The Expression And Function Of GLUT1 In The Decidua Of Preeclampsia

Preeclampsia(PE)is a hypertensive disorder in pregnancy that occurs at ≥20 weeks with new onset hypertension and/or proteinuria,complicated by multiple organs damage.PE is one of the main diseases leading to maternal and infant mortality.It is well established that the abnormal placentation is an important determinant in the development of PE.However,some studies have found that maternal abnormal decidualization is also involved in the occurrence of PE.Decidualization is a process that fibroblast-like stromal cells in endometrium rapidly proliferate and differentiate into secretory decidual cells at mid-secretory phase of the menstrual cycle.The fertile “soil”(decidua)is a prerequisite for embryo implantation,placentation and pregnancy maintenance.GLUT1 is a glucose uptake pump in glycolysis.Our previous RNA-seq results showed significantly decreased GLUT1 in the severe PE(s PE)decidua.However,the molecular mechanism by which GLUT1 is involved in the occurrence of PE has not been clearly understood.Consequently,we aimed to explore the role of GLUT1 in the decidualization and its relation with PE.According to the study on decidual tissues from twenty normal and twenty s PE pregnant women,we found that the levels of GLUT1 was significantly reduced in decidual tissues from s PE patients.During in vitro decidualization for 6 days,human endometrial stromal cells were oval.Meanwhile,the levels of decidualization markers IGFBP1 and PRL were sharply induced.The m RNA and protein levels of GLUT1 were markedly increased.Additionally,the m RNA levels of glycolysis-related genes LDHA and MCT4 were significantly increased.These increases were all time-dependent.Knocking GLUT1 down in human endometrial stromal cells and then induced decidualization resulted in significant reduction in the m RNA levels of LDHA and MCT4 and in glucose uptake and lactate production.In addition,the m RNA levels of decidualization markers IGFBP1 and PRL also reduced,and cells knocked down GLUT1 maintained undecidualized fibroblast-like shape.Moreover,the levels of cell cycle-regulated genes P53 and P21 were significantly increased,and the levels of cell apoptosis-related gene BCL2 were significantly reduced,whereas the levels of BAX were significantly reduced.Thus BCL2/BAX reduced,suggesting cells apoptosis.Furthermore,target prediction results,analysis of levels of mi RNAs in decidua,mi RNA mimics and mi RNA inhibitor transfection,and dual-luciferase analysis showed that GLUT1 is one of the targets of mi R-140-5p.Finally,cotransfection with mi RNA inhibitor and GLUT1-si RNA showed mi R-140-5p inhibits glycolysis and decidualization by downregulating GLUT1.Collectively,GLUT1 exerts pivotal role in human decidualization by participating in Warburg effect-like glycolysis.GLUT1 deficiency may trigger aberrant glycolysis and cell apoptosis thus leading to destructive decidualization,which influences the trophoblast invasion and spreading through decidua and spiral artery remodeling,leading to placentation defects that are associated with PE.