Diabetic retinopathy remains the fifth leading cause of preventable blindness worldwide. Interventions to prevent progression of diabetic retinopathy are limited to improved glycemic control (a challenging goal for all diabetic patients) and to lase photocoagulation (available only for advanced stages of retinopathy). We and others have reported that adrenergic signaling is lost in the diabetic retina, suggesting that development of novel agents to restore autonomic homeostasis is necessary. Unfortunately, currently available adrenergic agents are associated with adverse systemic or non-specific effects. These problems inspired our group to synthesize compound 49b, a novel and selective -adrenergic receptor agonist, as a potential paradigm shift in the prevention of diabetic retinopathy. Our preliminary data suggest that compound 49b prevents the formation of degenerate capillaries, which involves degenerate capillary formation, which are the hallmark pathology noted in the diabetic retinal vasculature. In addition to preventing degenerate capillaries in vivo, compound 49b prevents the cleavage of caspase 3, a well- established marker of apoptosis, in retinal endothelial cells (REC) in vitro, suggesting that Compound 49b can decrease apoptosis. In the oxygen-induced model of retinopathy, others have associated increased levels of insulin-like growth factor binding protein-3 (IGFBP-3) with protection from REC apoptosis. Furthermore, using the streptozotocin-induced diabetic rat model, we observed that chronic insulin deficiency reduced IGFBP-3 protein levels in whole retinal lysates, but topical application of compound 49b to the eye restored retinal IGFBP-3 to its control level in these insulin- deficient rats. Thus, we hypothesize that compound 49b prevents the critical vascular damage underlying diabetic retinopathy in part by restoring IGFBP-3 levels in retinal endothelial cells. This project focuses on a deeper understanding of the mechanisms underlying this protective action.

Public Health Relevance

We have shown that decreased -adrenergic receptor activity can directly produce retinal damage similar to diabetic retinopathy. This study will dissect the cellular mechanisms of the protective role of -adrenergic receptor agonists on IGFBP3 levels and retinal endothelial cell apoptosis

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY022045-06
Application #
9131738
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Shen, Grace L
Project Start
2012-09-01
Project End
2017-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
6
Fiscal Year
2016
Total Cost
$384,791
Indirect Cost
$134,791
Name
Wayne State University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
He, Hui; Weir, Rebecca L; Toutounchian, Jordan J et al. (2017) The quinic acid derivative KZ-41 prevents glucose-induced caspase-3 activation in retinal endothelial cells through an IGF-1 receptor dependent mechanism. PLoS One 12:e0180808
Liu, Li; Jiang, Youde; Chahine, Adam et al. (2017) Epac1 agonist decreased inflammatory proteins in retinal endothelial cells, and loss of Epac1 increased inflammatory proteins in the retinal vasculature of mice. Mol Vis 23:1-7
Ye, Eun-Ah; Liu, Li; Steinle, Jena J (2017) miR-15a/16 inhibits TGF-beta3/VEGF signaling and increases retinal endothelial cell barrier proteins. Vision Res 139:23-29
Ye, Eun-Ah; Steinle, Jena J (2017) Regulatory role of microRNA on inflammatory responses of diabetic retinopathy. Neural Regen Res 12:580-581
Jiang, Youde; Liu, Li; Steinle, Jena J (2017) Compound 49b Regulates ZO-1 and Occludin Levels in Human Retinal Endothelial Cells and in Mouse Retinal Vasculature. Invest Ophthalmol Vis Sci 58:185-189
Jiang, Youde; Liu, Li; Curtiss, Elizabeth et al. (2017) Epac1 Blocks NLRP3 Inflammasome to Reduce IL-1? in Retinal Endothelial Cells and Mouse Retinal Vasculature. Mediators Inflamm 2017:2860956
Berger, Elizabeth A; Carion, Thomas W; Jiang, Youde et al. (2016) ?-Adrenergic receptor agonist, compound 49b, inhibits TLR4 signaling pathway in diabetic retina. Immunol Cell Biol 94:656-61
Shi, Haoshen; Carion, Thomas W; Jiang, Youde et al. (2016) VIP protects human retinal microvascular endothelial cells against high glucose-induced increases in TNF-? and enhances RvD1. Prostaglandins Other Lipid Mediat 123:28-32
Liu, Li; Jiang, Youde; Steinle, Jena J (2016) Compound 49b Restores Retinal Thickness and Reduces Degenerate Capillaries in the Rat Retina following Ischemia/Reperfusion. PLoS One 11:e0159532
Ye, Eun-Ah; Steinle, Jena J (2015) miR-15b/16 protects primary human retinal microvascular endothelial cells against hyperglycemia-induced increases in tumor necrosis factor alpha and suppressor of cytokine signaling 3. J Neuroinflammation 12:44

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