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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+Foxp3+, Mres in the lungs and enhanced macrophage-mediated efferocytic capacity. Moreover, in allergic mice treated with Ang-(1-7) and then subjected to a secondary OVA challenge, inflammation was also reduced. Similarly, in mice exposed to LPS, Ang-(1-7) effectively prevented the lung inflammation. 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.
Assuntos
Angiotensina I , Lipopolissacarídeos , Pulmão , Ovalbumina , Fragmentos de Peptídeos , Animais , Angiotensina I/uso terapêutico , Angiotensina I/farmacologia , Angiotensina I/administração & dosagem , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/uso terapêutico , Fragmentos de Peptídeos/administração & dosagem , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/imunologia , Ovalbumina/imunologia , Camundongos , Masculino , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Camundongos Endogâmicos BALB C , Inflamação/tratamento farmacológico , Eosinofilia/tratamento farmacológico , Eosinofilia/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/citologiaRESUMO
Objective: The incidence of diabetic nephropathy (DN) is gradually increasing worldwide. Podocyte injury, such as podocyte apoptosis and loss of the slit diaphragm (SD)-specific markers are early pathogenic features of DN. Materials and methods: The cultured mouse podocytes were separated into a high glucose-treated (HG, 30mM) group to mimic DN in vitro, a low glucose-treated (LG, 5mM) group as a control and HG+ angiotensin-(1-7)(Ang-(1-7)) and HG+Ang-(1-7) + D-Ala7-Ang-(1-7) (A779, Ang-(1-7)/Mas receptor antagonist) experimental groups. The Cell Counting Kit-8 (CCK-8) method and flow cytometry was used to detect podocyte activity and podocyte apoptosis respectively. The expression of angiotensin type 1 receptor (AT1R), Mas receptor (MasR) and podocyte-specific markers were examined by q-PCR and Western blot, respectively. Results: The results showed that the decrease in podocyte activity; the increase in podocyte apoptosis; the decreased mRNA and protein expression of nephrin, podocin, WT-1 and MasR; and the upregulated expression of AT1R induced by HG could be reversed by Ang-(1-7). However, these effects were blocked by A779. The possible mechanisms of the Ang-(1-7)-mediated effect depended on MasR. In addition, the protective effect of Ang-(1-7) on podocyte activity was dose-dependent and most obvious at 10 µM. A779 had the greatest antagonistic action against Ang-(1-7) at a concentration of 10 µM. Conclusion: This study reveals that binding of Ang-(1-7) to its specific receptor MasR may counteract the effects of Ang II mediated by AT1R to significantly attenuate podocyte injury induced by high glucose. Ang-(1-7)/MasR targeting in podocytes may be a therapeutic approach to attenuate renal injury in DN.
Assuntos
Angiotensina II , Nefropatias Diabéticas , Podócitos , Animais , Camundongos , Angiotensina II/farmacologia , Glucose/farmacologia , Podócitos/metabolismo , Podócitos/patologiaRESUMO
The Coronavirus disease 2019 (COVID-19) affects several tissues, including the central and peripheral nervous system. It has also been related to signs and symptoms that suggest neuroinflammation with possible effects in the short, medium, and long term. Estrogens could have a positive impact on the management of the disease, not only due to its already known immunomodulator effect, but also activating other pathways that may be important in the pathophysiology of COVID-19, such as the regulation of the virus receptor and its metabolites. In addition, they can have a positive effect on neuroinflammation secondary to pathologies other than COVID-19. The aim of this study is to analyze the molecular mechanisms that link estrogens with their possible therapeutic effect for neuroinflammation related to COVID-19. Advanced searches were performed in scientific databases as Pub- Med, ProQuest, EBSCO, the Science Citation index, and clinical trials. Estrogens have been shown to participate in the immune modulation of the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to this mechanism, we propose that estrogens can regulate the expression and activity of the Angiotensin-converting enzyme 2 (ACE2), reestablishing its cytoprotective function, which may be limited by its interaction with SARS-CoV-2. In this proposal, estrogens and estrogenic compounds could increase the synthesis of Angiotensin-(1-7) (Ang-(1-7)) that acts through the Mas receptor (MasR) in cells that are being attacked by the virus. Estrogens can be a promising, accessible, and low-cost treatment for neuroprotection and neuroinflammation in patients with COVID-19, due to its direct immunomodulatory capacity in decreasing cytokine storm and increasing cytoprotective capacity of the axis ACE2/Ang (1-7)/MasR.
