Inhibitor of myogenic differentiation family isoform a, a new positive regulator of fibronectin production by glomerular mesangial cells

Parisa Yazdizadeh Shotorbani, Sarika Chaudhari, Yu Tao, Leonidas Tsiokas, Rong Ma

Research output: Contribution to journalArticle

Abstract

Overproduction of extracellular matrix proteins, including fibronectin by mesangial cells (MCs), contributes to diabetic nephropathy. Inhibitor of myogenic differentiation family isoform a (I-mfa) is a multifunctional cytosolic protein functioning as a transcriptional modulator or plasma channel protein regulator. However, its renal effects are unknown. The present study was conducted to determine whether I-mfa regulated fibronectin production by glomerular MCs. In human MCs, overexpression of I-mfa significantly increased fibronectin abundance. Silencing I-mfa significantly reduced the level of fibronectin mRNA and blunted transforming growth factor-β1-stimulated production of fibronectin. We further found that high glucose increased I-mfa protein content in a time course (≥48 h) and concentration (≥25 mM)-dependent manner. Although high glucose exposure increased I-mfa at the protein level, it did not significantly alter transcripts of I-mfa in MCs. Furthermore, the abundance of I-mfa protein was significantly increased in the renal cortex of rats with diabetic nephropathy. The I-mfa protein level was also elevated in the glomerulus of mice with diabetic kidney disease. However, there was no significant difference in glomerular I-mfa mRNA levels between mice with and without diabetic nephropathy. Moreover, H2O2 significantly increased I-mfa protein abundance in a dose-dependent manner in cultured human MCs. The antioxidants polyethylene glycol-catalase, ammonium pyrrolidithiocarbamate, and N-acetylcysteine significantly blocked the high glucose-induced increase of I-mfa protein. Taken together, our results suggest that I-mfa, increased by high glucose/diabetes through the production of reactive oxygen species, stimulates fibronectin production by MCs.

Original languageEnglish
Pages (from-to)F673-F682
JournalAmerican journal of physiology. Renal physiology
Volume318
Issue number3
DOIs
StatePublished - 1 Mar 2020

Keywords

  • fibronectin
  • high glucose
  • inhibitor of myogenic differentiation family isoform a
  • mesangial cells
  • reactive oxygen species

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