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Department of Obstetrics and Gynecology, Osaka University Faculty of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
¹ Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-0025, Japan

(Requests for offprints should be addressed to Masahiro Sakata; Email: msakata{at}gyne.med.osaka-u.ac.jp)

Glucose transporter 1 (GLUT1) plays an important role in the transport of glucose in the placenta. During early pregnancy, placentation occurs in a relatively hypoxic environment that is essential for appropriate embryonic development, and GLUT1 expression is enhanced in response to oxygen deficiency in the placenta. Hypoxia-inducible factor-1 (HIF-1) is involved in the induction of GLUT1 expression in other cells. The present study was designed to test whether HIF-1 is involved in hypoxia-induced activation of GLUT1 expression using trophoblast-derived human BeWo and rat Rcho-1 cells as models. GLUT1 mRNA and protein expression were elevated under 5% O₂ or in the presense of cobalt chloride, which has been shown to mimic hypoxia. Using rat GLUT1 (rGLUT1) promoter–luciferase constructs, we showed that this up-regulation was mediated at the transcriptional level. Deletion mutant analysis of the rGLUT1 promoter indicated that a 184 bp hypoxia-responsive element (HRE) of the promoter was essential to increase GLUT1 reporter gene expression in response to low-oxygen conditions. BeWo and Rcho-1 cells cultured under 5% O₂ or with CoCl₂ showed increased expression of HIF-1 protein compared with those cultured under 20% O₂. To test whether this factor is directly involved in hypoxia-induced GLUT1 promoter activation, BeWo and Rcho-1 cells were transiently transfected with an HIF-1 expression vector. Exogeneous HIF-1 markedly increased the GLUT1 promoter activity from constructs containing the HRE site, while the GLUT1 promoter constructs lacking the HRE site were not activated by exogenous HIF-1 These data demonstrate that GLUT1 is up-regulated under 5% O₂ or in the presence of CoCl₂ in the placental cell lines through HIF-1 interaction with a consensus HRE site of the GLUT1 promoter.

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