Angiotensin type 2 receptor in pancreatic islets of adult rats: a novel insulinotropic mediator.
Angiotensin type 2 receptor in pancreatic islets of adult rats: a novel insulinotropic mediator.
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DOI：
10.1152/ajpendo.00286.2013
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发表时间：
2013-11
期刊：
影响因子：
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通讯作者：
C. Shao;I. Zucker;Lie Gao
中科院分区：
文献类型：
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作者：
C. Shao;I. Zucker;Lie Gao
在本研究中，我们评估了血管紧张素2型受体（AT 2 R）蛋白在成年大鼠的各种组织中的相对丰度。我们发现，与所有其他组织相比，胰岛表达最高的AT 2 R蛋白。因此，我们随后通过单独使用血管紧张素II（ANG II）、氯沙坦（Los; AT 1 R拮抗剂）、化合物21（C21; AT 2 R激动剂）和PD-123319（PD; AT 2 R拮抗剂）在体内和体外实验中确定内分泌胰腺中AT 2 R的功能意义。大鼠实验结果表明：（1）ANG Ⅱ能显著提高进食状态下的血浆胰岛素浓度（1.51 ± 0.20对0.82 ± 0.14ng/ml，n = 7，P < 0.05）;联合应用ANG Ⅱ + Los可进一步增强这种促胰岛素作用（2.31 ± 0.25ng/ml，n = 7，P < 0.01）。C21还升高胰岛素水平（2.13 ± 0.20ng/ml，n = 7，P < 0.01），PD可完全消除C21的升高。2)ANG II损害葡萄糖耐量，而ANG II + Los或C21改善这一功能。3)所有治疗的大鼠显示出增强的胰岛素分泌反应的葡萄糖挑战。4)所有治疗组大鼠胰腺中胰岛素原2 mRNA和胰岛素蛋白表达均上调。在使用INS-1 E细胞和分离的大鼠胰岛的体外实验中，我们发现AT 2 R活化显著改善胰岛素的生物合成和分泌。这些结果表明，AT 2 R作为促胰岛素介质的功能。AT 2 R及其下游信号通路可能是糖尿病的潜在治疗靶点。
In the present study, we evaluated the relative abundance of angiotensin type 2 receptor (AT2R) protein in various tissues of adult rats. We found that pancreatic islets expressed the highest AT2R protein compared with all other tissues. Accordingly, we then determined the functional significance of AT2R in the endocrine pancreas in in vivo and in vitro experiments by using angiotensin II (ANG II) alone, losartan (Los; AT1R antagonist), compound 21 (C21; AT2R agonist), and PD-123319 (PD; AT2R antagonist). Experiments carried out in rats indicated that, 1) ANG II treatment significantly increased plasma insulin concentration (1.51 ± 0.20 vs. 0.82 ± 0.14 ng/ml, n = 7, P < 0.05) in the fed state. This insulinotropic effect was further augmented by combined treatment with ANG II + Los (2.31 ± 0.25 ng/ml, n = 7, P < 0.01). C21 also elevated insulin levels (2.13 ± 0.20 ng/ml, n = 7, P < 0.01), which was completely abolished by PD. 2) ANG II impaired glucose tolerance, whereas ANG II + Los or C21 improved this function. 3) All treated rats displayed an enhanced insulin secretory response to a glucose challenge. 4) All treated rats displayed upregulated proinsulin 2 mRNA and insulin protein expression in the pancreas. In in vitro experiments using INS-1E cells and isolated rat islets, we found that AT2R activation significantly improved insulin biosynthesis and secretion. These results suggest that the AT2R functions as an insulinotropic mediator. AT2R and its downstream signaling pathways may be potential therapeutic targets for diabetes.