title: Substance P promotes diabetic corneal epithelial wound healing through molecular mechanisms mediated via the neurokinin-1 receptor.
abstract: 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.
authors.affiliation: State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Yang
authors.affiliation: State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
authors.forename: Guohu
authors.initials: G
authors.lastname: Di
authors.affiliation: State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Qi
authors.affiliation: State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
authors.forename: Mingli
authors.initials: M
authors.lastname: Qu
authors.affiliation: State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
authors.forename: Haoyun
authors.initials: H
authors.lastname: Duan
authors.affiliation: Department of Integrative Medical Biology, Umeå University, Umeå, Sweden.
authors.forename: Patrik
authors.initials: P
authors.lastname: Danielson
authors.affiliation: State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China qjzhou2000@hotmail.com lixin_xie@hotmail.com.
authors.forename: Lixin
authors.initials: L
authors.lastname: Xie
authors.affiliation: State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China qjzhou2000@hotmail.com lixin_xie@hotmail.com.
authors.forename: Qingjun
authors.initials: Q
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002460:Cell Line; D003315:Cornea / Q000187:drug effects* / Q000378:metabolism; D065306:Corneal Injuries / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental; D003922:Diabetes Mellitus, Type 1; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000187:drug effects* / Q000378:metabolism; D056564:Sirtuin 1 / Q000187:drug effects / Q000378:metabolism; D013373:Substance P / Q000494:pharmacology*; D014110:Touch / Q000187:drug effects / Q000502:physiology; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology
chemical_list: D018377:Neurotransmitter Agents; D017382:Reactive Oxygen Species; D018040:Receptors, Neurokinin-1; D013373:Substance P; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1