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Y. Chen, Y. Hu, T. Zhou, K. K. Zhou, R. Mott, G. Gao, M. Wu, M. Boulton, T. J. Lyons, J.-X. Ma; A Pathogenic Role of the Wnt Pathway in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4980.
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The Wnt pathway is known to regulate multiple biological and pathological processes. The purpose of this study was to investigate whether Wnt signaling plays a pathogenic role in diabetic retinopathy (DR).
Retinal levels of β-catenin, a key effector of the Wnt pathway, were compared between diabetic human donors with non-proliferative retinopathy (NPDR) and non-diabetic donors, and between DR models including streptozotocin-induced diabetic rats, Akita mice and rats with oxygen-induced retinopathy (OIR) and their respective non-diabetic controls. Retinal inflammation was evaluated by retinal vascular permeability and inflammatory factor levels. Retinal neovascularization (NV) was examined by fluorescein angiography and counting pre-retinal vascular cells.
Elevated levels and nuclear translocation of β-catenin were observed in the retinas from human donors with NPDR and in all of the three DR animal models. Retinal levels of low-density lipoprotein receptor-related proteins 5 and 6, co-receptors of Wnts, were also elevated in the diabetic and OIR models. In cultured endothelial cells, high glucose induced nuclear translocation of β-catenin, which was attenuated by an antioxidant, suggesting that oxidative stress is the direct cause of the Wnt pathway activation in diabetes. DKK1, a specific inhibitor of the Wnt pathway, ameliorated retinal inflammation and retinal NV in the DR models. DKK1 also blocked the ROS generation induced by high glucose, suggesting that the Wnt pathway contributes to the oxidative stress in diabetes.
The Wnt pathway is activated in DR and plays a pathogenic role in retinal inflammation and retinal NV. The Wnt pathway activation represents a new pathogenic mechanism of DR and thus, represents a new therapeutic target.
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