Activation Of ACE2/angiotensin(1–7) Attenuates Pancreatic β Cell Dedifferentiation During Metabolic Stress

Objective.Angiotensin-converting enzyme 2(ACE2)has been detected in pancreatic islets and can protect β cells.This study was to assess the role of ACE2 and its end product,angiotensin 1-7(A1-7),in reducing β cell dedifferentiation in metabolic stress.Methods.Firstly,a lineage-tracing experiment was established to track β cells in mice fed a high-fat diet(HFD).Secondly,in the HFD mouse model,the ACE2/A1-7 axis was assesed.IPGTTs and IPITTs were performed.Phenotypic changes in β cells were assayed by immunohistochemistry and quantitative real-time PCR.Pancreatic sections were also immunostained for vascular endothelial growth factor(VEGF)and inducible nitric oxide synthase(i NOS).Finally,the effects of the ACE2/A1-7 axis were explored in isolated mouse islets which were exposed to different concentrations of glucose.Glucose-stimulated insulin release(GSIS)and levels of insulin m RNA and OCT4 m RNA were evaluated.Results.Both in vitro and in vivo,pancreatic β cell dedifferentiation occurred in response to metabolic stress and was accompanied by ACE2 reduction.HFD-induced glucose intolerance and insulin resistance were aggravated in ACE2-knockout(ACE2KO)mice but were relieved by exogenous administration of A1-7 in C57BL/6J mice.Nearly 20% of β cells were dedifferentiated in ACE2 KO mice fed a standard rodent chow diet(SD).A higher percentage of dedifferentiated β cells was identified in ACE2 KO mice than in wild-type(WT)mice exposure to HFD.In cont RASt,the intraperitoneal injection of A1-7 alleviated HFD-induced β cell dedifferentiation in C57BL/6J mice.Additionally,the exogenous administration of A1-7 improved microcirculation in islets and reduced the expression of i NOS in islets of C57BL/6J mice fed an HFD.Interestingly,ACE2 was found to be mainly expressed in α cells of mice,while Mas,the receptor of A1-7,was distributed in β cells,suggesting that ACE2 may be a paracrine modulator of β cell functions.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 i NOS.