Antiangiogenic and antineuroinflammatory effects of kallistatin through interactions with the canonical Wnt pathway.
Antiangiogenic and antineuroinflammatory effects of kallistatin through interactions with the canonical Wnt pathway.
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作者：
Liu X;Zhang B;McBride JD;Zhou K;Lee K;Zhou Y;Liu Z;Ma JX
卡利司他汀是丝氨酸蛋白酶抑制剂超家族的一员。在糖尿病视网膜病变（DR）患者中，卡利司他汀水平在玻璃体中降低而在循环中升高。为了研究kallistatin在DR和Wnt通路激活中的作用，我们在包括视网膜在内的多个组织中产生了过表达kallistatin的kallistatin转基因（kallistatin- tg）小鼠。在氧诱导视网膜病变（OIR）模型中，卡利司他汀过表达可减弱缺血诱导的视网膜新生血管。在糖尿病小鼠中，过表达卡利司他汀可改善视网膜血管渗漏、白细胞淤积、血管内皮生长因子和细胞内粘附分子的过表达。此外，kallistatin过表达也抑制了视网膜Wnt通路的激活。在糖尿病Wnt报告基因（BAT-gal）小鼠中，卡利司他汀过表达抑制视网膜Wnt报告基因的活性。在培养的视网膜细胞中，卡利司他汀阻断高糖和Wnt配体诱导的Wnt通路激活。共沉淀和配体结合实验均表明，卡利司他汀与Wnt共受体LRP6具有高亲和力（Kd = 4.5 nmol/L）。这些观察结果表明，卡利司他汀是一种内源性LRP6拮抗剂和Wnt信号传导抑制剂。阻断Wnt信号可能是其抗血管生成和抗神经炎症作用的一种机制。
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.
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