Hyperglycemia Promotes Schwann Cell De-differentiation and De-myelination via Sorbitol Accumulation and Igf1 Protein Down-regulation

Wu Hao,Syoichi Tashiro,Tomoka Hasegawa,Yuiko Sato,Tami Kobayashi,Toshimi Tando,Eri Katsuyama,Atsuhiro Fujie,Ryuichi Watanabe,Mayu Morita,Kana Miyamoto,Hideo Morioka,Masaya Nakamura,Morio Matsumoto,Norio Amizuka,Yoshiaki Toyama,Takeshi Miyamoto

doi:10.1074/jbc.m114.631291

Wu Hao, Syoichi Tashiro + Show 15 more

Open Access

https://doi.org/10.1074/jbc.m114.631291

Copy DOI

Abstract

Diabetes mellitus (DM) is frequently accompanied by complications, such as peripheral nerve neuropathy. Schwann cells play a pivotal role in regulating peripheral nerve function and conduction velocity; however, changes in Schwann cell differentiation status in DM are not fully understood. Here, we report that Schwann cells de-differentiate into immature cells under hyperglycemic conditions as a result of sorbitol accumulation and decreased Igf1 expression in those cells. We found that de-differentiated Schwann cells could be re-differentiated in vitro into mature cells by treatment with an aldose reductase inhibitor, to reduce sorbitol levels, or with vitamin D3, to elevate Igf1 expression. In vivo DM models exhibited significantly reduced nerve function and conduction, Schwann cell de-differentiation, peripheral nerve de-myelination, and all conditions were significantly rescued by aldose reductase inhibitor or vitamin D3 administration. These findings reveal mechanisms underlying pathological changes in Schwann cells seen in DM and suggest ways to treat neurological conditions associated with this condition.

Highlights

Factors that govern peripheral neuropathy associated with Schwann cell dysfunction are not fully understood
Cell and Sciatic Nerve Culture—Primary Schwann cells isolated from rat dorsal root ganglia, IMS32 cells, or sciatic nerves isolated from control, STZ, or db/db mice were cultured for 48 h in DMEM (Sigma) containing 3% (v/v) heat-inactivated FBS (JRH Biosciences, Lenexa, KS) and GlutaMAX (Invitrogen) under different glucose conditions (100, 300, or 540 mg/dl) in the presence or absence of AR inhibitor (ARI) (Epalrestat) (1.0 ␮M, provided by Ono Pharmaceutical Co., Ltd., Osaka, Japan), ED71 (0.1 ␮M, provided by Chugai Pharmaceutical Co., Ltd., Tokyo, Japan), 1,25(OH)2D3 (0.1 ␮M, Wako Pure Chemicals Industries, Osaka, Japan), or Insulin-like growth factor 1 (Igf1) (10 ng/ml, R&D Systems, Minneapolis, MN) with or without anti-Igf1 (1.0 ␮g/ml)
High Glucose Concentrations Induce Schwann Cell De-differentiation—Diabetes mellitus (DM) patients frequently suffer from peripheral nerve polyneuropathy

Summary

Background

Factors that govern peripheral neuropathy associated with Schwann cell dysfunction are not fully understood. In vivo DM models exhibited significantly reduced nerve function and conduction, Schwann cell de-differentiation, peripheral nerve de-myelination, and all conditions were significantly rescued by aldose reductase inhibitor or vitamin D3 administration. These findings reveal mechanisms underlying pathological changes in Schwann cells seen in DM and suggest ways to treat neurological conditions associated with this condition. We propose that loss of peripheral function in DM patients is due in part to direct effects of hyperglycemia on Schwann cell de-differentiation and subsequent peripheral nerve de-myelination and is a condition potentially treatable by ARI or vitamin D3

Experimental Procedures

Results

Discussion