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Article ; Online: Anxiolytic effect of alamandine in male transgenic rats with low brain angiotensinogen is dependent on activation of MrgD receptors.

Amado Costa, Laura / Oliveira Amaral, Laura B / Mourão, Flávio A G / Bader, Michael / Santos, Robson A S / Campagnole-Santos, Maria José / Kangussu, Lucas M

Hormones and behavior

2024 Volume 163, Page(s) 105551

Abstract: Alamandine is a peptide hormone belonging to the renin-angiotensin system (RAS). It acts through the Mas-related G-protein coupled receptor type D, MrgD, which is expressed in different tissues, including the brain. In the present study, we hypothesize ... ...

Abstract	Alamandine is a peptide hormone belonging to the renin-angiotensin system (RAS). It acts through the Mas-related G-protein coupled receptor type D, MrgD, which is expressed in different tissues, including the brain. In the present study, we hypothesize that a lack of alamandine, through MrgD, could cause the anxiety-like behavior in transgenic rats with low brain angiotensinogen [TGR(ASrAOGEN)680]. Adult male transgenic rats exhibited a significant increase in the latency to feeding time in the novelty suppressed feeding test and a decrease in the percentage of time and entries in the open arms in the elevated plus maze. These effects were reversed by intracerebroventricular infusion of alamandine. Pretreatment with D-Pro
Language	English
Publishing date	2024-04-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	214409-8
ISSN	1095-6867 ; 0018-506X
ISSN (online)	1095-6867
ISSN	0018-506X
DOI	10.1016/j.yhbeh.2024.105551
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Article ; Online: Increased angiotensin II formation in the brain modulates cardiovascular homeostasis and erythropoiesis.

Rodrigues, André Felipe / Todiras, Mihail / Qadri, Fatimunnisa / Campagnole-Santos, Maria Jose / Alenina, Natalia / Bader, Michael

Clinical science (London, England : 1979)

2021 Volume 135, Issue 11, Page(s) 1353–1367

Abstract: In spite of the fact that the modulatory effects of angiotensin II (Ang II) on the sympathetic nerve activity to targeted organs involved in blood pressure (BP) regulation is well acknowledged, the local production of this peptide in the brain and the ... ...

Abstract	In spite of the fact that the modulatory effects of angiotensin II (Ang II) on the sympathetic nerve activity to targeted organs involved in blood pressure (BP) regulation is well acknowledged, the local production of this peptide in the brain and the consequences of enhanced central Ang II beyond the cardiovascular system are not yet well comprehended. In the present study, we generated and validated a new transgenic mouse line overexpressing the rat full-length angiotensinogen (Agt) protein specifically in the brain (Agt-Tg). Adult Agt-Tg mice presented overall increased gene expression of total Agt in the brain including brainstem and hypothalamus. In addition, the excess of Agt led to abundantly detectable brain Ang II levels as well as increased circulating copeptin levels. Agt-Tg displayed raised BP in acute recordings, while long-term telemetrically measured basal BP was indistinguishable from wild-types. Agt-Tg has altered peripheral renin-angiotensin system and vasomotor sympathetic tone homeostasis because renal gene expression analysis, plasma Ang II measurements and ganglionic blockade experiments revealed suppressed renin expression and reduced Ang II and higher neurogenic pressure response, respectively. Plasma and urine screens revealed apparently normal fluid and electrolyte handling in Agt-Tg. Interestingly, hematological analyses showed increased hematocrit in Agt-Tg caused by enhanced erythropoiesis, which was reverted by submitting the transgenic mice to a long-term peripheral sympathectomy protocol. Collectively, our findings suggest that Agt-Tg is a valuable tool to study not only brain Ang II formation and its modulatory effects on cardiovascular homeostasis but also its role in erythropoiesis control via autonomic modulation.
MeSH term(s)	Angiotensin II/metabolism ; Animals ; Brain/metabolism ; Erythropoiesis/physiology ; Homeostasis/physiology ; Hypertension/metabolism ; Kidney/metabolism ; Mice ; Mice, Transgenic ; Receptor, Angiotensin, Type 1/metabolism ; Renin/metabolism ; Renin-Angiotensin System/physiology
Chemical Substances	Receptor, Angiotensin, Type 1 ; Angiotensin II (11128-99-7) ; Renin (EC 3.4.23.15)
Language	English
Publishing date	2021-05-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	206835-7
ISSN	1470-8736 ; 0301-0538 ; 0009-0360 ; 0143-5221
ISSN (online)	1470-8736
ISSN	0301-0538 ; 0009-0360 ; 0143-5221
DOI	10.1042/CS20210072
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Article ; Online: Impact of genetic deletion of MrgD or Mas receptors in depressive-like behaviour in mice.

