Reduced chondroitin sulfate content prevents diabetic neuropathy through transforming growth factor-β signaling suppression

Hajime Ishiguro; Takashi Ushiki; Atsuko Honda; Yasuhiro Yoshimatsu; Riuko Ohashi; Shujiro Okuda; Asami Kawasaki; Kaori Cho; Suguru Tamura; Tatsuya Suwabe; Takayuki Katagiri; Yiwei Ling; Atsuhiko Iijima; Tadahisa Mikami; Hiroshi Kitagawa; Akiyoshi Uemura; Kazunori Sango; Masayoshi Masuko; Michihiro Igarashi; Hirohito Sone

doi:10.1016/j.isci.2024.109528

Reduced chondroitin sulfate content prevents diabetic neuropathy through transforming growth factor-β signaling suppression

iScience. 2024 Mar 18;27(4):109528. doi: 10.1016/j.isci.2024.109528. eCollection 2024 Apr 19.

Authors

Hajime Ishiguro¹, Takashi Ushiki^{1

2

3}, Atsuko Honda^{4

5}, Yasuhiro Yoshimatsu⁶, Riuko Ohashi⁷, Shujiro Okuda⁸, Asami Kawasaki⁴, Kaori Cho¹, Suguru Tamura¹, Tatsuya Suwabe¹, Takayuki Katagiri¹, Yiwei Ling⁸, Atsuhiko Iijima⁹, Tadahisa Mikami¹⁰, Hiroshi Kitagawa¹⁰, Akiyoshi Uemura¹¹, Kazunori Sango¹², Masayoshi Masuko^{1

13}, Michihiro Igarashi⁴, Hirohito Sone¹

Affiliations

¹ Departments of Hematology, Endocrinology, and Metabolism, Graduate School of Medical and Dental Sciences, Niigata university, Niigata, Japan.
² Division of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Niigata, Japan.
³ Departments of Transfusion Medicine, Cell Therapy and Regenerative Medicine, Medical and Dental Hospital, Niigata University, Niigata, Japan.
⁴ Department of Neurochemistry and Molecular Cell Biology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
⁵ Center for Research Promotion, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
⁶ Division of Pharmacology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
⁷ Divisions of Molecular and Diagnostic Pathology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
⁸ Division of Bioinformatics, Graduate School of Medical and Dental Sciences, Niigata, Japan.
⁹ Neurophysiology & Biomedical Engineering Lab, Interdisciplinary Program of Biomedical Engineering, Assistive Technology and Art and Sports Sciences, Faculty of Engineering, Niigata University Niigata, Niigata, Japan.
¹⁰ Laboratory of Biochemistry, Kobe Pharmaceutical University, Kobe, Japan.
¹¹ Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
¹² Diabetic Neuropathy Project, Department of Diseases and Infection, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
¹³ Hematopoietic Cell Transplantation Niigata University Medical and Dental Hospital, , Niigata University, Niigata, Japan.

Abstract

Diabetic neuropathy (DN) is a major complication of diabetes mellitus. Chondroitin sulfate (CS) is one of the most important extracellular matrix components and is known to interact with various diffusible factors; however, its role in DN pathology has not been examined. Therefore, we generated CSGalNAc-T1 knockout (T1KO) mice, in which CS levels were reduced. We demonstrated that diabetic T1KO mice were much more resistant to DN than diabetic wild-type (WT) mice. We also found that interactions between pericytes and vascular endothelial cells were more stable in T1KO mice. Among the RNA-seq results, we focused on the transforming growth factor β signaling pathway and found that the phosphorylation of Smad2/3 was less upregulated in T1KO mice than in WT mice under hyperglycemic conditions. Taken together, a reduction in CS level attenuates DN progression, indicating that CS is an important factor in DN pathogenesis.

Keywords: Immunology; Molecular biology; Neuroscience; Omics; Transcriptomics.