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/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.

中文翻译：

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糖尿病引起的 Kallistatin 过表达通过抑制典型 Wnt 信号传导导致角膜伤口愈合缺陷的致病作用


此前有报道称，糖尿病患者体内的卡利司他（一种内源性 Wnt 信号抑制剂）循环水平升高。目前的研究旨在确定卡利他汀在糖尿病角膜伤口愈合延迟中的作用。免疫染色和蛋白质印迹分析显示，患有糖尿病的人类和啮齿动物的角膜中卡利司他汀水平上调。在小鼠角膜伤口愈合模型中，典型的 Wnt 信号在非糖尿病角膜中被激活，而在糖尿病角膜中被抑制，这与伤口愈合延迟相关。 kallistatin 的转基因表达抑制了角膜中 Wnt 信号的激活并延迟了伤口愈合。卡利司他（一种 LRP6 阻断抗体）或可溶性 VLDL 受体胞外域（一种内源性 Wnt 信号抑制剂）对角膜中 Wnt 信号的局部抑制会延迟伤口愈合。相反，VLDL受体的消融导致Wnt/β-连环蛋白信号过度激活并加速角膜伤口愈合。角膜中 Wnt 信号的激活加速了伤口愈合。 Wnt 信号传导的激活促进人角膜上皮细胞迁移和增殖，而卡利他汀可减弱这种作用。我们的研究结果表明，糖尿病诱导的卡利他汀过度表达通过抑制经典 Wnt 信号传导而导致角膜伤口愈合延迟。因此，角膜中的卡利他汀和 Wnt/β-连环蛋白信号传导可能是糖尿病角膜并发症的潜在治疗靶点。