Background: Islet β-cell dedifferentiation may be the main cause of reduced insulin secretion. Angiotensin-(1-7) [Ang-(1-7)] can attenuate high glucose-induced apoptosis and dedifferentiation of pancreatic β-cell, but the specific signal transduction pathway and mechanism are not yet clear. Objective: This study aimed to investigate the effects of Ang-(1-7) on high glucose-induced islet β-cell dedifferentiation by activating the phosphatidylinositol-3-kinase/Protein kinase B/ Forkhead box transcription factor O1 (PI3K/Akt/FoxO1) signaling pathway. Methods: The mouse islet β-cell line MIN6 cells were passaged and cultured and randomly divided into five groups: control (Con) group, high glucose (HG) group, HG with Ang-(1-7) group, HG with Ang-(1-7) and specific MasR antagonist A-779 group, and HG with Ang-(1-7) and PI3K inhibitor LY294002 group. After 48 hours, glucose-stimulated insulin secretion (GSIS) was detected by Enzyme-Linked Immunosorbent Assay (ELISA). The mRNA and protein expression levels of β-cell-specific factors (Pancreatic duodenal homeobox-1 (Pdx1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog A(MafA)) and endocrine progenitor cell-specific factors (Octamer binding transcription factor 4(Oct4), Nanog) were measured by Real Time-PCR and Western blot. The factors of protein expression levels of PI3K/Akt/FoxO1 signaling pathway (Akt, p-Akt, Fox- O1, p-FoxO1) were determined by Western blot. Results: We observed for the first time that high glucotoxicity can induce dedifferentiation of pancreatic islet β-cell, causing a decrease in insulin secretion levels and expression of Pdx1, MafA, p-- FoxO1, and p-Akt and an increase in expression of Oct4 and Nanog. After Ang-(1-7) intervention, insulin secretion levels and expression of Pdx1, MafA, p-FoxO1 and p-Akt were increased, and the levels of Oct4 and Nanog were reduced. However, A-779 and LY294002 could reverse this effect. During these processes, the total Akt and total FoxO1 expression did not change significantly. Conclusion: Ang-(1-7) may prevent high glucose-induced pathological dedifferentiation of pancreatic β-cell by activating the PI3K/Akt/FoxO1 signaling pathway.

中文翻译：

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血管紧张素-(1-7) 通过激活 PI3K/Akt/FoxO1 通路改善胰岛 β 细胞去分化


背景：胰岛β细胞去分化可能是胰岛素分泌减少的主要原因。血管紧张素-(1-7)[Ang-(1-7)]可减弱高糖诱导的胰腺β细胞凋亡和去分化，但其具体信号转导途径和机制尚不清楚。目的：本研究旨在探讨Ang-(1-7)通过激活磷脂酰肌醇-3-激酶/蛋白激酶B/叉头盒转录因子O1(PI3K/Akt/ FoxO1) 信号通路。方法：将小鼠胰岛β细胞系MIN6细胞传代培养，随机分为5组：对照组（Con）、高糖（HG）组、HG+Ang-（1-7）组、HG+Ang- (1-7)和特异性MasR拮抗剂A-779组，以及HG与Ang-(1-7)和PI3K抑制剂LY294002组。 48小时后，通过酶联免疫吸附测定（ELISA）检测葡萄糖刺激的胰岛素分泌（GSIS）。 β细胞特异性因子（胰腺十二指肠同源盒-1（Pdx1）、v-maf肌肉腱膜纤维肉瘤癌基因同源物A（MafA））和内分泌祖细胞特异性因子（八聚体结合转录因子4（Oct4）的mRNA和蛋白表达水平）、Nanog）通过实时 PCR 和蛋白质印迹进行测量。采用Western blot法测定PI3K/Akt/FoxO1信号通路（Akt、p-Akt、Fox-O1、p-FoxO1）蛋白表达水平的影响因素。结果：我们首次观察到高糖毒性可诱导胰岛β细胞去分化，导致胰岛素分泌水平和Pdx1、MafA、p-- FoxO1和p-Akt表达减少，以及p-Akt表达增加Oct4 和 Nanog。 Ang-(1-7)干预后，胰岛素分泌水平和Pdx1、MafA、p-FoxO1和p-Akt表达增加，Oct4和Nanog水平降低。然而，A-779 和 LY294002 可以逆转这种效应。在这些过程中，总 Akt 和总 FoxO1 表达没有显着变化。结论：Ang-(1-7)可能通过激活PI3K/Akt/FoxO1信号通路来阻止高糖诱导的胰腺β细胞病理性去分化。