Angiotensin AT2 receptor stimulates ERK1 and ERK2 in quiescent but inhibits ERK in NGF-stimulated PC12W cells

ArticleinMolecular Brain Research 78(1-2):175-180 · June 2000with16 Reads
DOI: 10.1016/S0169-328X(00)00093-0
Abstract
To investigate the influence of AT2 receptor stimulation on the ERK pathway and elucidate potential mechanisms of angiotensin II (ANG II)-mediated neuronal differentiation, we analysed tyrosine phosphorylation and activity of ERK after ANG II treatment of both quiescent and NGF-treated PC12W cells. Tyrosine phosphorylation of ERK1 and ERK2 corresponded with the activity of ERK. While ANG II induced an initial activation of ERK in quiescent cells, the NGF-mediated plateau of ERK-stimulation was lowered by costimulation with ANG II. All effects of ANG II were sensitive to AT2 – but not AT1 receptor blockade. Ang II-mediated neurite outgrowth in PC12W cells was inhibited by co-treatment with the MEK inhibitor PD 098059. These findings demonstrate that the AT2 receptor modulates ERK activity depending on the overall cellular input. The distinct regulation of ERK by ANG II and NGF further indicates basic differences in AT2 receptor- and NGF-induced neuronal differentiation.
    • "CGP42112A treatment led to an early induction of ERK1/2 phosphorylation, which is related to neuroprotection after TBI [58, 59], and to reduced neuronal apoptosis [60]. The phosphorylation of ERK1/2 was the first described downstream effector of AT 2 in neuronal cell lines and is a key event for differentiation and the induction of neurite outgrowth [61, 62]. The induction of both Akt and ERK1/2 may be a result of the enhanced levels of the neurotrophins NGF and BDNF. "
    [Show abstract] [Hide abstract] ABSTRACT: Angiotensin II receptor type 2 (AT2) agonists have been shown to limit brain ischemic insult and to improve its outcome. The activation of AT2 was also linked to induced neuronal proliferation and differentiation in vitro. In this study, we examined the therapeutic potential of AT2 activation following traumatic brain injury (TBI) in mice, a brain pathology that displays ischemia-like secondary damages. The AT2 agonist CGP42112A was continuously infused immediately after closed head injury (CHI) for 3 days. We have followed the functional recovery of the injured mice for 35 days post-CHI, and evaluated cognitive function, lesion volume, molecular signaling, and neurogenesis at different time points after the impact. We found dose-dependent improvement in functional recovery and cognitive performance after CGP42112A treatment that was accompanied by reduced lesion volume and induced neurogenesis in the neurogenic niches of the brain and also in the injury region. At the cellular/molecular level, CGP42112A induced early activation of neuroprotective kinases protein kinase B (Akt) and extracellular-regulated kinases ½ (ERK½), and the neurotrophins nerve growth factor and brain-derived neurotrophic factor; all were blocked by treatment with the AT2 antagonist PD123319. Our results suggest that AT2 activation after TBI promotes neuroprotection and neurogenesis, and may be a novel approach for the development of new drugs to treat victims of TBI.
