Activation of ACE2/angiotensin (1–7) attenuates pancreatic β cell dedifferentiation in a high-fat-diet mouse model

Abstract Objective Angiotensin-converting enzyme 2 (ACE2) has been identified in pancreatic islets and can preserve β cells. In this study, we aimed to examine the possible role of ACE2 and its end product, angiotensin 1–7 (A1–7), in reducing β cell dedifferentiation during metabolic stress. Methods First, a lineage-tracing experiment was performed to track β cells in mice fed a high-fat diet (HFD). Second, the ACE2/A1–7 axis was evaluated in the HFD mouse model. Intraperitoneal glucose tolerance tests (IPGTTs) and intraperitoneal insulin tolerance tests (IPITTs) were conducted. Phenotypic changes in β cells were detected by immunohistochemistry and quantitative real-time PCR. Pancreatic sections were immunostained for vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS). Finally, the effects of the ACE2/A1–7 axis were explored in isolated mouse islets exposed to different concentrations of glucose. Glucose-stimulated insulin release and levels of insulin mRNA and OCT4 mRNA were measured. Results Pancreatic β cell dedifferentiation occurred both in vitro and in vivo in response to metabolic stress and was accompanied by ACE2 reduction. HFD-induced insulin resistance and glucose intolerance were exacerbated in ACE2-knockout (ACE2KO) mice but were alleviated by exogenous A1–7 in C57BL/6J mice. Approximately 20% of β cells were dedifferentiated in ACE2KO mice fed a standard rodent chow diet (SD). A higher percentage of dedifferentiated β cells was detected in ACE2KO mice than in wild-type (WT) mice under HFD conditions. In contrast, the administration of A1–7 alleviated HFD-induced β cell dedifferentiation in C57BL/6J mice. Moreover, the exogenous injection of A1–7 improved microcirculation in islets and decreased the production of iNOS in islets of C57BL/6J mice fed an HFD. Additionally, ACE2 was found to be mainly expressed in α cells of mice, while Mas, the receptor of A1–7, was distributed in β cells. Conclusions Overall, this study is the first to demonstrate that the ACE2/A1–7/Mas axis may be one of the intra-islet paracrine mechanisms of communication between α and β cells. Enhancing the ACE2/A1–7 axis exerts a protective effect by ameliorating β cell dedifferentiation, and this effect might be partially mediated through improvements in islet microcirculation and suppression of islet iNOS.