and function of retinal vascular cells including astrocytes (AC) leading to breakdown of BRB. However, the detailed cellular mechanisms leading to retinal AC dysfunction under high glucose conditions remain unclear. Here we show that high glucose conditions did not induce the apoptosis of retinal AC, but instead increased their rate of DNA synthesis and adhesion to extracellular matrix proteins. These alterations were associated with changes in intracellular signaling pathways involved in cell survival, migration and proliferation. High glucose conditions also affected the expression of inflammatory cytokines in retinal AC, activated NF-κB, and prevented their network formation on Matrigel. In addition, we showed that the attenuation of retinal AC migration under high glucose conditions, and capillary morphogenesis of retinal endothelial cells on Matrigel, was mediated through increased oxidative stress. Antioxidant proteins including heme oxygenase-1 and peroxiredoxin-2 levels were also increased in retinal AC under high glucose conditions through nuclear localization of transcription factor nuclear factor-erythroid 2-related factor-2. Together our results demonstrated that high glucose conditions alter the function of retinal AC by increased production of inflammatory cytokines and oxidative stress with significant impact on their proliferation, adhesion, and migration.
Highlights
Astrocytes (AC) are macroglial cells with important role in retinal vascular development, and provide physical support and nutrient for neurons in the central nerveous system
We recently showed activation of STAT1, through production of inflammatory cytokines in response to high glucose, is responsible for increased expression of proapoptotic protein Bim, increased oxidative stress, and retinal pericyte apoptosis [15].To respond to oxidative stress, protective mechanisms are implicated in cells exposed to various stress including high glucose conditions
High glucose conditions increased the expression of Glial fibrillary acidic protein (GFAP) in retinal AC, and attenuated the migration and morphogenesis of AC on Matrigel
Summary
Astrocytes (AC) are macroglial cells with important role in retinal vascular development, and provide physical support and nutrient for neurons in the central nerveous system. AC have foot processes that envelop retinal endothelial cells (EC) in blood vessels to maintain blood retina barrier (BRB) [1,2]. AC regulate fluid and electrolyte balance by expressing channel proteins including water channel proteins, aquaporin 4 and the potassium channel Kir4.1 at the luminal spaces of their end foot processes [3,4]. Astrocytes regulate blood barrier function by secreting growth factors such as transforming growth factor-b (TGF-b), glial-derived neurotrophic factor (GDNF), basic fibroblast growth factor (bFGF) and angiopoetin 1(ANG1) [5,6]. AC secretion of sonic hedgehog (Shh) enhances barrier function and decrease inflammatory mediators of the endothelium [7].
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