TY - JOUR
T1 - Pathogenic Role of Diabetes-Induced Overexpression of Kallistatin in Corneal Wound Healing Deficiency Through Inhibition of Canonical Wnt Signaling
AU - Liang, Wentao
AU - Huang, Li
AU - Ma, Xiang
AU - Dong, Lijie
AU - Cheng, Rui
AU - Dehdarani, Marcus
AU - Karamichos, Dimitrios
AU - Ma, Jian Xing
N1 - Funding Information:
Funding. This study was supported by National Institutes of Health National Eye Institute grants (EY019309, EY012231, EY028949, EY032930, EY032931) and Fujian Provincial Natural Science Foundation (grant 2018J01310). The authors like to thank the technical support from the Diabetic Animal Core and Histology and Image Core of Diabetes Center of Biomedical Research Excellence (CoBRE) by National Institute of General Medical Sciences (GM122744), and the Vision Core supported by National Eye Institute P30 (EY021725). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. W.L. and L.H. performed experiments, acquired and analyzed data, and wrote the manuscript. X.M., L.D., and R.C. conducted experiments and acquired data. M.D. generated the kallistatin protein and Mab2F1 antibody used in this study. D.K. and J.-x.M. designed the research, analyzed data, and wrote and edited the manuscript. J.-x.M. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in abstract form at the 2020 Trans-Agency Scientific Meeting on Developing Medical Countermeasures to Treat the Acute and Chronic Effects of Ocular Chemical Toxicity, Bethesda, MD, 25–26 February 2020.
Publisher Copyright:
© 2022 by the American Diabetes Association.
PY - 2022/4
Y1 - 2022/4
N2 - It was reported previously that circulation levels of kallistatin, an endogenous Wnt signaling inhibitor, are increased in patients with diabetes. The current study was conducted to determine the role of kallistatin in delayed wound healing in diabetic corneas. Immunostaining and Western blot analysis showed kallistatin levels were upregulated in corneas from humans and rodents with diabetes. In murine corneal wound healing models, the canonical Wnt signaling was activated in nondiabetic corneas and suppressed in diabetic corneas, 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 VLDL receptor ectodomain (an endogenous Wnt signaling inhibitor) delayed wound healing. In contrast, ablation of the VLDL receptor resulted in overactivation of Wnt/b-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/ b-catenin signaling in the cornea could be potential therapeutic targets for diabetic corneal complications.
AB - It was reported previously that circulation levels of kallistatin, an endogenous Wnt signaling inhibitor, are increased in patients with diabetes. The current study was conducted to determine the role of kallistatin in delayed wound healing in diabetic corneas. Immunostaining and Western blot analysis showed kallistatin levels were upregulated in corneas from humans and rodents with diabetes. In murine corneal wound healing models, the canonical Wnt signaling was activated in nondiabetic corneas and suppressed in diabetic corneas, 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 VLDL receptor ectodomain (an endogenous Wnt signaling inhibitor) delayed wound healing. In contrast, ablation of the VLDL receptor resulted in overactivation of Wnt/b-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/ b-catenin signaling in the cornea could be potential therapeutic targets for diabetic corneal complications.
UR - http://www.scopus.com/inward/record.url?scp=85128000045&partnerID=8YFLogxK
U2 - 10.2337/db21-0740
DO - 10.2337/db21-0740
M3 - Article
C2 - 35044447
AN - SCOPUS:85128000045
SN - 0012-1797
VL - 71
SP - 747
EP - 761
JO - Diabetes
JF - Diabetes
IS - 4
ER -