Becari, Luca / Fonseca, Maria Luiza A / Gonçalves, Sthéfanie C A / Bader, Michael / Santos, Robson A S / Campagnole-Santos, Maria José / Kangussu, Lucas M

Acta neuropsychiatrica

2022 Volume 35, Issue 1, Page(s) 27–34

Abstract: Objectives: To evaluate the impact of genetic deletion of receptors of the counterregulatory arms of the renin-angiotensin system in depressive-like behaviours.: Methods: 8-12 weeks-old male mice wild type (WT, C57BL/6J) and mice with genetic ... ...

Abstract	Objectives: To evaluate the impact of genetic deletion of receptors of the counterregulatory arms of the renin-angiotensin system in depressive-like behaviours. Methods: 8-12 weeks-old male mice wild type (WT, C57BL/6J) and mice with genetic deletion of MrgD (MrgD KO) or Mas receptors (Mas KO) were subjected to the Forced Swim Test (FST) and the Tail Suspension Test (TST). Brain-derived neurotrophic factor (BDNF) levels were measured by enzyme-linked immunosorbent assay (ELISA). Blockade of Mas was performed by acute intracerebroventricular ( Results: No statistical difference in immobility time was observed between MrgD KO and WT male animals subjected to FST and TST. However, acute Conclusion: Our data showed that Mas plays an important role in the neurobiology of depression probably by modulating BDNF expression. On the contrary, lack of MrgD did not alter depressive-like behaviour, which was supported by the lack of alterations in BDNF levels.
MeSH term(s)	Mice ; Male ; Animals ; Depression/genetics ; Depression/metabolism ; Brain-Derived Neurotrophic Factor/genetics ; Brain-Derived Neurotrophic Factor/metabolism ; Mice, Inbred C57BL ; Hindlimb Suspension ; Prefrontal Cortex/metabolism ; Hippocampus/metabolism
Chemical Substances	Brain-Derived Neurotrophic Factor
Language	English
Publishing date	2022-08-18
Publishing country	England
Document type	Journal Article
ZDB-ID	1154361-9
ISSN	1601-5215 ; 0924-2708
ISSN (online)	1601-5215
ISSN	0924-2708
DOI	10.1017/neu.2022.20
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Zs.A 3708: Show issues

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Article ; Online: Adipose tissue plasticity mediated by the counterregulatory axis of the renin-angiotensin system: Role of Mas and MrgD receptors.

Proença, Ana Beatriz / Medeiros, Gabriela Rodrigues / Reis, Guilherme Dos Santos / Losito, Luiza da França / Ferraz, Luiza Mazzali / Bargut, Thereza Cristina Lonzetti / Soares, Nícia Pedreira / Alexandre-Santos, Beatriz / Campagnole-Santos, Maria Jose / Magliano, D'Angelo Carlo / Nobrega, Antonio Claudio Lucas da / Santos, Robson Augusto Souza / Frantz, Eliete Dalla Corte

Journal of cellular physiology

2024

Abstract: The renin-angiotensin system (RAS) is an endocrine system composed of two main axes: the classical and the counterregulatory, very often displaying opposing effects. The classical axis, primarily mediated by angiotensin receptors type 1 (AT1R), is linked ...

