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Yang Lingling, Guohu Di, Qi Xia, Mingli Qu, Yao Wang, Haoyun Duan, Lixin Xie, Qingjun Zhou; Substance P promotes diabetic corneal epithelial wound healing by rescuing NK-1 receptor expression. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4699.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the protective mechanism of subtance P (SP) against hyperglycemia-induced delay of corneal epithelial wound healing.
C57BL/6 diabetic mice were induced by Streptozotocin and treated with SP topically. For NK-1 receptor (NK-1R) inhibition, NK-1R antagonist (L-733,060) was injected subconjunctivally 1 day before corneal epithelium crape or SP application. Control mice were treated with PBS vehicle. Corneal epithelial wound healing and corneal sensitivity were detected. All animal experiments were carried out in accordance with the Association for Research in Vision and Ophthalmology (ARVO) Statement for the Use of Animals in Ophthalmic and Vision Research. Mouse corneal epithelial cells (TKE2) were treated with 30 mM glucose in the absence or presence of SP or NK-1R antagonist for 3 days. The NK-1R expression (full-length and total isoforms), ROS, glutathione and mitochondria membrane potential, antioxidant genes expression, and the phosphorylation of Akt, EGFR and ERK1/2 in mouse corneal epithelium or TKE2 cells was determined by immuno-staining, western blotting and quantitative PCR assay.
Hyperglycemia or high glucose induced the decreasing expression of full-length NK-1R in corneal epithelium but no change in the expression of total NK-1R, accompanied with mitochondria dysfunction, decreased phosphorylation of Akt, EGFR and ERK1/2, and SOD2, catalase and NQO1 expression. However, SP promoted corneal epithelial wound healing, the recovery expression of full-length NK-1R, the improvement of mitochondria function, as well as the reactivation of Akt, EGFR and ERK1/2 phosphorylation and antioxidant proteins in both diabetic mouse corneal epithelium and high-glucose treated corneal epithelial cells. Moreover, the NK-1R antagonist abolished the promotion of SP on corneal epithelial wound healing, the improvement of signaling activation and ROS accumulation in hyperglycemia. In addition, the subconjunctival injection of NK-1R antagonist in normal mice caused similar impairments of corneal epithelial wound healing in diabetic mice.
The rescuing of full-length NK-1R by SP contributed to the promotion of diabetic corneal epithelial wound healing, and NK-1R may be a promising therapeutic target to treat diabetic keratopathy.
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