Dopamine regulates adult neurogenesis in the ventricular‐subventricular zone via dopamine D3 angiotensin type 2 receptor interactions

The renin–angiotensin system (RAS), and particularly its angiotensin type-2 receptors (AT2), have been classically involved in processes of cell proliferation and maturation during development. However, the potential role of RAS in adult neurogenesis in the ventricular-subventricular zone (V-SVZ) and its aging-related alterations have not been investigated. In the present study, we analyzed the role of major RAS receptors on neurogenesis in the V-SVZ of adult mice and rats. In mice, we showed that the increase in proliferation of cells in this neurogenic niche was induced by activation of AT2 receptors but depended partially on the AT2-dependent antagonism of AT1 receptor expression, which restricted proliferation. Furthermore, we observed a functional dependence of AT2 receptor actions on Mas receptors. In rats, where the levels of the AT1 relative to those of AT2 receptor are much lower, pharmacological inhibition of the AT1 receptor alone was sufficient in increasing AT2 receptor levels and proliferation in the V-SVZ. Our data revealed that interactions between RAS receptors play a major role in the regulation of V-SVZ neurogenesis, particularly in proliferation, generation of neuroblasts, and migration to the olfactory bulb, both in young and aged brains, and suggest potential beneficial effects of RAS modulators on neurogenesis.

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Faculty Opinions recommendation of Angiotensin type 2 receptor-mediated hypotension in angiotensin type-1 receptor-blocked rats.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.3374958.3065057 ◽

2010 ◽

Author(s):

Raouf Khalil

Keyword(s):

Angiotensin Type 2 Receptor ◽

Angiotensin Type

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Angiotensin Type 2 Receptor Mediates Valsartan-Induced Hypotension in Conscious Rats

Hypertension ◽

10.1161/01.hyp.35.5.1074 ◽

2000 ◽

Vol 35 (5) ◽

pp. 1074-1077 ◽

Cited By ~ 106

Author(s):

Helmy M. Siragy ◽

Marc de Gasparo ◽

Robert M. Carey

Keyword(s):

Induced Hypotension ◽

Conscious Rats ◽

Angiotensin Type 2 Receptor ◽

Angiotensin Type

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High-Salt Diet Inhibits Expression of Angiotensin Type 2 Receptor in Resistance Arteries

Hypertension ◽

10.1161/01.hyp.0000161990.98383.ad ◽

2005 ◽

Vol 45 (5) ◽

pp. 853-859 ◽

Cited By ~ 24

Author(s):

Magdalena Gonzalez ◽

Lorena Lobos ◽

Felipe Castillo ◽

Lorna Galleguillos ◽

Nandy C. Lopez ◽

...

Keyword(s):

High Salt ◽

Resistance Arteries ◽

High Salt Diet ◽

Salt Diet ◽

Angiotensin Type 2 Receptor ◽

Angiotensin Type

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Angiotensin Type 2 Receptor in Resistance Arteries of Type 2 Diabetic Hypertensive Patients

Hypertension ◽

10.1161/01.hyp.0000253968.95136.b8 ◽

2007 ◽

Vol 49 (2) ◽

pp. 341-346 ◽

Cited By ~ 89

Author(s):

Carmine Savoia ◽

Rhian M. Touyz ◽

Massimo Volpe ◽

Ernesto L. Schiffrin

Keyword(s):

Resistance Arteries ◽

Hypertensive Patients ◽

Angiotensin Type 2 Receptor ◽

Type 2 Diabetic ◽

Angiotensin Type

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Activation of angiotensin type 2 receptor attenuates testosterone-induced hypertension and uterine vascular resistance in pregnant rats

Biology of Reproduction ◽

10.1093/biolre/ioab051 ◽

2021 ◽

Author(s):

Jay S Mishra ◽

Sathish Kumar

Keyword(s):

