Dept of Endocrinology, Xiang-Ya Hospital, Central South University, Changsha, China.
Dept of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, China.
Mol Cell Endocrinol. 2018 Sep 5;472:107-116. doi: 10.1016/j.mce.2017.11.025. Epub 2017 Dec 5.
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.
小纤维神经病（SFN）是糖尿病的常见并发症，其特征是表皮内神经纤维密度（IENFD）降低。Semaphorin 3A（Sema3A）由角质形成细胞产生，对表皮内神经纤维具有化学排斥作用。mTOR 信号可以介导局部蛋白质合成，这对于轴突和树突的生长至关重要。因此，本研究旨在探讨糖尿病角质形成细胞中 Sema3A 是否通过 mTOR 介导的 p70 S6K 和 4E-BP1 信号通路上调，以及它是否参与糖尿病 SFN 的发病机制。评估了糖尿病伴 SFN 患者和对照组皮肤中的 IENFD、Sema3A 表达和 mTOR 信号。还评估了高糖（HG）或重组 Sema3A（rSema3A）处理的 HaCaT 细胞以及雷帕霉素存在或不存在时的 Sema3A 和 mTOR 信号。通过检查 IENFD 和使用行为测试，评估了对照和链脲佐菌素诱导的糖尿病大鼠的小纤维功能障碍，这些大鼠接受或不接受雷帕霉素治疗。我们发现，与对照组相比，糖尿病患者皮肤中的 Sema3A 表达增加和 mTOR 信号过度激活伴随着 IENFD 降低。在 HG 或 rSema3A 孵育的 HaCaT 细胞中，Sema3A 和 mTOR 信号表达上调，雷帕霉素可减弱其表达。糖尿病大鼠也检测到痛觉过敏、IENFD 降低、Sema3A 和 mTOR 信号上调。雷帕霉素治疗可改善这些影响。我们的数据表明，HG 通过激活糖尿病角质形成细胞中的 mTOR 信号上调 Sema3A 表达。该途径可能在糖尿病 SFN 中发挥关键作用。
