High glucose up-regulates Semaphorin 3A expression via the mTOR signaling pathway in keratinocytes: A potential mechanism and therapeutic target for diabetic small fiber neuropathy
High glucose up-regulates Semaphorin 3A expression via the mTOR signaling pathway in keratinocytes: A potential mechanism and therapeutic target for diabetic small fiber neuropathy
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高葡萄糖通过角质形成细胞中的 mTOR 信号通路上调 Semaphorin 3A 表达：糖尿病小纤维神经病变的潜在机制和治疗靶点
DOI：
10.1016/j.mce.2017.11.025
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发表时间：
2017-12
期刊：
影响因子：
--
通讯作者：
wang shan
中科院分区：
文献类型：
--
作者：
wang shan
小纤维神经病（SFN）是糖尿病常见的并发症，其特征是表皮内神经纤维密度降低（IENFD）。由角质形成细胞产生的脑信号蛋白3A（Sema 3A）对表皮内神经纤维具有化学排斥作用。mTOR信号传导可以介导对于轴突和树突的生长至关重要的局部蛋白质合成。因此，本研究旨在研究Sema 3A是否通过mTOR介导的p70 S6 K和4 E-BP 1信号通路在糖尿病角质形成细胞中上调，以及它是否参与糖尿病SFN的发病机制。IENFD、Sema 3A的表达和mTOR信号传导在患有SFN的糖尿病患者以及对照受试者的皮肤中进行评价。还在HaCaT细胞中评估了Sema 3A和mTOR信号传导，这些细胞在存在或不存在雷帕霉素的情况下用高葡萄糖（HG）或重组Sema 3A（rSema 3A）处理。通过检查IENFD和使用行为测试在对照组和链脲佐菌素诱导的糖尿病大鼠（用或不用雷帕霉素治疗）中评估小纤维功能障碍。我们发现，与对照受试者相比，糖尿病患者皮肤中Sema 3A的表达和mTOR信号的过度激活伴随着IENFD的降低。HG或rSema 3A孵育的HaCaT细胞中Sema 3A和mTOR信号的表达上调，并且这可以被雷帕霉素减弱。在糖尿病大鼠中还检测到痛觉过敏、IENFD降低以及Sema 3A和mTOR信号传导上调。雷帕霉素治疗可改善这些效应。我们的数据表明，HG通过激活糖尿病角质形成细胞中的mTOR信号而上调Sema 3A表达。因此，该途径可能在糖尿病SFN中起关键作用。
Small fiber neuropathy (SFN) is a common complication in diabetes, and is characterized by decreased intraepidermal nerve fiber density (IENFD). Semaphorin 3A (Sema3A), which is produced by keratinocytes, has a chemorepulsive effect on intraepidermal nerve fibers. mTOR signaling can mediate local protein synthesis that is critical for growth of axons and dendrites. Therefore, this study aimed to investigate whether Sema3A is up-regulated in diabetic keratinocytes via the mTOR-mediated p70 S6K and 4E-BP1 signaling pathways, and furthermore whether it is involved in the pathogenesis of diabetic SFN. IENFD, expression of Sema3A, and mTOR signaling, were evaluated in the skin of diabetic patients with SFN as well as control subjects. Sema3A and mTOR signaling were also assessed in HaCaT cells which had been treated with high glucose (HG) or recombinant Sema3A (rSema3A) in the presence or absence of rapamycin. Small fiber dysfunction was evaluated by examining IENFD and using behavioral tests in control and streptozotocin-induced diabetic rats treated with or without rapamycin. We found that higher Sema3A expression and over-activation of mTOR signaling, was accompanied by reduced IENFD in the skin of diabetic patients compared with control subjects. The expression of Sema3A, and mTOR signaling were up-regulated in HaCaT cells incubated with HG or rSema3A, and this could be attenuated by rapamycin. Hyperalgesia, reduced IENFD, and up-regulated Sema3A and mTOR signaling were also detected in diabetic rats. These effects were ameliorated by rapamycin treatment. Our data indicate that HG up-regulates Sema3A expression by activating mTOR signaling in diabetic keratinocytes. This pathway may therefore play a critical role in diabetic SFN.
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DOI：
10.1016/j.bbrc.2014.04.063
发表时间：
2014-05-30
影响因子：
3.1
作者：
Procaccia, Vera;Nakayama, Hironao;Shimizu, Akio;Klagsbrun, Michael
通讯作者：
Klagsbrun, Michael
影响因子：
7.7
作者：
Houde VP;Brûlé S;Festuccia WT;Blanchard PG;Bellmann K;Deshaies Y;Marette A
通讯作者：
Marette A
影响因子：
9.9
作者：
Liu, Ying;Billiet, Jennifer;Polydefkis, Michael
通讯作者：
Polydefkis, Michael
高糖通过 Cav-1-mTOR 通路诱导 tau 蛋白过度磷酸化形成：糖尿病引起认知功能障碍的潜在分子机制
影响因子：
--
作者：
Wu J;Zhou SL;Pi LH;Shi XJ;Ma LR;Chen Z;Qu ML;Li X;Nie SD;Liao DF;Pei JJ;Wang S
通讯作者：
Wang S
DOI：
10.1080/09168451.2015.1136881
发表时间：
2016-02
期刊：
Bioscience, Biotechnology, and Biochemistry
影响因子：
--
作者：
D. Yamada;K. Kawahara;M. Ozaki;T. Maeda
通讯作者：
D. Yamada;K. Kawahara;M. Ozaki;T. Maeda