Muñoz Marina C, Giani Jorge F, Burghi Valeria, Mayer Marcos A, Carranza Andrea, Taira Carlos A, Dominici Fernando P
Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
Regul Pept. 2012 Aug 20;177(1-3):1-11. doi: 10.1016/j.regpep.2012.04.001. Epub 2012 May 1.
Angiotensin (Ang)-(1-7) stimulates proteins belonging to the insulin signaling pathway and ameliorates the Ang II negative effects at this level. However, up to date, receptors involved and mechanisms behind these observations remain unknown. Accordingly, in the present study, we explored the in vivo effects of antagonism of the Ang-(1-7) specific Mas receptor on insulin signal transduction in rat insulin-target tissues. We evaluated the acute modulation of insulin-stimulated phosphorylation of Akt, GSK-3β (Glycogen synthase kinase-3β) and AS160 (Akt substrate of 160kDa) by Ang-(1-7) and/or Ang II in the presence and absence of the selective Mas receptor antagonist A-779 in insulin-target tissues of normal rats. Also using A-779, we determined whether the Mas receptor mediates the improvement of insulin sensitivity exerted by chronic Ang-(1-7) treatment in fructose-fed rats (FFR), a model of insulin resistance, dyslipidemia and mild hypertension. The two major findings of the present work are as follows; 1) Ang-(1-7) attenuates acute Ang II-mediated inhibition of insulin signaling components in normal rats via a Mas receptor-dependent mechanism; and 2). The Mas receptor appears to be involved in beneficial effects of Ang-(1-7) on the phosphorylation of crucial insulin signaling mediators (Akt, GSK-3β and AS160), in liver, skeletal muscle and adipose tissue of FFR. These results shed light into the mechanism by which Ang-(1-7) exerts its positive physiological modulation of insulin actions in classical metabolic tissues and reinforces the central role of Akt in these effects.
血管紧张素（Ang）-(1-7)刺激胰岛素信号通路中的相关蛋白，并改善该水平下Ang II的负面影响。然而，迄今为止，这些现象背后涉及的受体和机制仍不清楚。因此，在本研究中，我们探究了Ang-(1-7)特异性Mas受体拮抗作用对大鼠胰岛素靶组织中胰岛素信号转导的体内影响。我们评估了在正常大鼠胰岛素靶组织中，在存在和不存在选择性Mas受体拮抗剂A-779的情况下，Ang-(1-7)和/或Ang II对胰岛素刺激的Akt、糖原合成酶激酶-3β（GSK-3β）和160kDa的Akt底物（AS160）磷酸化的急性调节作用。同样使用A-779，我们确定Mas受体是否介导了慢性Ang-(1-7)治疗对果糖喂养大鼠（FFR）胰岛素敏感性的改善，FFR是一种胰岛素抵抗、血脂异常和轻度高血压的模型。本研究的两个主要发现如下：1）Ang-(1-7)通过Mas受体依赖性机制减弱正常大鼠中急性Ang II介导的胰岛素信号成分抑制作用；2）Mas受体似乎参与了Ang-(1-7)对FFR肝脏、骨骼肌和脂肪组织中关键胰岛素信号介质（Akt、GSK-3β和AS160）磷酸化的有益作用。这些结果揭示了Ang-(1-7)在经典代谢组织中对胰岛素作用发挥正向生理调节的机制，并强化了Akt在这些作用中的核心地位。
