High glucose-repressed CITED2 expression through miR-200b triggers the unfolded protein response and endoplasmic reticulum stress

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

*Corresponding author for this work

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

High glucose in vivo and in vitro induces neural tube defects (NTDs). CITED2 (CBP/p300-interacting transactivator with ED-rich tail 2) is essential for neural tube closure. We explored the regulatory mechanism underlying CITED2 expression and its relationship with miRNA and endoplasmic reticulum (ER) stress. miR-200b levels were increased by maternal diabetes or high glucose in vitro, and this increase was abrogated by transgenic overexpression of superoxide dismutase 1 (SOD1) or an SOD1 mimetic. CITED2 was the target of miR-200b and was downregulated by high glucose. Two miR-200b binding sites in the 39-untranslated region of the CITED2 mRNA were required for inhibiting CITED2 expression. The miR-200b mimic and a CITED2 knockdown mimicked the stimulative effect of high glucose on unfolded protein response (UPR) and ER stress, whereas the miR-200b inhibitor and CITED2 overexpression abolished high glucose-induced UPR signaling, ER stress, and apoptosis. The ER stress inhibitor, 4-phenylbutyrate, blocked CITED2 knockdown-induced apoptosis. Furthermore, the miR-200b inhibitor reversed high glucose-induced CITED2 downregulation, ER stress, and NTDs in cultured embryos. Thus, we showed a novel function of miR-200b and CITED2 in high glucose-induced UPR and ER stress, suggesting that miR-200b and CITED2 are critical for ER homeostasis and NTD formation in the developing embryo.

Original languageEnglish (US)
Pages (from-to)149-163
Number of pages15
JournalDiabetes
Volume65
Issue number1
DOIs
StatePublished - Jan 2016

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Fingerprint Dive into the research topics of 'High glucose-repressed CITED2 expression through miR-200b triggers the unfolded protein response and endoplasmic reticulum stress'. Together they form a unique fingerprint.

Cite this