AT2-receptor stimulation enhances axonal plasticity after spinal cord injury by upregulating BDNF expression

Namsolleck, Pawel; Boato, Francesco; Schwengel, Katja; Paulis, Ludovít; Matho, Katherine; Geurts, Nathalie; Thöne-Reineke, Christa; Lucht, Kristin; Seidel, Kerstin; Hallberg, Anders; Dahlöf, Björn; Unger, Thomas; Hendrix, Sven; Steckelings, Ulrike Muscha

doi:10.1016/j.nbd.2012.11.008

Cited by 82 publications

(72 citation statements)

References 47 publications

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“…This phenomenon has also been confirmed in piglets (3) and humans (22) and was suggested to be associated with islet remodeling and/or changes in ␤-cell maturation (1). Given the antiapoptotic effect of AT 2 R observed in neurons (28) and myocardial cells (20), the transient downregulation of AT 2 R expression in the pancreas at 3 wk after birth may be responsible for the transient burst of ␤-cell apoptosis during the period of weaning. The antiapoptotic effect of the AT 2 R in ␤-cells should be an attractive area for therapy.…”

Section: Discussionmentioning

confidence: 71%

“…When we characterized the tissue distribution of AT 2 R in adult rats, we found that, in addition to the pancreas, the brain stem and testicle also expressed high levels of AT 2 R protein. Although no data are available to associate AT 2 R with testicular function, the brain AT 2 R has been demonstrated to participate in the regulation of sympathetic tone by facilitating potassium channel activity (17) and exerts neuroprotective effects by suppressing apoptosis (28). In a previous study, we have demonstrated an agerelated upregulation of AT 2 R protein expression in mouse brain stem (15).…”

Section: Discussionmentioning

confidence: 92%

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Angiotensin type 2 receptor in pancreatic islets of adult rats: a novel insulinotropic mediator

Shao

Zucker

Gao

2013

American Journal of Physiology-Endocrinology and Metabolism

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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 Ϯ 0.20 vs. 0.82 Ϯ 0.14 ng/ml, n ϭ 7, P Ͻ 0.05) in the fed state. This insulinotropic effect was further augmented by combined treatment with ANG II ϩ Los (2.31 Ϯ 0.25 ng/ml, n ϭ 7, P Ͻ 0.01). C21 also elevated insulin levels (2.13 Ϯ 0.20 ng/ml, n ϭ 7, P Ͻ 0.01), which was completely abolished by PD. 2) ANG II impaired glucose tolerance, whereas ANG II ϩ 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. compound 21; insulin production; INS-1E cells AS ONE OF THE PRIMARY ANGIOTENSIN II (ANG II) receptor subtypes, the angiotensin type 2 receptor (AT 2 R) was pharmacologically identified (10, 41) and molecularly cloned (19,27) around 20 years ago. However, a complete understanding of the function of the AT 2 R is still incomplete. Evidence implies that the AT 2 R exerts numerous effects such as vasodilatation, tissue protection, and regeneration (21). These biological actions, however, are rarely observed in intact animals because of the relatively lower expression level of AT 2 R compared with its antagonistic twin, the angiotensin type 1 receptor (AT 1 R), and the absence of an exclusive native ligand to the AT 2 R (13).Another reason that AT 2 R actions are not well appreciated comes from the prevailing concept concerning its ontogeny (13). The AT 2 R has long been considered to express at high levels in the fetus and then dramatically decline within 24 h after birth. As a consequence, the AT 2 R in the adult animal has been believed to be a retrogressive receptor and play a minor regulatory role (5). Recent data from our laboratory, however, documented that this dogma may not be true (42). We found that adult rat (43) and mouse (15) expressed significantly higher AT 2 R protein compared with the fetus and neonate. We believe that these results suggest an important function for the AT 2 R in adulthood (16,17).ANG II has been recently assumed to play a role in the regulation of pancre...