Abstract	The renin-angiotensin system (RAS) is an endocrine system composed of two main axes: the classical and the counterregulatory, very often displaying opposing effects. The classical axis, primarily mediated by angiotensin receptors type 1 (AT1R), is linked to obesity-associated metabolic effects. On the other hand, the counterregulatory axis appears to exert antiobesity effects through the activation of two receptors, the G protein-coupled receptor (MasR) and Mas-related receptor type D (MrgD). The local RAS in adipose organ has prompted extensive research into white adipose tissue and brown adipose tissue (BAT), with a key role in regulating the cellular and metabolic plasticity of these tissues. The MasR activation favors the brown plasticity signature in the adipose organ by improve the thermogenesis, adipogenesis, and lipolysis, decrease the inflammatory state, and overall energy homeostasis. The MrgD metabolic effects are related to the maintenance of BAT functionality, but the signaling remains unexplored. This review provides a summary of RAS counterregulatory actions triggered by Mas and MrgD receptors on adipose tissue plasticity. Focus on the effects related to the morphology and function of adipose tissue, especially from animal studies, will be given targeting new avenues for treatment of obesity-associated metabolic effects.
Language	English
Publishing date	2024-04-05
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	3116-1
ISSN	1097-4652 ; 0021-9541
ISSN (online)	1097-4652
ISSN	0021-9541
DOI	10.1002/jcp.31265
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Article ; Online: A single dose of angiotensin-(1-7) resolves eosinophilic inflammation and protects the lungs from a secondary inflammatory challenge.

Magalhaes, Giselle Santos / Gregorio, Juliana Fabiana / Beltrami, Vinicius Amorim / Felix, Franciel Batista / Oliveira-Campos, Livia / Bonilha, Caio Santos / Righetti, Renato Fraga / Tibério, Iolanda de Fátima Lopes Calvo / De Sousa, Frederico B / Rezende, Barbara Maximino / Teixeira-Carvalho, Andréa / Santos, Robson As / Campagnole-Santos, Maria José / Rodrigues-Machado, Maria da Gloria / Teixeira, Mauro Martins / Pinho, Vanessa

Inflammation research : official journal of the European Histamine Research Society ... [et al.

2024

Abstract: Objective: Angiotensin-(1-7) [Ang-(1-7)] is a pro-resolving mediator. It is not known whether the pro-resolving effects of Ang-(1-7) are sustained and protect the lung from a subsequent inflammatory challenge. This study sought to investigate the impact ...

Abstract	Objective: Angiotensin-(1-7) [Ang-(1-7)] is a pro-resolving mediator. It is not known whether the pro-resolving effects of Ang-(1-7) are sustained and protect the lung from a subsequent inflammatory challenge. This study sought to investigate the impact of treatment in face of a second allergic or lipopolysaccharide (LPS) challenge. Methods: Mice, sensitized and challenged with ovalbumin (OVA), received a single Ang-(1-7) dose at the peak of eosinophilic inflammation, 24 h after the final OVA challenge. Subsequently, mice were euthanized at 48, 72, 96, and 120 h following the OVA challenge, and cellular infiltrate, inflammatory mediators, lung histopathology, and macrophage-mediated efferocytic activity were evaluated. The secondary inflammatory stimulus (OVA or LPS) was administered 120 h after the last OVA challenge, and subsequent inflammatory analyses were performed. Results: Treatment with Ang-(1-7) resulted in elevated levels of IL-10, CD4 Conclusion: A single dose of Ang-(1-7) resolves lung inflammation and protect the lung from a subsequent inflammatory challenge highlighting its potential therapeutic for individuals with asthma.
Language	English
Publishing date	2024-04-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1221794-3
ISSN	1420-908X ; 1023-3830
ISSN (online)	1420-908X
ISSN	1023-3830
DOI	10.1007/s00011-024-01880-x
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Zs.A 675: Show issues

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Article ; Online: The Renin-Angiotensin System and the Neurodegenerative Diseases: A Brief Review.

