Am. J. Respir. Cell Mol. Biol., Volume 21, Number 6, December, 1999 710-718

Hypoxia Upregulates Activity and Expression of the Glucose Transporter GLUT1 in Alveolar Epithelial Cells

Achour Ouiddir, Carole Planès, Isabelle Fernandes, Alexandra VanHesse, and Christine Clerici

Department of Physiology, Faculté de Médecine Léonard de Vinci Bobigny, Université Paris 13; and IFR 02 and Unité INSERM 426, Faulté X. Bichat, Université Paris 7, Paris, France

Alveolar epithelial cells (AEC) are directly exposed to high alveolar O₂ tension. Many pulmonary disorders are associated with a decrease in alveolar O₂ tension and AEC need to develop adaptative mechanisms to cope with O₂ deprivation. Under hypoxia, because of inhibition of oxidative phosphorylation, adenosine triphosphate supply is dependent on the ability of cells to increase anaerobic glycolysis. In this study we show that under hypoxia, primary rat AEC maintained their energy status close to that of normoxic cells through increasing anaerobic glycolysis. We therefore examined the effect of hypoxia on glucose transport and evaluated the mechanisms of this regulation. Hypoxia induced a stimulation of Na-independent glucose transport, as shown by the increase in 2-deoxy-D-glucose (DG) uptake. This increase was dependent on time and O₂ concentration: maximal at 0% O₂ for 18 h, and reversible after hypoxic cells were allowed to recover in normoxia. Concomitantly, exposure of AEC to hypoxia (18 h 0% O₂) induced a 3-fold increase of glucose transporter GLUT1 at both protein and messenger RNA (mRNA) levels. To determine whether the increase in GLUT1 mRNA level was dependent on O₂ deprivation per se or resulted from decrease of oxidative phosphorylation, we examined in normoxic cells the effects of cobalt chloride and Na azide, respectively. Cobalt chloride (100 µM) and Na azide (1 mM) increased both mRNA levels and DG uptake, mimicking the effect of hypoxia. Electrophoretic mobility shift assays revealed a hypoxic and a cobalt chloride induction of a hypoxia-inducible factor (HIF) that bound to the sequence of nucleotides, corresponding to a hypoxia-inducible element upstream of the GLUT1 gene. AEC also expressed this factor under nonhypoxic conditions. Together, our results demonstrate that AEC increased glucose transport in response to hypoxia by regulating GLUT1 gene-encoding protein. This regulation likely occurred at the transcriptional level through the activation of an HIF, the nature of which remains to be elucidated.

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