Substance P Promotes Diabetic Corneal Epithelial Wound Healing Through Molecular Mechanisms Mediated via the Neurokinin-1 Receptor
Substance P Promotes Diabetic Corneal Epithelial Wound Healing Through Molecular Mechanisms Mediated via the Neurokinin-1 Receptor
复制标题
P 物质通过 Neurokinin-1 受体介导的分子机制促进糖尿病角膜上皮伤口愈合
DOI：
10.2337/db14-0163
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发表时间：
2014-12-01
期刊：
影响因子：
7.7
通讯作者：
Zhou, Qingjun
中科院分区：
文献类型：
--
作者：
Yang, Lingling;Di, Guohu;Zhou, Qingjun
P物质（SP）是一种神经肽，主要由感觉神经纤维释放，在糖尿病角膜上皮伤口愈合中具有潜在的保护作用。然而，其分子机制仍不清楚。我们研究了SP对高血糖诱导的角膜上皮伤口愈合缺陷的保护机制，使用1型糖尿病小鼠和高糖处理的角膜上皮细胞。高眼压诱导角膜上皮伤口愈合延迟，伴随角膜感觉减弱、线粒体功能障碍、Akt、表皮生长因子受体（EGFR）和Sirt 1活化受损以及活性氧（ROS）清除能力降低。然而，SP应用促进上皮伤口愈合，角膜感觉的恢复，线粒体功能的改善，Akt，EGFR和Sirt 1的重新激活，以及增加ROS清除能力，在糖尿病小鼠角膜上皮和高糖处理的角膜上皮细胞。SP对糖尿病角膜上皮愈合的促进作用可被神经激肽-1（NK-1）受体拮抗剂完全阻断。此外，结膜下注射NK-1受体拮抗剂也可引起正常小鼠糖尿病性角膜病变。总之，结果表明，SP-NK-1受体信号转导在维持角膜上皮稳态中起着关键作用，并且通过NK-1受体的SP信号转导有助于通过拯救Akt、EGFR和Sirt 1的激活、改善线粒体功能和增加ROS清除能力来促进糖尿病角膜上皮伤口愈合。
Substance P (SP) is a neuropeptide, predominantly released from sensory nerve fibers, with a potentially protective role in diabetic corneal epithelial wound healing. However, the molecular mechanism remains unclear. We investigated the protective mechanism of SP against hyperglycemia-induced corneal epithelial wound healing defects, using type 1 diabetic mice and high glucose–treated corneal epithelial cells. Hyperglycemia induced delayed corneal epithelial wound healing, accompanied by attenuated corneal sensation, mitochondrial dysfunction, and impairments of Akt, epidermal growth factor receptor (EGFR), and Sirt1 activation, as well as decreased reactive oxygen species (ROS) scavenging capacity. However, SP application promoted epithelial wound healing, recovery of corneal sensation, improvement of mitochondrial function, and reactivation of Akt, EGFR, and Sirt1, as well as increased ROS scavenging capacity, in both diabetic mouse corneal epithelium and high glucose–treated corneal epithelial cells. The promotion of SP on diabetic corneal epithelial healing was completely abolished by a neurokinin-1 (NK-1) receptor antagonist. Moreover, the subconjunctival injection of NK-1 receptor antagonist also caused diabetic corneal pathological changes in normal mice. In conclusion, the results suggest that SP-NK-1 receptor signaling plays a critical role in the maintenance of corneal epithelium homeostasis, and that SP signaling through the NK-1 receptor contributes to the promotion of diabetic corneal epithelial wound healing by rescued activation of Akt, EGFR, and Sirt1, improvement of mitochondrial function, and increased ROS scavenging capacity.