Figure 6.

ER stress: a major regulator of the loss of epithelial cell phenotype in hypoxic environment. Loss of alveolar phenotype is a consequence of a long term exposure of the cells to a hypoxic microenvironment. Hypoxia leads to the activation of the PERK/ATF4 and ATF6α/ATF6N branches of the UPR, to the upregulation of Tgfβ1, Ctgf, Zeb1 and Twist1 gene expression, to a decrease in TTF1 expression, and finally to a disruption of ZO-1 expression (black arrows). In vitro, pharmacological inhibitors (dotted arrow) revealed that this effect is partly mediated by the stabilization of HIF-1α. Calcium chelation induced by BAPTA-AM prevents the loss of epithelial phenotype observed under hypoxia, by blunting the induction of the UPR and HIF-1 transcriptional activity.