Fig. 10.

Roles of the autocrine angiotensin system in ER stress-induced apoptosis of alveolar epithelial cells. Induction of ER stress activates cathepsin D (CAT-D), one of the enzymes capable of producing ANGII by cleaving angiotensinogen (AGT) synthesized by either AECs or underlying myofibroblasts (10). ER stress also decreases ACE-2, the primary pathway for ANGII degradation that normally generates the antiapoptotic heptapeptide ANG1–7. ER stress-induced apoptosis of AECs in response to either proteasome inhibition (MG132) or the SP-C BRICHOS domain mutant G100S (17) can be prevented by either ANG receptor blockade (saralasin) or by administration of ANG1–7. Activation of the ANG1–7 receptor mas reduces ANGII receptor-mediated JNK phosphorylation by unknown mechanisms (??) that are currently under investigation.