Reduced chondroitin sulfate content prevents diabetic neuropathy through TGF-β signaling suppression

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 phosphorylation of Smad2/3 was less upregulated in T1KO than in WT mice under hyperglycemic conditions. Taken together, reduction of CS level attenuates DN progression, indicating that CS is an important factor in DN pathogenesis.