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  2. The Akt/mTOR cascade mediates high glucose-induced reductions in BDNF via DNMT1 in Schwann cells in diabetic peripheral neuropathy

The Akt/mTOR cascade mediates high glucose-induced reductions in BDNF via DNMT1 in Schwann cells in diabetic peripheral neuropathy

  • Exp Cell Res. 2019 Oct 1;383(1):111502. doi: 10.1016/j.yexcr.2019.111502.
Cui-Hong Zhang 1 Xin Lv 2 Wei Du 2 Mei-Juan Cheng 2 Ya-Ping Liu 2 Lin Zhu 3 Jun Hao 4
Affiliations

Affiliations

  • 1 Department of Pathology, Hebei Medical University, Shijiazhuang, China; Department of Radiation Oncology, Bethune International Peace Hospital, Shijiazhuang, China.
  • 2 Department of Pathology, Hebei Medical University, Shijiazhuang, China.
  • 3 Department of Electromyogram, The Third Hospital of Hebei Medical University, Shijiazhuang, China. Electronic address: zhulin_930@163.com.
  • 4 Department of Pathology, Hebei Medical University, Shijiazhuang, China. Electronic address: haojun@hebmu.edu.cn.
Abstract

Brain-derived neurotropic factor (BDNF) deficiency in Schwann cells plays an important role in the pathogenesis of diabetic peripheral neuropathy (DPN). Little is known about the mechanism involved in BDNF downregulation in Schwann cells in DPN. In this study, we first confirmed downregulation of BDNF and neurotrophin 3 expression in the sciatic nerves of diabetic mice, which was accompanied by myelin sheath abnormalities. Moreover, in vitro, high glucose was revealed to cause downregulation of BDNF, but not neurotrophin 3, expression in RSC96 cells, which was accompanied by DNA hypermethylation of BDNF promoters I and II. DNMT1 was subsequently revealed to be enhanced at the mRNA and protein levels in high glucose-stimulated RSC96 cells, and inhibition of DNMT1 with 5-Aza treatment or shRNA vector transfection reversed high glucose-induced reductions in BDNF expression. Furthermore, the mTOR and upstream Akt pathways were indicated to mediate high glucose-induced DNMT1 and BDNF expression in RSC96 cells. Taken together, our results suggest that the Akt/mTOR cascade mediates high glucose-induced reductions in BDNF via DNMT1 in Schwann cells in DPN.

Keywords

BDNF; DNMT1; Diabetic peripheral neuropathy; High glucose; Schwann cell; mTOR.

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