Almeida-Santos, Ana Flavia / Kangussu, Lucas M / Campagnole-Santos, Maria Jose

Protein and peptide letters

2017 Volume 24, Issue 9, Page(s) 841–853

Abstract: Background: A large body of studies characterized the renal and cardiovascular effects of the peptides of the renin-angiotensin system (RAS). We now recognize that, in addition to angiotensin (Ang) II and Ang III, other peptides, such as, Ang-(1-7), Ang- ...

Abstract	Background: A large body of studies characterized the renal and cardiovascular effects of the peptides of the renin-angiotensin system (RAS). We now recognize that, in addition to angiotensin (Ang) II and Ang III, other peptides, such as, Ang-(1-7), Ang-(1-9), Ang IV and Alamandine can mediate actions of the RAS in different tissues, including the brain. Effects elicited by angiotensins in the brain are complex, site specific and dependent on the interaction with selective receptors, angiotensin type 1 receptor (AT1), AT2, Mas or MrgD, which present widespread distribution in the central nervous system. Although the majority of studies indicate a neuroprotective action for the inhibition of angiotensin converting enzyme or blockade of AT1 receptor, recent studies point to the participation of other angiotensin peptides in the pathophysiology of the neurodegenerative diseases. Objectives and methods: In this article, we revised the literature to describe recent findings related to the role of RAS in neurodegenerative diseases such as, Parkinson, Alzheimer, Huntington and Multiple Sclerosis. Results: The results obtained are promising and may stimulate the development of novel and more effective pharmacological tools to prevent and better control neurodegenerative diseases. In this brief review, we present results from studies showing the participation of the RAS with respect to neurodegenerative diseases, such as, Parkinson, Alzheimer, Huntington and Multiple Sclerosis. Conclusion: Increased RAS activity leading to increase in Ang II levels, may increase the risk of developing PD, AD, HD or MS. However, the alteration in the balance among angiotensin peptides resulting in increasing Ang-(1-7) or Alamandine may represent effective neuroprotective strategy in population groups at high risk or as coadjutant treatment to reduce the progression of these diseases. Although most studies suggest a neuroprotective action for ACE inhibition or AT1 receptor antagonism, many studies will still be needed to characterize the relative importance (and intracellular mechanisms) of each RAS peptide for the pathophysiology of neurodegenerative diseases. The results to date are promising and may lead to new and more effective pharmacological tools to prevent and better control neurodegenerative diseases.
MeSH term(s)	Alzheimer Disease/drug therapy ; Alzheimer Disease/metabolism ; Alzheimer Disease/physiopathology ; Angiotensin II Type 1 Receptor Blockers/therapeutic use ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; Animals ; Humans ; Huntington Disease/drug therapy ; Huntington Disease/metabolism ; Huntington Disease/physiopathology ; Multiple Sclerosis/drug therapy ; Multiple Sclerosis/metabolism ; Multiple Sclerosis/physiopathology ; Neurodegenerative Diseases/drug therapy ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/physiopathology ; Neuroprotective Agents/therapeutic use ; Parkinson Disease/drug therapy ; Parkinson Disease/metabolism ; Parkinson Disease/physiopathology ; Peptidyl-Dipeptidase A/metabolism ; Receptor, Angiotensin, Type 1/metabolism ; Renin-Angiotensin System/drug effects ; Renin-Angiotensin System/physiology
Chemical Substances	Angiotensin II Type 1 Receptor Blockers ; Angiotensin-Converting Enzyme Inhibitors ; Neuroprotective Agents ; Receptor, Angiotensin, Type 1 ; Peptidyl-Dipeptidase A (EC 3.4.15.1)
Language	English
Publishing date	2017-08-22
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	1280776-x
ISSN	1875-5305 ; 0929-8665
ISSN (online)	1875-5305
ISSN	0929-8665
DOI	10.2174/0929866524666170822120258
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Article ; Online: Transgenic rat with overproduction of ubiquitous angiotensin-(1-7) presents neuroprotection in a model of ischemia and reperfusion.