Blood Pressure ◽

Blood Flow ◽

Vascular Function ◽

Uterine Artery ◽

Artery Blood Flow ◽

Protein Levels ◽

Angiotensin Type 2 Receptor ◽

Enos Protein ◽

Angiotensin Type

Abstract Preeclampsia is a pregnancy-related hypertensive disorder with unclear mechanisms. While hypersensitivity to angiotensin II via vasoconstrictive angiotensin type-1 receptor (AT1R) is observed in preeclampsia, the importance of vasodilatory angiotensin type-2 receptor (AT2R) in the control of vascular dysfunction is less clear. We assessed whether AT1R, AT2R and eNOS expression is altered in placental vessels of preeclamptic women and tested if ex vivo incubation with AT2R agonist Compound 21 (C21; 1 μM) could restore AT1R, AT2R and eNOS balance. Further, using a rat model of gestational hypertension induced by elevated testosterone, we examined whether C21 (1 μg·kg−1·day−1, oral) could preserve AT1R and AT2R balance and improve blood pressure, uterine artery blood flow, and vascular function. Western blots revealed that AT1R protein level was higher while AT2R and eNOS protein were reduced in preeclamptic placental vessels, and AT2R agonist C21 decreased AT1R and increased AT2R and eNOS protein levels in preeclamptic vessels. In testosterone-dams, blood pressure was higher, and uterine artery blood flow was reduced, and C21 treatment reversed these levels similar to those in controls dams. C21 attenuated the exaggerated Ang II contraction and improved endothelium-dependent vasorelaxation in uterine arteries of testosterone-dams. These C21-mediated vascular effects were associated with decreased AT1R and increased AT2R and eNOS protein levels. C21 also increased serum nitrate/nitrite and bradykinin production in testosterone-dams and attenuated the feto-placental growth restriction. Thus, AT1R upregulation and AT2R downregulation is observed in preeclampsia and testosterone-model, and increasing AT2R activity could help restore AT1R and AT2R balance and improve gestational vascular function.

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Angiotensin1-9 antagonises pro-hypertrophic signalling in cardiomyocytes via the angiotensin type 2 receptor

The Journal of Physiology ◽

10.1113/jphysiol.2010.203075 ◽

2011 ◽

Vol 589 (4) ◽

pp. 939-951 ◽

Cited By ~ 57

Author(s):

M. Flores-Muñoz ◽

N. J. Smith ◽

C. Haggerty ◽

G. Milligan ◽

S. A. Nicklin

Keyword(s):

Angiotensin Type 2 Receptor ◽

Angiotensin Type

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Abstract P288: Systemic Administration of an Angiotensin Type-2 Receptor Agonist Decreases Renal Regulatory T Cells

Hypertension ◽

10.1161/hyp.70.suppl_1.p288 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Ellen E Gillis ◽

Jennifer C Sullivan

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Critical Role ◽

High Dose ◽

Ang Ii ◽

Osmotic Minipump ◽

Angiotensin Type 2 Receptor ◽

Angiotensin Type

There is increasing evidence supporting a critical role of the immune system in the development of hypertension. Our lab has previously reported sex differences in the renal T cell profile in both Spontaneously Hypertensive Rats (SHR) and Angiotensin II (Ang II) models of hypertension, with females having more anti-inflammatory regulatory T cells (Tregs) than males. Ang II has a well-defined role in the activation of pro-inflammatory T cells in hypertension via the angiotensin type-1 receptor (AT1R). Less is known about the role of the angiotensin type-2 receptor (AT2R) in the regulation of immune cells, although the AT2R has been shown to be cardioprotective and AT2R expression is greater in females than males. Based on the potential anti-hypertensive role of AT2Rs, we hypothesized that administration of an AT2R agonist, Compound 21 (C21), would increase renal Tregs, and this increase would be greater in females due to greater AT2R expression. Male and female SHR (10 weeks of age, n=3-4) were implanted with telemetry units for continuous monitoring of mean arterial pressure (MAP). Following 10 days of recovery, baseline MAP was recorded for 5 days. Rats were then divided into the following treatment groups: surgical controls, low dose C21 (150 ng/kg/min, sc by osmotic minipump), high dose C21 (300 ng/kg/min, sc by osmotic minipump). Kidneys were harvested after 2 weeks of treatment and flow cytometry was performed on whole kidney homogenates. MAP was not altered by C21 treatment in males (137±4 vs 134±4 vs 134±4 mmHg; n.s.) or females (128±2 vs 136±5 vs 134±4 mmHg; n.s.). Interestingly, despite having no effect on MAP, there was a significant decrease in renal CD3 + CD4 + FoxP3 + Tregs in females following both low and high doses of C21 (data expressed as % CD3 + CD4 + cells: 6±0.6 vs 3±0.6 vs 3.5±1.3 %, respectively; p=0.02). Tregs decrease in males following the high dose of C21 only (data expressed as % CD3 + CD4 + cells: 3.3±0.3 vs 3.3±0.5 vs 1.7±0.7 %, respectively; p=0.05). Total CD3 + T cells, CD3 + CD4 + T cells, and Th17 cells were not altered by C21 treatment. In conclusion, AT2R activation suppresses renal Tregs, and females are more sensitive than males. These data suggest a novel role for AT2R regulation in the kidney in hypertension.

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Abstract 081: Reporter Mouse Strain Provides a Novel Look at Angiotensin Type-2 Receptor Distribution in Central Nervous System Cardiovascular Control Centers

Hypertension ◽

10.1161/hyp.64.suppl_1.081 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Annette D de Kloet ◽

Lei Wang ◽

Jacob A Ludin ◽

Helmut Hiller ◽

Justin A Smith ◽

...

