The Unfolded Protein Response Regulates Apoptosis of Alveolar Epithelial Cells (AECs) by Modulating Autocrine Angiotensin (ANG)II and ANG1‐7

Abstract

STUDY OBJECTIVEOur prior work showed that ER stress‐induced apoptosis of AECs is regulated by the autocrine ANGII/ANG1‐7 system. MG132 or surfactant protein C (SP‐C) BRICHOS domain mutation G100S induced apoptosis in human AECs by activating cathepsin D and by decreasing the protective angiotensin‐converting enzyme 2 (ACE‐2). This study tested the hypothesis that ER stress‐induced apoptosis of human AECs might be mediated by UPR pathways that in turn modulate the autocrine ANGII/ANG1‐7 system of these cells.METHODSA549 cells were challenged with the proteasome inhibitor MG132 or the SP‐C mutant G100S. UPR markers and ANG system components were measured by Western blotting. Apoptosis was measured by caspase activation and nuclear fragmentation.RESULTSMG132‐ or G100S mutation‐induced ER stress activated the UPR pathways (phospho PERK, phospho eIF2α, ATF4, phospho IRE1, spliced XBP1, ATF6), which led to an increase of cathepsin D and a decrease of anti‐apoptotic ACE‐2. Blockade of UPR pathways with UPR chaperone 4‐PBA or siRNAs (siATF6, siIRE1, siPERK) prevented both the changes in cathepsin D and ACE‐2 and the AEC apoptosis caused by MG132 or G100S.CONCLUSIONSThese data show that ER stress induces apoptosis in human AECs through UPR‐mediated pathways that in turn modulate the autocrine ANGII/ANG1‐7 system. They also demonstrate that ER stress‐induced apoptosis of human AECs can be prevented by inhibition of UPR‐specific pathways.