Antiangiogenic and Antineuroinflammatory Effects of Kallistatin Through Interactions With the Canonical Wnt Pathway
- Xiaochen Liu1,2,
- Bin Zhang3,
- Jeffrey D. McBride4,
- Kevin Zhou2,
- Kyungwon Lee4,
- Yueping Zhou1,
- Zuguo Liu1⇑ and
- Jian-xing Ma2⇑
- 1Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, China
- 2Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- 3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
- 4Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- Corresponding authors: Zuguo Liu, , and Jian-xing Ma, .
Kallistatin is a member of the serine proteinase inhibitor superfamily. Kallistatin levels have been shown to be decreased in the vitreous while increased in the circulation of patients with diabetic retinopathy (DR). Overactivation of the Wnt pathway is known to play pathogenic roles in DR. To investigate the role of kallistatin in DR and in Wnt pathway activation, we generated kallistatin transgenic (kallistatin-TG) mice overexpressing kallistatin in multiple tissues including the retina. In the oxygen-induced retinopathy (OIR) model, kallistatin overexpression attenuated ischemia-induced retinal neovascularization. In diabetic kallistatin-TG mice, kallistatin overexpression ameliorated retinal vascular leakage, leukostasis, and overexpression of vascular endothelial growth factor and intracellular adhesion molecule. Furthermore, kallistatin overexpression also suppressed Wnt pathway activation in the retinas of the OIR and diabetic models. In diabetic Wnt reporter (BAT-gal) mice, kallistatin overexpression suppressed retinal Wnt reporter activity. In cultured retinal cells, kallistatin blocked Wnt pathway activation induced by high glucose and by Wnt ligand. Coprecipitation and ligand-binding assays both showed that kallistatin binds to a Wnt coreceptor LRP6 with high affinity (Kd = 4.5 nmol/L). These observations suggest that kallistatin is an endogenous antagonist of LRP6 and inhibitor of Wnt signaling. The blockade of Wnt signaling may represent a mechanism for its antiangiogenic and antineuroinflammatory effects.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-1710/-/DC1.
See accompanying commentary, p. 3993.
- Received December 11, 2012.
- Accepted July 20, 2013.
- © 2013 by the American Diabetes Association.
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