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13 February 2018 Dysfunction of DNA damage-inducible transcript 4 in the decidua is relevant to the pathogenesis of preeclampsia
Jieqiong Yang, Yachao Zhang, Jing Tong, Hong Lv, Cong Zhang, Zi-Jiang Chen
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Abstract

Preeclampsia (PE) is a pregnancy-related disorder that occurs after 20 weeks of gestation and affects 3–5% of all human pregnancies worldwide. However, the pathogenesis of PE still remains poorly understood. A deficiency in decidualization is considered a contributing factor to the development of PE. The DNA damage inducible transcript 4 (DDIT4) gene encodes a protein whose main function is inhibiting mammalian target of rapamycin (mTOR) under stress, and several studies have demonstrated that its expression promotes tumor cell apoptosis. Our previous RNA-Seq results showed that DDIT4 is significantly decreased in the decidua of PE women. Here, we aimed to define the role of DDIT4 in human decidualization and its relationship with PE. The results indicated that DDIT4 was markedly decreased in the decidua of severe PE compared with those from uncomplicated pregnancies. The expression of DDIT4 in human endometrial stromal cell (hESC) line and primary hESCs was up-regulated during decidualization. Knockdown DDIT4 in hESCs and primary hESCs caused a significant reduction in the transcription of decidualization markers, insulin-like growth factor binding protein 1 (IGFBP1) and prolactin (PRL). In addition, silencing DDIT4 caused up-regulated p-mTOR and p-p70s6k and reduced apoptosis, whereas rapamycin, an inhibitor of mTOR, reversed the result of apoptosis. Moreover, the expression of cleaved-caspase 3 in severe PE was significantly lower than that of uncomplicated pregnancies, which was unfavorable for trophoblast invasion. Our data suggest that DDIT4 is critical for normal decidualization and the apoptosis of decidual cells. DDIT4 deficiency is likely involved in the development of PE.

Summary Sentence

DDIT4 deficiency is likely involved in the development of PE.

© The Author(s) 2018. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Jieqiong Yang, Yachao Zhang, Jing Tong, Hong Lv, Cong Zhang, and Zi-Jiang Chen "Dysfunction of DNA damage-inducible transcript 4 in the decidua is relevant to the pathogenesis of preeclampsia ," Biology of Reproduction 98(6), 821-833, (13 February 2018). https://doi.org/10.1093/biolre/ioy038
Received: 14 November 2017; Accepted: 12 February 2018; Published: 13 February 2018
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