科研之友
微信
新浪微博
Facebook
分享链接
摘要
Objective. Angiotensin-converting enzyme 2 (ACE2) has been identified in pancreatic islets and can preserve beta cells. In this study, we aimed to examine the possible role of ACE2 and its end product, angiotensin 1-7 (A1-7), in reducing beta cell dedifferentiation during metabolic stress. @@@ Methods. First, a lineage-tracing experiment was performed to track beta 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 beta 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 beta 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 beta cells were dedifferentiated in ACE2KO mice fed a standard rodent chow diet (SD). A higher percentage of dedifferentiated beta cells was detected in ACE2K0 mice than in wild-type (WT) mice under HFD conditions. In contrast, the administration of A1-7 alleviated HFD-induced beta 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 alpha cells of mice, while Mas, the receptor of A1-7, was distributed in beta 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 alpha and beta cells. Enhancing the ACE2/A1-7 axis exerts a protective effect by ameliorating beta cell dedifferentiation, and this effect might be partially mediated through improvements in islet microcirculation and suppression of islet iNOS.
- 出版日期2018-4
- 单位华中科技大学
