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Elevated glucose alters global gene expression and tenascin-C alternative splicing in mesangial cells

Author(s): Vega, Maria E; Finlay, John B; Vasishtha, Mansi; Schwarzbauer, Jean E

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Abstract: Mesangial cells are the major extracellular matrix (ECM)-producing cells in the kidney glomerulus and, when exposed to elevated glucose levels, they up-regulate assembly of fibronectin (FN) and other ECM proteins. Increases in glucose concentration are known to alter gene expression; here we investigated the connection between increased ECM production and changes in gene expression in mesangial cells. Comparison of mesangial cells grown in normal or high glucose conditions by RNA-sequencing showed significant expression changes in over 6000 genes and, when grouped by KEGG pathway analysis, identified the ECM-receptor interaction and focal adhesion pathways among the top 5 upregulated pathways. Of note was the significant increase in expression of tenascin-C (TN-C), a known regulator of FN matrix assembly. Mouse TN-C has multiple isoforms due to alternative splicing of 6 FNIII repeat exons. In addition to the transcriptional increase with high glucose, exon inclusion via alternative splicing was also changed resulting in production of higher molecular weight isoforms of TN-C. Mesangial cells grown in normal glucose secreted small isoforms with 1–2 variable repeats included whereas in high glucose large isoforms estimated to include 5 repeats were secreted. Unlike the smaller isoforms, the larger TN-C was not detected in the FN matrix. This change in TN-C isoforms may affect the regulation of FN matrix assembly and in this way may contribute to increased ECM accumulation under high glucose conditions.
Publication Date: Nov-2020
Citation: Vega, Maria E, Finlay, John B, Vasishtha, Mansi, Schwarzbauer, Jean E. (2020). Elevated glucose alters global gene expression and tenascin-C alternative splicing in mesangial cells. Matrix Biology Plus, 8 (100048 - 100048. doi:10.1016/j.mbplus.2020.100048
DOI: doi:10.1016/j.mbplus.2020.100048
ISSN: 2590-0285
Language: en
Type of Material: Journal Article
Journal/Proceeding Title: Matrix Biology Plus
Version: Final published version. This is an open access article.

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