Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, United States.
Neuropeptides. 2011 Oct;45(5):329-35. doi: 10.1016/j.npep.2011.07.002. Epub 2011 Jul 23.
Angiotensin (Ang) III is a biologically active metabolite of Ang II with similar effects and receptor binding properties as Ang II. Most Ang III studies delineate physiological effects of the peptide but, the intracellular pathways leading to the actions are unknown and are a focus of these studies. We investigated in cultured brainstem and cerebellum rat astrocytes whether Ang III stimulates ERK1/2 mitogen activated protein (MAP) kinases and astrocyte growth. Ang III significantly stimulated ERK1/2 MAP kinases in a dose- and time-dependent manner. The maximal stimulation occurred with 100 nM Ang III (2.8±0.3 and 2.3±0.1-fold over basal, in brainstem and cerebellum astrocytes, respectively). This stimulation occurred as early as 1 min, and was sustained for at least 15 min. Moreover, inhibition of the ERK1/2 MAP kinase pathway by 10 μM PD98059 attenuated Ang III-induced ERK1/2 phosphorylation. Ang III induction of ERK1/2 occurred via stimulation of the Ang AT(1) receptor since pretreatment with 10 μM Losartan, a selective AT(1) receptor blocker, prevented Ang III-induced ERK1/2 phosphorylation. The selective AT(2) Ang receptor blocker PD123319 was ineffective. Comparable to Ang II, Ang III also stimulated astrocyte growth in a concentration-dependent manner, an effect that occurred via activation of the AT(1) receptor as well. These findings suggest that Ang III has similar effects as Ang II in astrocytes since it rapidly stimulates the phosphorylation of the ERK1/2 MAP kinases and induces astrocyte proliferation through activation of the AT(1) receptor. These studies are important in establishing signaling pathways for Ang III and provide validation of the central role of Ang III.
血管紧张素（Ang）III 是血管紧张素 II（Ang II）的生物活性代谢物，具有相似的作用和受体结合特性。大多数 Ang III 研究描述了该肽的生理作用，但导致其作用的细胞内途径尚不清楚，这是这些研究的重点。我们在培养的脑干和小脑大鼠星形胶质细胞中研究了 Ang III 是否刺激 ERK1/2 有丝分裂原激活蛋白（MAP）激酶和星形胶质细胞生长。Ang III 以剂量和时间依赖的方式显著刺激 ERK1/2 MAP 激酶。最大刺激发生在 100 nM Ang III（分别在脑干和小脑星形胶质细胞中使 ERK1/2 基础水平增加 2.8±0.3 和 2.3±0.1 倍）。这种刺激早在 1 分钟即可发生，并持续至少 15 分钟。此外，通过 10 μM PD98059 抑制 ERK1/2 MAP 激酶通路可减弱 Ang III 诱导的 ERK1/2 磷酸化。Ang III 诱导 ERK1/2 的发生是通过刺激 Ang AT(1)受体，因为用 10 μM Losartan（一种选择性 AT(1)受体阻滞剂）预处理可防止 Ang III 诱导的 ERK1/2 磷酸化。选择性 AT(2) Ang 受体阻滞剂 PD123319 无效。与 Ang II 类似，Ang III 也以浓度依赖的方式刺激星形胶质细胞生长，这种作用也是通过激活 AT(1)受体而发生的。这些发现表明，Ang III 在星形胶质细胞中具有与 Ang II 相似的作用，因为它能迅速刺激 ERK1/2 MAP 激酶的磷酸化，并通过激活 AT(1)受体诱导星形胶质细胞增殖。这些研究对于确定 Ang III 的信号通路具有重要意义，并为 Ang III 的中枢作用提供了验证。
