Vascular inflammation plays a critical role in the pathogenesis of diabetic retinopathy. Recently, Interleukin-6 (IL-6) trans-signaling via soluble IL-6 receptor (sIL-6R) has emerged as a prominent regulator of inflammation in endothelial cells. This study was designed to test the hypothesis that selective inhibition of the IL-6 trans-signaling pathway will attenuate inflammation and subsequent barrier disruption in retinal endothelial cells. Human retinal endothelial cells (HRECs) were exposed to IL-6 and sIL-6R to induce IL-6 trans-signaling and the commercially available compound sgp130Fc (soluble gp-130 fused chimera) was used to selectively inhibit IL-6 trans-signaling. IL-6 trans-signaling activation caused a significant increase in STAT3 phosphorylation, expression of adhesion molecules, ROS production and apoptosis in HRECs whereas a significant decrease in mitochondrial membrane potential and NO production was observed in IL-6 trans-signaling activated cells. These changes were not observed in cells pre-treated with sgp130Fc. IL-6 trans-signaling activation was sufficient to cause barrier disruption in endothelial monolayers and pre-treatment of HRECs with sgp130Fc, maintained endothelial barrier function similar to that of untreated cells. Thus, in conclusion, these results indicate that IL-6 trans-signaling is an important mediator of inflammation, apoptosis and barrier disruptive effects in the retinal endothelial cells and inhibition of the IL-6 trans-signaling pathway using sgp130-Fc attenuates vascular inflammation and endothelial barrier disruption.

Diabetic retinopathy (DR) is a microvascular disease of the retina and the leading cause of visual disability in diabetic patients. Genetic factors have shown to play a pivotal role in DR onset, and several candidate genes have been associated with its progression. A literature search was performed to identify the genes known to be associated with DR through linkage analysis, candidate gene association, and genome-wide association studies (GWAS). A further literature search was performed to discover their potential connection with various biological pathways. A total of 65 genes were found and several of these genes belong to major signaling pathways known to play a significant role in DR, including systemic inflammation, angiogenesis, and neurogenesis. A comprehensive analysis presented in this review will be helpful in unraveling the role of genetics in the pathogenesis of DR.

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