Keyword(s):

Blood Pressure ◽

Fluid Balance ◽

Hypothalamic Nucleus ◽

Reporter Mouse ◽

Arterial Blood ◽

Egfp Reporter ◽

Angiotensin Type 2 Receptor ◽

The Brain ◽

Angiotensin Type

It is established that angiotensin-II acts at its type-1 receptor (AT1R) in the brain to increase sympathetic outflow and blood pressure, and modulate fluid balance. However, the role of the angiotensin type-2 receptor (AT2R) in the neural control of these processes has received far less attention, largely because of an inability to effectively localize these receptors at a cellular level in the brain. The present studies combine the use of a bacterial artificial chromosome transgenic AT2R-eGFP reporter mouse with recent advances in in situ hybridization (ISH) to circumvent this obstacle. Dual IHC/ ISH studies validated the AT2R-eGFP reporter mice by determining that eGFP and AT2R mRNA were highly co-localized within the nucleus of the solitary tract (NTS; 98.0 ± 0.18 %; 125 ± 3.6 of 127 ± 3.9 cells; n = 4). Analysis of eGFP immunoreactivity in the brain revealed localization to neurons within nuclei that regulate blood pressure and fluid balance (e.g., NTS and median preoptic nucleus [MnPO]). Additional IHC/ISH studies uncovered the phenotype of specific AT2R-eGFP cells. For example, within the NTS, AT2R-eGFP neurons primarily express glutamic acid decarboxylase-67 (GABAergic; 80 ± 2.8 %; 225 ± 12.5 of 280 ± 8.4 cells; n = 4), while only a subset express vesicular glutamate transporter-2 (glutamatergic; 18.2 ± 2.9 %; 50.8 ± 7.7 of 280 ± 8.4 cells) or AT1R (8.7 ± 1.0 %; 22 ± 2.2 of 256 ± 11.7 cells). No co-localization was observed with tyrosine hydroxylase in the NTS. Although AT2R-eGFP neurons were not observed within the paraventricular hypothalamic nucleus (PVN), eGFP was localized to efferents terminating in the PVN and to GABAergic neurons surrounding this nucleus. Retrograde neuronal tract tracing studies revealed that many eGFP-positive efferents to the PVN arise from neurons in the MnPO. Based on these neuroanatomical results, we hypothesized that activation of central AT2R would decrease blood pressure. Consistent with this hypothesis, chronic administration of the selective AT2R agonist, compound 21 (7.5 ng/h into the lateral cerebral ventricle) reduced baseline mean arterial blood pressure relative to control mice (103 ± 1.65 v. 110 ± 1.70 mmHg; n = 16; p = 0.02). These studies demonstrate that central AT2R are positioned to regulate blood pressure.

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Abstract WP101: Involvement of the Contralesional Angiotensin Type 2 Receptor in Compound 21 Mediated Functional Recovery After Stroke

Stroke ◽

10.1161/str.47.suppl_1.wp101 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Abdelrahman Y Fouda ◽

Tauheed Ishrat ◽

Heba Ahmed ◽

Bindu Pillai ◽

Sandeep Artham ◽

...

Keyword(s):

Western Blotting ◽

Functional Recovery ◽

Artery Occlusion ◽

Behavioral Outcome ◽

Brain Hemisphere ◽

Angiotensin Type 2 Receptor ◽

Male Wistar Rats ◽

Compound 21 ◽

Angiotensin Type

Introduction: We have recently shown that the angiotensin type 2 receptor (AT2R) agonist, compound 21 (C21), provides sustained functional recovery after ischemic stroke. This was associated with upregulation of the AT2R and the neurotrophin, brain derived neurotrophic factor (BDNF), in the contralesional brain hemisphere. Here, we aimed to study the contribution of this hemisphere in C21 mediated functional recovery after stroke through localized knockdown of the AT2R. Methods: male wistar rats (34) received two intrastriatal injections of short hairpin RNA (shRNA) lentiviral particles against AT2R, or non-targeting control vector (NTC) into the left brain hemisphere to achieve localized AT2R knockdown. After 14 days, rats were subjected to 90 minutes right middle cerebral artery occlusion (MCAO) and received either C21 (0.03 mg/kg) or saline at reperfusion (IV) then daily (IP) for 7 days. Rats were blindly assessed for behavioral outcome up to 10 days as well as molecular analysis. Results (table): PCR and Western blotting confirmed successful knockdown of the AT2R in the left (contralesional) hemisphere by about 50%. All groups showed worsened outcome on days 1 to 3 then recovered on days 7 to 10. The C21/NTC group showed better behavioral outcome compared to other groups at days 7 and 10, while the saline/shRNA group was associated with the least recovery. Using Western blotting, C21/NTC group showed higher BDNF and lower proBDNF (pro-form) levels in the ischemic and contralesional hemispheres respectively. Expression of the pro-apoptotic P75NTR receptor of proBDNF was decreased with C21 treatment irrespective of AT2R knockdown. Conclusion: Contralesional AT2R could be involved in C21 mediated functional recovery after stroke.

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