Assuntos
COVID-19 , Humanos , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Sistema Renina-Angiotensina/fisiologia , Peptidil Dipeptidase A/metabolismo , Doenças Neuroinflamatórias , Estrogênios/uso terapêutico , Neuroproteção , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêuticoRESUMO
ABSTRACT Objective: The incidence of diabetic nephropathy (DN) is gradually increasing worldwide. Podocyte injury, such as podocyte apoptosis and loss of the slit diaphragm (SD)-specific markers are early pathogenic features of DN. Materials and methods: The cultured mouse podocytes were separated into a high glucose-treated (HG, 30mM) group to mimic DN in vitro, a low glucose-treated (LG, 5mM) group as a control and HG+ angiotensin-(1-7)(Ang-(1-7)) and HG+Ang-(1-7) + D-Ala7-Ang-(1-7) (A779, Ang-(1-7)/Mas receptor antagonist) experimental groups. The Cell Counting Kit-8 (CCK-8) method and flow cytometry was used to detect podocyte activity and podocyte apoptosis respectively. The expression of angiotensin type 1 receptor (AT1R), Mas receptor (MasR) and podocyte-specific markers were examined by q-PCR and Western blot, respectively. Results: The results showed that the decrease in podocyte activity; the increase in podocyte apoptosis; the decreased mRNA and protein expression of nephrin, podocin, WT-1 and MasR; and the upregulated expression of AT1R induced by HG could be reversed by Ang-(1-7). However, these effects were blocked by A779. The possible mechanisms of the Ang-(1-7)-mediated effect depended on MasR. In addition, the protective effect of Ang-(1-7) on podocyte activity was dose-dependent and most obvious at 10 µM. A779 had the greatest antagonistic action against Ang-(1-7) at a concentration of 10 μM. Conclusion: This study reveals that binding of Ang-(1-7) to its specific receptor MasR may counteract the effects of Ang II mediated by AT1R to significantly attenuate podocyte injury induced by high glucose. Ang-(1-7)/MasR targeting in podocytes may be a therapeutic approach to attenuate renal injury in DN.
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Angiotensin-(1-7) re-balance the Renin-Angiotensin system affected during several pathologies, including the new COVID-19; cardiovascular diseases; and cancer. However, one of the limiting factors for its therapeutic use is its short half-life, which might be overcome with the use of dendrimers as nanoprotectors. In this work, we addressed the following issues: (1) the capacity of our computational protocol to reproduce the experimental structural features of the (hydroxyl/amino)-terminated PAMAM dendrimers as well as the Angiotensin-(1-7) peptide; (2) the coupling of Angiotensin-(1-7) to (hydroxyl/amino)-terminated PAMAM dendrimers in order to gain insight into the structural basis of its molecular binding; (3) the capacity of the dendrimers to protect Angiotensin-(1-7); and (4) the effect of pH changes on the peptide binding and covering. Our Molecular-Dynamics/Metadynamics-based computational protocol well modeled the structural experimental features reported in the literature and our double-docking approach was able to provide reasonable initial structures for stable complexes. At neutral pH, PAMAM dendrimers with both terminal types were able to interact stably with 3 Angiotensin-(1-7) peptides through ASP1, TYR4 and PRO7 key amino acids. In general, they bind on the surface in the case of the hydroxyl-terminated compact dendrimer and in the internal zone in the case of the amino-terminated open dendrimer. At acidic pH, PAMAM dendrimers with both terminal groups are still able to interact with peptides either internalized or in its periphery, however, the number of contacts, the percentage of coverage and the number of hydrogen bonds are lesser than at neutral pH, suggesting a state for peptide release. In summary, amino-terminated PAMAM dendrimer showed slightly better features to bind, load and protect Angiotensin-(1-7) peptides.
