Abstract
Background: Preeclampsia (PE), a hypertensive complication in pregnancy, is a major contributor to maternal and fetal morbidity and mortality. Thus far, the molecular mechanism underlying PE has not been investigated thoroughly. Glucose transporter 1 (GLUT1) is a central rate-limiting pump for glucose uptake and subsequent utilization. Our previous RNA-seq results demonstrated it was significantly downregulated in the decidua of severe preeclampsia (sPE) patients. Therefore, we aimed to explore the role of GLUT1 in the occurrence of PE. Methods: GLUT1 levels were evaluated by quantitative PCR, Western blotting and immunohistochemical staining in severe preeclamptic decidua. The regulatory role of GLUT1 in decidualization was further studied in human endometrial stromal cells (hESCs). We also explored the regulatory role of miRNA in GLUT1 expression. Findings: We observed a significant downregulation of GLUT1 mRNA and protein levels in the decidual tissues of women with sPE. Additionally, the expression of GLUT1 was substantially induced during in vitro decidualization. Moreover, GLUT1 knockdown in human endometrial stromal cells resulted in significant reduction in the mRNA levels of decidualization markers (IGFBP1 and PRL) and aerobic glycolysis-related genes (LDHA and MCT4), and decreased glucose uptake and lactate production. Furthermore, the expression of apoptotic signaling genes P53, P21 and BAX increased whereas the expression of BCL2 decreased after GLUT1 knockdown. Target prediction results and luciferase analysis showed that GLUT1 is one of the targets of miR-140-5p, which is partly responsible for the impaired GLUT1 level. Interpretation: Collectively, these results demonstrate that GLUT1 exerts pivotal role in human decidualization by participating in glycolysis, and its deficiency may trigger aberrant glycolysis and thus leads to destructive decidualization, which may be a pathogenetic mechanism of PE. These data suggest GLUT1 might be a promising target for PE therapy. Funding: This study was supported by grants from the National Key R&D Program of China (2019YFA0802600 and 2017YFC1001403), and National Natural Science Foundation of China (NSFC: 31871512 and 31671199) to C. Zhang. Support was also obtained by the Shanghai Commission of Science and Technology (17DZ2271100). Declaration of Interest: The authors declare no conflict of interest. Ethical Approval: This study was approved by the Ethics Committee of Ji’nan Maternity and Child Care Hospital and informed written consent forms were obtained from all pregnant women.
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