Development of cytosolic hypoxia and hypoxia-inducible factor stabilization are facilitated by aquaporin-1 expression

O-2 is essential for aerobic life, and the classic view is that it diffuses freely across the plasma membrane. However, measurements of O-2 permeability of lipid bilayers have indicated that it is much lower than previously thought, and therefore, the existence of membrane O-2 channels has been suggested. Wehypothesized that, besides its role as a water channel, aquaporin-1 (AQP-1) could also work as an O-2 transporter, because this transmembrane protein appears to be CO2-permeable and is highly expressed in cells with rapid O2 turnover (erythrocytes and microvessel endothelium). Here we show that in mammalian cells overexpressing AQP-1 and exposed to hypoxia, the loss of cytosolic O-2, as well as stabilization of the O-2-dependent hypoxia-inducible transcription factor and expression of its target genes, is accelerated. In normoxic endothelial cells, knocking down AQP-1 produces induction of hypoxia-inducible genes. Moreover, lung AQP-1 is markedly up-regulated in animals exposed to hypoxia. These data suggest that AQP-1 has O-2 permeability and thus could facilitate O-2 diffusion across the cell membrane.