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

Maria E. Vega, John B. Finlay, Mansi Vasishtha, Jean E. Schwarzbauer

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number100048
JournalMatrix Biology Plus
DOIs
StateAccepted/In press - 2020

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Biochemistry
  • Biophysics
  • Cell Biology
  • Genetics
  • Histology

Keywords

  • Alternative splicing
  • Diabetic nephropathy
  • Extracellular matrix
  • Fibronectin
  • Gene expression
  • Tenascin-C

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