1. Academic Validation
  2. Trichostatin A increases BDNF protein expression by improving XBP-1s/ATF6/GRP78 axis in Schwann cells of diabetic peripheral neuropathy

Trichostatin A increases BDNF protein expression by improving XBP-1s/ATF6/GRP78 axis in Schwann cells of diabetic peripheral neuropathy

  • Biomed Pharmacother. 2021 Jan;133:111062. doi: 10.1016/j.biopha.2020.111062.
Jiahui An 1 Xiang Zhang 1 Keqi Jia 1 Cuihong Zhang 2 Lin Zhu 3 Meijuan Cheng 4 Fan Li 1 Song Zhao 5 Jun Hao 6
Affiliations

Affiliations

  • 1 Department of Pathology, Hebei Medical University, Shijiazhuang, China; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang, China.
  • 2 Department of Radiation Oncology, Bethune International Peace Hospital, Shijiazhuang, China.
  • 3 Department of Electromyogram, The Third Hospital of Hebei Medical University, Shijiazhuang, China.
  • 4 Department of Nephrology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
  • 5 Department of Pathology, Hebei Medical University, Shijiazhuang, China; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang, China. Electronic address: xljer606@163.com.
  • 6 Department of Pathology, Hebei Medical University, Shijiazhuang, China; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang, China. Electronic address: haojun2004@hotmail.com.
Abstract

Diabetic peripheral neuropathy (DPN) is the common complication of diabetes mellitus. Histone deacetylase (HDAC) inhibitor trichostatin A (TSA) is reported to ameliorate the peripheral nerves degeneration of DPN. However, the exact mechanism is still not well elucidated. Here, we first revealed that TSA promoted nerve conduction and brain derived neurotrophic factor (BDNF) expression in the sciatic nerves of diabetic mice. In line, TSA also reversed high glucose-reduced mature BDNF expression in vitro cultured rat Schwann cells (RSC96). Then unexpectedly, the downstream targets of TSA HDAC1 and HDAC5 were not involved in TSA-improved BDNF expression. Furthermore, unfolded protein response (UPR) chaperone GRP78 was revealed to be downregulated with high glucose stimulation in RSC96 cells, which was avoided with TSA treatment. Also, GRP78 upregulation mediated TSA-improved mature BDNF expression in high glucose-cultured RSC96 cells by binding with BDNF. As well, TSA treatment enhanced the binding of GRP78 with BDNF in RSC96 cells. Again, UPR-associated transcription factors XBP-1s and ATF6 were involved in TSA-increased GRP78 expression in high glucose-stimulated RSC96 cells. Finally, conditioned medium from high glucose-cultured RSC96 cells delayed neuron SH-SY5Y differentiation and that from TSA-treated high glucose-cultured RSC96 cells promoted SH-SY5Y cell differentiation. Taken together, our findings suggested that TSA increased BDNF expression to ameliorate DPN by improving XBP-1s/ATF6/GRP78 axis in Schwann cells.

Keywords

BDNF; Diabetic peripheral neuropathy; GRP78; Schwann cells; Trichostatin A.

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