Kangussu, Lucas Miranda / Almeida-Santos, Ana Flávia / Fernandes, Lorena Figueiredo / Alenina, Natalia / Bader, Michael / Santos, Robson A S / Massensini, André Ricardo / Campagnole-Santos, Maria José

Brain research bulletin

2022 Volume 192, Page(s) 184–191

Abstract: Recent studies showed that angiotensin-(1-7) has cerebroprotective actions in stroke. In the present study, we aim to test whether tissue overexpression of Angiotensin-(1-7), mainly in the brain provides neuroprotection in a model of ischemia/reperfusion ...

Abstract	Recent studies showed that angiotensin-(1-7) has cerebroprotective actions in stroke. In the present study, we aim to test whether tissue overexpression of Angiotensin-(1-7), mainly in the brain provides neuroprotection in a model of ischemia/reperfusion by bilateral common carotid arteries occlusion/reperfusion (BCCAo/R). Evaluation of neurological deficit scores and bilateral asymmetry test (BAT) were performed seven days after transient BCCAo/R in transgenic rats (TG-7371) overexpressing Angiotensin-(1-7) and Sprague-Dawley (SD) rats. To assess blood-brain barrier (BBB) permeability Evans blue dye (EB) was intravenously injected. Cytokine levels were quantified in the whole brain through Elisa assay and oxidative stress was measured 7 days after ischemia. The expression of AT
Language	English
Publishing date	2022-11-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	197620-5
ISSN	1873-2747 ; 0361-9230
ISSN (online)	1873-2747
ISSN	0361-9230
DOI	10.1016/j.brainresbull.2022.11.017
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Article: Activation of Ang-(1-7)/Mas Receptor Is a Possible Strategy to Treat Coronavirus (SARS-CoV-2) Infection.

Magalhaes, Giselle Santos / Rodrigues-Machado, Maria da Gloria / Motta-Santos, Daisy / Campagnole-Santos, Maria Jose / Santos, Robson A Souza

Frontiers in physiology

2020 Volume 11, Page(s) 730

Keywords	covid19
Language	English
Publishing date	2020-06-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2020.00730
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Article ; Online: ACE2 in the renin-angiotensin system.

Verano-Braga, Thiago / Martins, Ana Luiza Valle / Motta-Santos, Daisy / Campagnole-Santos, Maria José / Santos, Robson Augusto Souza

Clinical science (London, England : 1979)

2020 Volume 134, Issue 23, Page(s) 3063–3078

Abstract: In 2020 we are celebrating the 20th anniversary of the angiotensin-converting enzyme 2 (ACE2) discovery. This event was a landmark that shaped the way that we see the renin-angiotensin system (RAS) today. ACE2 is an important molecular hub that connects ... ...