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 92%

Angiotensin type 2 receptor in pancreatic islets of adult rats: a novel insulinotropic mediator

Shao

Zucker

Gao

2013

American Journal of Physiology-Endocrinology and Metabolism

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“…TIMP1 is also known to possess antiapoptotic activity, 35 and this fact is in accordance with antiapoptotic properties of C21 demonstrated previously. 15,36 Thus, TIMP1 may be a major mediator of the cardioprotective effects of C21. Given that MMPs generally play a pivotal role in extracellular matrix degradation, the antiproteolytic effect of C21 might be of great relevance for tissue remodeling in various pathologies.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin Type 2 Receptor Stimulation Ameliorates Left Ventricular Fibrosis and Dysfunction via Regulation of Tissue Inhibitor of Matrix Metalloproteinase 1/Matrix Metalloproteinase 9 Axis and Transforming Growth Factor β1 in the Rat Heart

Lauer

Slavić²,

Sommerfeld³

et al. 2014

Hypertension

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Left ventricular (LV) remodeling is the main reason for the development of progressive cardiac dysfunction after myocardial infarction (MI). This study investigated whether stimulation of the angiotensin type 2 receptor is able to ameliorate post-MI cardiac remodeling and what the underlying mechanisms may be. MI was induced in Wistar rats by permanent ligation of the left coronary artery. Treatment with the angiotensin type 2 receptor agonist compound 21 ( 0.03 mg/kg) was started 6 hours post-MI and continued for 6 weeks. Hemodynamic parameters were measured by echocardiography and intracardiac catheter. Effects on proteolysis were studied in heart tissue and primary cardiac fibroblasts. Compound 21 significantly improved systolic and diastolic functions, resulting in improved ejection fraction (71.2±4.7% versus 53.4±7.0%; P <0.001), fractional shortening ( P <0.05), LV internal dimension in systole ( P <0.05), LV end-diastolic pressure (16.9±1.2 versus 22.1±1.4 mm Hg; P <0.05), ratio of early (E) to late (A) ventricular filling velocities, and maximum and minimum rate of LV pressure rise ( P <0.05). Compound 21 improved arterial stiffness parameters and reduced collagen content in peri-infarct myocardium. Tissue inhibitor of matrix metalloproteinase 1 was strongly upregulated, whereas matrix metalloproteinases 2 and 9 and transforming growth factor β1 were diminished in LV of treated animals. In cardiac fibroblasts, compound 21 initially induced tissue inhibitor of matrix metalloproteinase 1 expression followed by attenuated matrix metalloproteinase 9 and transforming growth factor β1 secretion. In conclusion, angiotensin type 2 receptor stimulation improves cardiac function and prevents cardiac remodeling in the late stage after MI, suggesting that angiotensin type 2 receptor agonists may be considered a future pharmacological approach for the improvement of post-MI cardiac dysfunction.

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“…However, in vitro experiments have revealed that AT 2 activation involves subsequent activation of tropomyosin-related kinase receptor A (TrkA) and its downstream effectors p42/p44 mitogenactivated protein kinase [extracellular signal-regulated kinases (ERKs) 1 and 2] [17], as well as the release of nitric oxide (NO) and subsequent activation of protein kinase B (Akt) activation [18,19]. Recently, Namsolleck et al [20] suggested that activation of AT 2 increases the levels of brain-derived neurotrophic factor (BDNF) and TrkA/B mRNA in primary neurons. Moreover, accumulating evidence is shedding light on an important role for AT 2 in neuronal differentiation and neuronal stem cell proliferation [21][22][23][24][25][26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Angiotensin Receptor Type 2 Activation Induces Neuroprotection and Neurogenesis After Traumatic Brain Injury

et al. 2014

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Angiotensin II receptor type 2 (AT 2 ) agonists have been shown to limit brain ischemic insult and to improve its outcome. The activation of AT 2 was also linked to induced neuronal proliferation and differentiation in vitro. In this study, we examined the therapeutic potential of AT 2 activation following traumatic brain injury (TBI) in mice, a brain pathology that displays ischemia-like secondary damages. The AT 2 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 AT 2 antagonist PD123319. Our results suggest that AT 2 activation after TBI promotes neuroprotection and neurogenesis, and may be a novel approach for the development of new drugs to treat victims of TBI.

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AT2-receptor stimulation enhances axonal plasticity after spinal cord injury by upregulating BDNF expression

Cited by 82 publications

References 47 publications

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

Angiotensin Type 2 Receptor Stimulation Ameliorates Left Ventricular Fibrosis and Dysfunction via Regulation of Tissue Inhibitor of Matrix Metalloproteinase 1/Matrix Metalloproteinase 9 Axis and Transforming Growth Factor β1 in the Rat Heart

Angiotensin Receptor Type 2 Activation Induces Neuroprotection and Neurogenesis After Traumatic Brain Injury

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