Previous studies have shown that apoptosis of alveolar cells can be regulated by autocrine of ANGII and its counter regulatory ACE-2/ANG1-7 axis. Our earlier study has shown that ER stress in response to seawater aspiration eventually led to apoptosis in lung tissue. In this study, we examined the hypothesis that ER stress induced apoptosis in seawater aspiration-induced ALI might also be regulated by ANGII/ANG1-7 system. ER stress was induced by seawater stimulation and proteasome inhibitor MG132 (an ER stress inductor) . Moreover, ER stress in seawater stimulated lung tissues and RPMVECs promoted the ANGII expression and decreased ACE-2/ANG1-7 expression. ER stress induced by seawater stimulation also lea... More
Previous studies have shown that apoptosis of alveolar cells can be regulated by autocrine of ANGII and its counter regulatory ACE-2/ANG1-7 axis. Our earlier study has shown that ER stress in response to seawater aspiration eventually led to apoptosis in lung tissue. In this study, we examined the hypothesis that ER stress induced apoptosis in seawater aspiration-induced ALI might also be regulated by ANGII/ANG1-7 system. ER stress was induced by seawater stimulation and proteasome inhibitor MG132 (an ER stress inductor) . Moreover, ER stress in seawater stimulated lung tissues and RPMVECs promoted the ANGII expression and decreased ACE-2/ANG1-7 expression. ER stress induced by seawater stimulation also lead to apoptosis. Apoptosis induced by seawater stimulation and MG132 were inhibited by ANGII receptor blocker and abrogated by addition of ANG1-7. These results suggest that apoptosis induced by ER stress in seawater aspiration-induced ALI is regulated by ANG II/ANG1-7 in lung tissues and RPMVECs. In addition, the active form of X-box binding protein 1 (XBP1), spliced XBP1 (XBP1s), a transcription factor that regulates ER associated degradation genes during ER stress, was significantly activated in seawater stimulated cells. Based on this phenomenon, we designed a tandem gene, Wfs1 promoter (a target gene promoter of XBP1s)-ACE2 and ANG1-7, and transfected this tandem gene into seawater stimulated cells. ACE-2/ANG1-7 expression were significantly promoted and apoptosis was inhibited in cells transfected with tandem gene. These results suggest that stimulation of ACE-2/ANG1-7 may be a therapeutic target of ER stress-induced apoptosis in seawater aspiration-induced ALI.