Assuntos
COVID-19 , Dendrímeros , Aminoácidos , Angiotensina I , Dendrímeros/química , Humanos , Simulação de Dinâmica Molecular , Fragmentos de Peptídeos , PeptídeosRESUMO
Oral Squamous Cell Carcinoma (OSCC) is the most common malignant cancer affecting the oral cavity. It is characterized by high morbidity and very few therapeutic options. Angiotensin (Ang)-(1-7) is a biologically active heptapeptide, generated predominantly from AngII (Ang-(1-8)) by the enzymatic activity of angiotensin-converting enzyme 2 (ACE 2). Previous studies have shown that Ang-(1-7) counterbalances AngII pro-tumorigenic actions in different pathophysiological settings, exhibiting antiproliferative and anti-angiogenic properties in cancer cells. However, the prevailing effects of Ang-(1-7) in the oral epithelium have not been established in vivo. Here, we used an inducible oral-specific mouse model, where the expression of a tamoxifen-inducible Cre recombinase (CreERtam), which is under the control of the cytokeratin 14 promoter (K14-CreERtam), induces the expression of the K-ras oncogenic variant KrasG12D (LSLK-rasG12D). These mice develop highly proliferative squamous papilloma in the oral cavity and hyperplasia exclusively in oral mucosa within one month after tamoxifen treatment. Ang-(1-7) treated mice showed a reduced papilloma development accompanied by a significant reduction in cell proliferation and a decrease in pS6 positivity, the most downstream target of the PI3K/Akt/mTOR signaling route in oral papilloma. These results suggest that Ang-(1-7) may be a novel therapeutic target for OSCC.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , Papiloma , Infecções por Papillomavirus , Angiotensina I/farmacologia , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Camundongos , Camundongos Transgênicos , Neoplasias Bucais/tratamento farmacológico , Papiloma/tratamento farmacológico , Papiloma/patologia , Papiloma/prevenção & controle , Infecções por Papillomavirus/tratamento farmacológico , Fragmentos de Peptídeos , Fosfatidilinositol 3-Quinases/metabolismo , Tamoxifeno/uso terapêuticoRESUMO
Coronavirus disease 2019 (COVID-19) has become the most critical pandemic of the 21st Century and the most severe since the 1918 influenza pandemic. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects the host by binding to angiotensin-converting enzyme 2 (ACE2). The role of ACE2 in the pathophysiology of coronavirus disease 2019 (COVID-19) is a topic of debate, with clinical and experimental evidence indicating a multifaceted relationship between ACE2 activity and disease severity. Here, we review the mechanisms by which the peptidergic substrates and products of ACE and ACE2 contribute to physiological and pathophysiological processes and hypothesise how down-regulation of ACE2 by SARS-CoV-2 cellular entry disrupts homeostasis. A better understanding of the endocrinology of the disease, in particular the neuroendocrinology of ACE2 during COVID-19, may contribute to the timely design of new therapeutic strategies, including the regulation of ACE2 itself by steroid hormones, to ameliorate the severity of COVID-19.
Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Tratamento Farmacológico da COVID-19 , COVID-19/metabolismo , Estrogênios/uso terapêutico , Peptídeos/metabolismo , SARS-CoV-2/metabolismo , Humanos , Ligação ProteicaRESUMO
The effects of the renin-angiotensin system (RAS) on stem cells isolated from human dental apical papilla (SCAPs) are completely unknown. Therefore, the aim of this study was to identify RAS components expressed in SCAPs and the effects of angiotensin (Ang) II and Ang-(1-7) on cell proliferation. SCAPs were collected from third molar teeth of adolescents and maintained in cell culture. Messenger RNA expression and protein levels of angiotensin-converting enzyme (ACE), ACE2, and Mas, Ang II type I (AT1) and type II (AT2) receptors were detected in SCAPs. Treatment with either Ang II or Ang-(1-7) increased the proliferation of SCAPs. These effects were inhibited by PD123319, an AT2 antagonist. While Ang II augmented mTOR phosphorylation, Ang-(1-7) induced ERK1/2 phosphorylation. In conclusion, SCAPs produce the main RAS components and both Ang II and Ang-(1-7) treatments induced cell proliferation mediated by AT2 activation through different intracellular mechanisms.
