Therapeutic Potential of a Monoclonal Antibody Blocking the Wnt Pathway in Diabetic Retinopathy
- Kyungwon Lee1,
- Yang Hu2,
- Lexi Ding2,
- Ying Chen2,
- Yusuke Takahashi3,
- Robert Mott2 and
- Jian-xing Ma1,2⇓
- 1Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- 2Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- 3Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- Corresponding author: Jian-xing Ma, .
Dysregulation of Wnt/β-catenin signaling contributes to the development of diabetic retinopathy by inducing retinal inflammation, vascular leakage, and neovascularization. Here, we evaluated the inhibitory effect of a monoclonal antibody (Mab) specific for the E1E2 domain of Wnt coreceptor low-density lipoprotein receptor–related protein 6, Mab2F1, on canonical Wnt signaling and its therapeutic potential for diabetic retinopathy. Mab2F1 displayed robust inhibition on Wnt signaling with a half-maximal inhibitory concentration (IC50) of 20 μg/mL in retinal pigment epithelial cells. In addition, Mab2F1 also attenuated the accumulation of β-catenin and overexpression of vascular endothelial growth factor, intercellular adhesion molecule-1, and tumor necrosis factor-α induced by high-glucose medium in retinal endothelial cells. In vivo, an intravitreal injection of Mab2F1 significantly reduced retinal vascular leakage and decreased preretinal vascular cells in oxygen-induced retinopathy (OIR) rats, demonstrating its inhibitory effects on ischemia-induced retinal neovascularization. Moreover, Mab2F1 blocked the overexpression of the inflammatory/angiogenic factors, attenuated leukostasis, and reduced retinal vascular leakage in both early and late stages of streptozotocin-induced diabetes. In conclusion, Mab2F1 inhibits canonical Wnt signaling, vascular leakage, and inflammation in the retina of diabetic retinopathy models, suggesting its potential to be used as a therapeutic agent in combination with other antiangiogenic compounds.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-0300/-/DC1.
- Received March 13, 2011.
- Accepted May 11, 2012.
- © 2012 by the American Diabetes Association.
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