Abstract
This study aimed to investigate the high glucose damage on human retinal pigment epithelial (RPE) cells, the role of p38 MAPK signaling pathway and how dimethyl fumarate can regulate that. We carried out in vitro studies on ARPE-19 cells exposed to physiological and high glucose (HG) conditions, to evaluate the effects of DMF on cell viability, apoptosis, and expression of inflammatory and angiogenic biomarkers such as COX-2, iNOS, IL-1β, and VEGF. Our data have demonstrated that DMF treatment attenuated HG-induced apoptosis, as confirmed by reduction of BAX/Bcl-2 ratio. Furthermore, in RPE cells exposed to HG we observed a significant increase of iNOS, COX-2, and IL-1β expression, that was reverted by DMF treatment. Moreover, DMF reduced the VEGF levels elicited by HG, inhibiting p38 MAPK signaling pathway. The present study demonstrated that DMF provides a remarkable protection against high glucose-induced damage in RPE cells through p38 MAPK inhibition and the subsequent down-regulation of VEGF levels, suggesting that DMF is a small molecule that represents a good candidate for diabetic retinopathy treatment and warrants further in vivo and clinical evaluation.
Highlights
Diabetic retinopathy (DR) is the leading cause of visual impairment and preventable blindness, and it represents an important cost in terms of social and economic issues for health care systems worldwide
In the present study we explored the hypothesis that the DMF is able to interfere with p38 MAPK signaling and down-regulate vascular endothelial growth factor (VEGF) levels in retinal pigment epithelial (RPE) cells exposed to high glucose damage
Anti-Apoptotic Effect of DMF on RPE Cells Exposed to High Glucose
Summary
Diabetic retinopathy (DR) is the leading cause of visual impairment and preventable blindness, and it represents an important cost in terms of social and economic issues for health care systems worldwide. Vision loss is associated with retinal pigment epithelial (RPE) damage, these retinal cells play a key role in terms of protection and functional maintenance of photoreceptors (Plafker et al, 2012). It has been observed that sustained hyperglycemia promotes the activation of both apoptotic (Kowluru et al, 2004) and inflammatory mechanisms (Yuuki et al, 2001) as well as dysregulation of growth factors and hypoxia-inducible factors (Grant et al, 2004; Schlingemann, 2004; D’Amico et al, 2015). Upregulation of cytokines and other proinflammatory mediators inducing chronic inflammation, is believed to actively contribute to the DR-associated damage to the retinal vasculature (Zheng and Kern, 2009; Boss et al, 2017) by triggering apoptosis of RPE cells and promotion of retinal neovascularization (Kim et al, 2015; Xiao et al, 2017).
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