Abstract	In 2020 we are celebrating the 20th anniversary of the angiotensin-converting enzyme 2 (ACE2) discovery. This event was a landmark that shaped the way that we see the renin-angiotensin system (RAS) today. ACE2 is an important molecular hub that connects the RAS classical arm, formed mainly by the octapeptide angiotensin II (Ang II) and its receptor AT1, with the RAS alternative or protective arm, formed mainly by the heptapeptides Ang-(1-7) and alamandine, and their receptors, Mas and MrgD, respectively. In this work we reviewed classical and modern literature to describe how ACE2 is a critical component of the protective arm, particularly in the context of the cardiac function, coagulation homeostasis and immune system. We also review recent literature to present a critical view of the role of ACE2 and RAS in the SARS-CoV-2 pandemic.
MeSH term(s)	Angiotensin-Converting Enzyme 2/drug effects ; Angiotensin-Converting Enzyme Inhibitors/pharmacology ; COVID-19/drug therapy ; COVID-19/virology ; Humans ; Oligopeptides/pharmacology ; Renin-Angiotensin System/drug effects ; Renin-Angiotensin System/physiology ; SARS-CoV-2/drug effects ; SARS-CoV-2/pathogenicity
Chemical Substances	Angiotensin-Converting Enzyme Inhibitors ; Oligopeptides ; alamandine ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Language	English
Publishing date	2020-12-15
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	206835-7
ISSN	1470-8736 ; 0301-0538 ; 0009-0360 ; 0143-5221
ISSN (online)	1470-8736
ISSN	0301-0538 ; 0009-0360 ; 0143-5221
DOI	10.1042/CS20200478
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Article: Different reactive species modulate the hypotensive effect triggered by angiotensins at CVLM of 2K1C hypertensive rats

de Sousa, Graziele Galdino / Barbosa, Maria Andréa / Barbosa, Claudiane Maria / Lima, Taynara Carolina / Souza dos Santos, Robson Augusto / Campagnole-Santos, Maria José / Alzamora, Andréia Carvalho

Peptides. 2020 Sept. 15,

2020

Abstract: Hypertension is associated with increased central activity of the renin-angiotensin system (RAS) and oxidative stress. Here, we evaluated whether reactive species and neurotransmitters could contribute to the hypotensive effect induced by angiotensin ( ... ...

Abstract	Hypertension is associated with increased central activity of the renin-angiotensin system (RAS) and oxidative stress. Here, we evaluated whether reactive species and neurotransmitters could contribute to the hypotensive effect induced by angiotensin (Ang) II and Ang-(1-7) at the caudal ventrolateral medulla (CVLM) in renovascular hypertensive rats (2K1C). Therefore, we investigated the effect of Ang II, Ang-(1-7), and the Ang-(1-7) antagonist A-779 microinjected before and after CVLM microinjection of the nitric oxide (NO)-synthase inhibitor, (L-NAME), vitamin C (Vit C), bicuculline, or kynurenic acid in 2K1C and SHAM rats. Baseline values of the mean arterial pressure (MAP) in 2K1C rats were higher than in SHAM rats. CVLM microinjection of Ang II, Ang-(1-7), L-NAME, or bicuculline induced decreases in the MAP in SHAM and 2K1C rats. In addition, Vit C and A-779 produced decreases in the MAP only in 2K1C rats. Kynurenic acid increased the MAP in both SHAM and 2K1C rats. Only the Ang-(1-7) effect was increased by L-NAME and reduced by bicuculline in SHAM rats. L-NAME also reduced the A-779 effect in 2K1C rats. Only the Ang II effect was abolished by CVLM Vit C and enhanced by CVLM kynurenic acid in SHAM and 2K1C rats. Overall, the superoxide anion and glutamate participated in the hypotensive effect of Ang II, while NO and GABA participated in the hypotensive effect of Ang-(1-7) in CVLM. The higher hypotensive response of A-779 in the CVLM of 2K1C rats suggests that Ang-(1-7) contributes to renovascular hypertension.
Keywords	angiotensins ; animal disease models ; antagonists ; antihypertensive effect ; ascorbic acid ; enzyme inhibitors ; enzymes ; gamma-aminobutyric acid ; glutamic acid ; hypertension ; neurotransmitters ; nitric oxide ; normal values ; oxidative stress ; rats ; renin-angiotensin system ; superoxide anion
Language	English
Dates of publication	2020-0915
Publishing place	Elsevier Inc.
Document type	Article
Note	Pre-press version
ZDB-ID	769028-9
ISSN	1873-5169 ; 0196-9781
ISSN (online)	1873-5169
ISSN	0196-9781
DOI	10.1016/j.peptides.2020.170409
Database	NAL-Catalogue (AGRICOLA)

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