MANF Promotes Diabetic Corneal Epithelial Wound Healing and Nerve Regeneration by Attenuating Hyperglycemia-Induced Endoplasmic Reticulum Stress
MANF Promotes Diabetic Corneal Epithelial Wound Healing and Nerve Regeneration by Attenuating Hyperglycemia-Induced Endoplasmic Reticulum Stress
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MANF 通过减轻高血糖引起的内质网应激促进糖尿病角膜上皮伤口愈合和神经再生
DOI：
10.2337/db19-0835
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发表时间：
2020-06-01
期刊：
影响因子：
7.7
通讯作者：
Xie, Lixin
中科院分区：
文献类型：
--
作者：
Wang, Xiaochuan;Li, Weina;Xie, Lixin
中脑星形胶质细胞源性神经营养因子（MANF）是一种广泛表达于哺乳动物组织中的神经营养因子，在各种疾病模型（如糖尿病模型）中对神经元和其他细胞类型发挥关键的保护作用。然而，迄今为止，MANF在有或无糖尿病性角膜病变（DK）的角膜中的表达和作用仍不清楚。在这里，我们表明，MANF是丰富的表达在正常角膜上皮细胞，然而，MANF的表达显着减少，在未受伤和受伤的角膜上皮链脲佐菌素诱导的1型糖尿病C57 BL/6小鼠。重组人MANF能显著促进正常和糖尿病角膜上皮损伤愈合和神经再生。此外，MANF抑制高血糖诱导的内质网（ER）应激和ER应激介导的细胞凋亡。用4-苯基丁酸（4-PBA）减弱ER应激也改善了角膜上皮闭合和神经再生。然而，MANF和4-PBA的有益作用被Akt抑制剂和Akt特异性小干扰RNA（siRNA）消除。最后，我们揭示了结膜下注射MANF特异性siRNA可以阻止角膜上皮伤口愈合和神经再生。我们的研究结果提供了重要的证据，高血糖抑制MANF表达可能有助于延迟角膜上皮伤口愈合和受损的神经再生，通过增加ER应力，MANF可能是一个有用的治疗方式治疗DK。
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neurotrophic factor widely expressed in mammalian tissues, and it exerts critical protective effects on neurons and other cell types in various disease models, such as those for diabetes. However, to date, the expression and roles of MANF in the cornea, with or without diabetic keratopathy (DK), remain unclear. Here, we demonstrate that MANF is abundantly expressed in normal corneal epithelial cells; however, MANF expression was significantly reduced in both unwounded and wounded corneal epithelium in streptozotocin-induced type 1 diabetic C57BL/6 mice. Recombinant human MANF significantly promoted normal and diabetic corneal epithelial wound healing and nerve regeneration. Furthermore, MANF inhibited hyperglycemia-induced endoplasmic reticulum (ER) stress and ER stress–mediated apoptosis. Attenuation of ER stress with 4-phenylbutyric acid (4-PBA) also ameliorated corneal epithelial closure and nerve regeneration. However, the beneficial effects of MANF and 4-PBA were abolished by an Akt inhibitor and Akt-specific small interfering RNA (siRNA). Finally, we reveal that the subconjunctival injection of MANF-specific siRNA prevents corneal epithelial wound healing and nerve regeneration. Our results provide important evidence that hyperglycemia-suppressed MANF expression may contribute to delayed corneal epithelial wound healing and impaired nerve regeneration by increasing ER stress, and MANF may be a useful therapeutic modality for treating DK.