Hypoxia upregulates activity and expression of the glucose transporter GLUT1 in alveolar epithelial cells

Alveolar epithelial cells (AEC) are directly exposed to high alveolar O-2 t ension. Many pulmonary disorders are associated with a decrease in alveolar O-2 tension and AEC need to develop adaptative mechanisms to cope with O-2 deprivation. Under hypoxia, because of inhibition of oxidative phosphoryla tion, adenosine triphosphate supply is dependent on the ability of cells to increase anaerobic glycolysis. In this study we show that under hypoxia, p rimary rat AEC maintained their energy status close to that of normoxic cel ls through increasing anaerobic glycolysis. We therefore examined the effec t of hypoxia on glucose transport and evaluated the mechanisms of this regu lation. Hypoxia induced a stimulation of Na-independent glucose transport, as shown by the increase in 2-deoxy-D-glucose (DG) uptake. This increase wa s dependent on time and O-2 concentration: maximal at 0% O-2 for 18 h, and reversible after hypoxic cells were allowed to recover in normoxia. Concomi tantly, exposure of AEC to hypoxia (18 h 0% O-2) induced a 3-fold increase of glucose transporter GLUT 1 at both protein and messenger RNA (mRNA) leve ls. To determine whether the increase in GLUT1 mRNA level was dependent on O-2 deprivation per se or resulted from decrease of oxidative phosphorylati on, we examined in normoxic cells the effects of cobalt chloride and Na azi de, respectively. Cobalt chloride (100 mu M) and Na azide (1 mM) increased both mRNA levels and DG uptake, mimicking the effect of hypoxia. Electropho retic mobility shift assays revealed a hypoxic and a cobalt chloride induct ion of a hypoxia-inducible factor (HIF) that bound to the sequence of nucle otides, 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 t o hypoxia by regulating GLUT1 gene-encoding protein. This regulation likely oc curred at the transcriptional level through the activation of an HIF, t he nature of which remains to be elucidated. Ouiddir, A., C. Planes, I. Fer nandes, A. VanHesse, and C. Clerici. 1999. Hypoxia upregulates activity and expression of the glucose transporter GLUT1 in alveolar epithelial cells.