The miR-322-TRAF3 circuit mediates the pro-apoptotic effect of high glucose on neural stem cells

Hui Gu, Jingwen Yu, Daoyin Dong, Qun Zhou, Jian Ying Wang, Peixin Yang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Maternal diabetes increases the risk of neural tube defects (NTDs), and caspase-dependent apoptosis and gene dysregulation are implicated in this disease process. This study investigates the role of miR-322 and its putative target gene, TNF receptor-associated factor 3 (TRAF3), in high glucose-induced apoptosis. miR-322 and TRAF3 expression were assessed in embryos of nondiabetic and diabetic dams, and in neural stem cells under high glucose conditions. Maternal diabetes in vivo and high glucose in vitro significantly down-regulated miR-322 and up-regulated TRAF3 protein expression. Overexpression of the antioxidant enzyme, superoxide dismutase 1 (SOD1), or treatment with the SOD1 mimetic Tempol, abolished the effect of maternal diabetes or high glucose on miR-322 and TRAF3 expression, respectively. A miRNA target prediction algorithm reveals 2 miR-322 binding sites the 30-untranslated region (UTR) of TRAF3 mRNA. A RNA pull-down assay using biotin-labeled miR-322 revealed that miR-322 interacted with the 30-UTR of TRAF3 mRNA at one specific binding site. The miR-322 mimic or TRAF3 knockdown blocked high glucose-increased TRAF3 protein expression and apoptosis, whereas the miR-322 inhibitor mimicked the effect of high glucose leading to TRAF3 up-regulation and apoptosis. This study demonstrates that both maternal diabetes and high glucose negatively regulate miR-322 through oxidative stress. miR-322 interacts with the 30-UTR of TRAF3 and represses its translation. The miR-322-TRAF3 pathway is implicated in high glucose-induced caspase activation and apoptosis.

Original languageEnglish (US)
Pages (from-to)186-196
Number of pages11
JournalToxicological Sciences
Volume144
Issue number1
DOIs
StatePublished - Mar 1 2015

Keywords

  • Apoptosis
  • High glucose
  • MicroRNA-322
  • Neural stem cells
  • Oxidative stress
  • TRAF3

ASJC Scopus subject areas

  • Toxicology

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