The derangement of endoplasmic reticulum (ER) homeostasis triggers β-cell dysfunction and apoptosis, leading to diabetes. The angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) [Ang-(1-7)]/Mas axis has been evidenced to protect islet function, but its role in ER stress remains undefined. Here we confirmed that upon treatment with the ER stress inducers thapsigargin (TG) or palmitic acid (PA), the protein levels of ACE2 rapidly increased in mouse islets. ACE2 overexpression and Ang-(1-7) treatment in islets reduced EIF2α-ATF4-mediated ER stress induced by TG or PA. On the contrary, islets from aged Ace2−/y mice (20-month old) were substantially more sensitive to ER stress and cell loss compared with Ace2+/y mice. ACE2 overexpression improved glucose-stimulated insulin secretion (GSIS) and ACE2 ablation resulted in impaired GSIS in mice islets. In vitro, the defective GSIS and ER stress in Ace2−/y islets were rescued by replenishment of ACE2. Furthermore, PI3K-Akt signaling was activated by ACE2 and participated in ER stress in islets. The present study is the first to clarify the possible mechanisms of ACE2/Ang-(1-7)/Mas axis regulate ER stress in islets.


T. Shi: None. J. Lu: None.


National Natural Science Foundation of China (81561128015, 81370946, 81400824)

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