Dysfunction Of DDIT4 In The Decidua Is Relevant To The Pathogenesis Of Preeclampsia

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 RNASeq 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 women with uncomplicated pregnancies.The expression of DDIT4 in a cultured human endometrial stromal cell(hESC)line and primary hESCs was up-regulated during decidualization.Knockdown DDIT4 with small interfering RNA 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-p70s6 k and reduced apoptosis,whereas rapamycin,an inhibitor of mTOR,reversed the result of apoptosis.Moreover,the expression of cleaved-caspase 3 in women with severe preeclampsia(SPE)was significantly lower than that of women with 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.