American Diabetes Association
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Pathogenic Role of Diabetes-induced Overexpression of Kallistatin in Corneal Wound Healing Deficiency through Inhibition of Canonical Wnt Signaling

posted on 2022-01-21, 16:44 authored by Wentao Liang, Li Huang, Xiang Ma, Lijie Dong, Rui Cheng, Marcus Dehdarani, Dimitrios Karamichos, Jian-xing Ma
It was reported previously that circulation levels of kallistatin, an endogenous Wnt signaling inhibitor, are increased in diabetic patients. The present study was to determine the role of kallistatin in delayed wound healing in diabetic cornea. Immunostaining and Western blot analysis showed kallistatin levels were upregulated in diabetic human and rodent corneas. In murine corneal wound healing models, the canonical Wnt signaling was activated in non-diabetic cornea and suppressed in diabetic cornea, correlating with delayed wound healing. Transgenic expression of kallistatin suppressed the activation of Wnt signaling in the cornea and delayed wound healing. Local inhibition of Wnt signaling in the cornea by kallistatin, an LRP6-blocking antibody, or the soluble VLDLR ectodomain (an endogenous Wnt signaling inhibitor) delayed wound healing. In contrast, ablation of VLDLR resulted in overactivation of Wnt/β-catenin signaling and accelerated corneal wound healing. Activation of Wnt signaling in the cornea accelerated wound healing. Activation of Wnt signaling promoted human corneal epithelial cell migration and proliferation, which was attenuated by kallistatin. Our findings suggested that diabetes-induced overexpression of kallistatin contributes to delayed corneal wound healing by inhibiting the canonical Wnt signaling. Thus, kallistatin and Wnt/β-catenin signaling in the cornea could be potential therapeutic targets for diabetic corneal complications.


This study was supported by National Institutes of Health (NIH) grants (EY019309, EY012231, EY028949, EY032930, EY032931) and Fujian Provincial Natural Science Foundation (Grant numbers 2018J01310).


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