    Full-text · Article · Jun 2014
    • "CGP42112A treatment led to an early induction of ERK1/2 phosphorylation, which is related to neuroprotection after TBI [58, 59], and to reduced neuronal apoptosis [60]. The phosphorylation of ERK1/2 was the first described downstream effector of AT 2 in neuronal cell lines and is a key event for differentiation and the induction of neurite outgrowth [61, 62]. The induction of both Akt and ERK1/2 may be a result of the enhanced levels of the neurotrophins NGF and BDNF. "
    [Show abstract] [Hide abstract] ABSTRACT: Long-term exposure of mice to mild heat (34°C±1°C) confers neuroprotection against traumatic brain injury (TBI); however, the underling mechanisms are not fully understood. Heat acclimation (HA) increases hypothalamic angiotensin II receptor type 2 (AT2) expression and hypothalamic neurogenesis. Accumulating data suggest that activation of the brain AT2 receptor confers protection against several types of brain pathologies, including ischemia, a hallmark of the secondary injury occurring following TBI. As AT2 activates the same pro-survival pathways involved in HA-mediated neuroprotection (e.g., Akt phosphorylation, hypoxia-inducible factor 1α (HIF-1α), and brain-derived neurotrophic factor (BDNF)), we examined the role of AT2 in HA-mediated neuroprotection after TBI. Using an AT2-specific antagonist PD123319, we found that the improvements in motor and cognitive recovery as well as reduced lesion volume and neurogenesis seen in HA mice were all diminished by AT2 inhibition, whereas no significant alternations were observed in control mice. We also found that nerve growth factor/tropomyosin-related kinase receptor A (TrkA), BDNF/TrkB, and HIF-1α pathways are upregulated by HA and inhibited on PD123319 administration, suggesting that these pathways play a role in AT2 signaling in HA mice. In conclusion, AT2 is involved in HA-mediated neuroprotection, and AT2 activation may be protective and should be considered a novel drug target in the treatment of TBI patients.Journal of Cerebral Blood Flow & Metabolism (2014) 0, 000-000. doi:10.1038/jcbfm.2014.93.
    Full-text · Article · May 2014
    • "While AT- 1R has been linked to the Ang II-induced activation of ERK [56], AT-2R is reported to inhibit the AT-1R-induced ERK activation [57]. In other cell models, AT-2R is reported to activate the ERK pathway[58], in agreement with our present findings. Endogenous FGF-2 expression would also be expected to contribute to overall levels of activated ERK in hMFs via both intracrine and autocrine routes, as we have documented in previous studies[25]. "
    [Show abstract] [Hide abstract] ABSTRACT: Fibroblast growth factor 2 (FGF-2) is a multifunctional protein synthesized as high (Hi-) and low (Lo-) molecular weight isoforms. Studies using rodent models showed that Hi- and Lo-FGF-2 exert distinct biological activities: after myocardial infarction, rat Lo-FGF-2, but not Hi-FGF-2, promoted sustained cardioprotection and angiogenesis, while Hi-FGF-2, but not Lo-FGF-2, promoted myocardial hypertrophy and reduced contractile function. Because there is no information regarding Hi-FGF-2 in human myocardium, we undertook to investigate expression, regulation, secretion and potential tissue remodeling-associated activities of human cardiac (atrial) Hi-FGF-2. Human patient-derived atrial tissue extracts, as well as pericardial fluid, contained Hi-FGF-2 isoforms, comprising, respectively, 53%(±20 SD) and 68% (±25 SD) of total FGF-2, assessed by western blotting. Human atrial tissue-derived primary myofibroblasts (hMFs) expressed and secreted predominantly Hi-FGF-2, at about 80% of total. Angiotensin II (Ang II) up-regulated Hi-FGF-2 in hMFs, via activation of both type 1 and type 2 Ang II receptors; the ERK pathway; and matrix metalloprotease-2. Treatment of hMFs with neutralizing antibodies selective for human Hi-FGF-2 (neu-AbHi-FGF-2) reduced accumulation of proteins associated with fibroblast-to-myofibroblast conversion and fibrosis, including α-smooth muscle actin, extra-domain A fibronectin, and procollagen. Stimulation of hMFs with recombinant human Hi-FGF-2 was significantly more potent than Lo-FGF-2 in upregulating inflammation-associated proteins such as pro-interleukin-1β and plasminogen-activator-inhibitor-1. Culture media conditioned by hMFs promoted cardiomyocyte hypertrophy, an effect that was prevented by neu-AbHi-FGF-2 in vitro. In conclusion, we have documented that Hi-FGF-2 represents a substantial fraction of FGF-2 in human cardiac (atrial) tissue and in pericardial fluid, and have shown that human Hi-FGF-2, unlike Lo-FGF-2, promotes deleterious (pro-fibrotic, pro-inflammatory, and pro-hypertrophic) responses in vitro. Selective targeting of Hi-FGF-2 production may, therefore, reduce pathological remodelling in the human heart.
    Full-text · Article · May 2014
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