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

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.

SUBMITTER: Ishiguro H

PROVIDER: S-EPMC11002665 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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

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

iScience 20240318 4

Diabetic neuropathy (DN) is a major complication of <i>diabetes mellitus</i>. 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 inter ...[more]

PMID: 38595797

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Project description:Transforming growth factor-beta (TGF-β), a member of the TGF-β cytokine superfamily, is known to bind to sulfated glycosaminoglycans (GAGs), but the nature of this interaction remains unclear. In a recent study, we found that preterm human milk TGF-β2 is sequestered by chondroitin sulfate (CS) in its proteoglycan form. To understand the molecular basis of the TGF-β2-CS interaction, we utilized the computational combinatorial virtual library screening (CVLS) approach in tandem with molecular dynamics (MD) simulations. All possible CS oligosaccharides were generated in a combinatorial manner to give 24 di- (CS02), 192 tetra- (CS04), and 1536 hexa- (CS06) saccharides. This library of 1752 CS oligosaccharides was first screened against TGF-β2 using the dual filter CVLS algorithm in which the GOLDScore and root-mean-square-difference (RMSD) between the best bound poses were used as surrogate markers for in silico affinity and in silico specificity. CVLS predicted that both the chain length and level of sulfation are critical for the high affinity and high specificity recognition of TGF-β2. Interestingly, CVLS led to identification of two distinct sites of GAG binding on TGF-β2. CVLS also deduced the preferred composition of the high specificity hexasaccharides, which were further assessed in all-atom explicit solvent MD simulations. The MD results confirmed that both sites of binding form stable GAG-protein complexes. More specifically, the highly selective CS chains were found to engage the TGF-β2 monomer with high affinity. Overall, this work present key principles of recognition with regard to the TGF-β2-CS system. In the process, it led to the generation of the in silico library of all possible CS oligosaccharides, which can be used for advanced studies on other protein-CS systems. Finally, the study led to the identification of unique CS sequences that are predicted to selectively recognize TGF-β2 and may out-compete common natural CS biopolymers.

Dataset Information

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

Publications

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

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