Assuntos
Angiotensina II/farmacologia , Angiotensina I/farmacologia , Proliferação de Células/efeitos dos fármacos , Papila Dentária/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Células-Tronco/efeitos dos fármacos , Adolescente , Células Cultivadas , Papila Dentária/metabolismo , Feminino , Humanos , Imidazóis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Peptidil Dipeptidase A/metabolismo , Fosforilação/efeitos dos fármacos , Piridinas/farmacologia , RNA Mensageiro/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Células-Tronco/metabolismoRESUMO
The last decade was crucial for our understanding of the renin-angiotensin-aldosterone system (RAAS) as a two-axis, counter-regulatory system, divided into the classical axis, formed by angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and the angiotensin type 1 receptor (AT1R), and the alternative axis comprising angiotensin-converting enzyme 2 (ACE2), angiotensin-(1-7) (Ang-(1-7)), and the Mas receptor. Breakthrough discoveries also took place, with other RAAS endopeptides being described, including alamandine and angiotensin A. In this review, we characterize the two RAAS axes and the role of their components in pediatric kidney diseases, including childhood hypertension (HTN), pediatric glomerular diseases, congenital abnormalities of the kidney and urinary tract (CAKUT), and chronic kidney disease (CKD). We also present recent findings on potential interactions between the novel coronavirus, SARS-CoV-2, and components of the RAAS, as well as potential implications of coronavirus disease 2019 (COVID-19) for pediatric kidney diseases.
Assuntos
COVID-19/fisiopatologia , Nefropatias/fisiopatologia , Sistema Renina-Angiotensina/fisiologia , Criança , HumanosRESUMO
The emergence of SARS-CoV-2/human/Wuhan/X1/2019, a virus belonging to the species Severe acute respiratory syndrome-related coronavirus, and the recognition of Coronavirus Disease 2019 (COVID-19) as a pandemic have highly increased the scientific research regarding the pathogenesis of COVID-19. The Renin Angiotensin System (RAS) seems to be involved in COVID-19 natural course, since studies suggest the membrane-bound Angiotensin-converting enzyme 2 (ACE2) works as SARS-CoV-2 cellular receptor. Besides the efforts of the scientific community to understand the virus' molecular interactions with human cells, few studies summarize what has been so far discovered about SARS-CoV-2 signaling mechanisms and its interactions with RAS molecules. This review aims to discuss possible SARS-CoV-2 intracellular signaling pathways, cell entry mechanism and the possible consequences of the interaction with RAS components, including Angiotensin II (Ang II), Angiotensin-(1-7) [Ang-(1-7)], Angiotensin-converting enzyme (ACE), ACE2, Angiotensin II receptor type-1 (AT1), and Mas Receptor. We also discuss ongoing clinical trials and treatment based on RAS cascade intervention. Data were obtained independently by the two authors who carried out a search in the PubMed, Embase, LILACS, Cochrane, Scopus, SciELO and the National Institute of Health databases using Medical Subject Heading terms as "SARS-CoV-2," "COVID-19," "Renin Angiotensin System," "ACE2," "Angiotensin II," "Angiotensin-(1-7)," and "AT1 receptor." Similarly to other members of Coronaviridae family, the molecular interactions between the pathogen and the membrane-bound ACE2 are based on the cleavage of the spike glycoprotein (S) in two subunits. Following the binding of the S1 receptor-binding domain (RBD) to ACE2, transmembrane protease/serine subfamily 2 (TMPRSS2) cleaves the S2 domain to facilitate membrane fusion. It is very likely that SARS-CoV-2 cell entry results in downregulation of membrane-bound ACE2, an enzyme that converts Ang II into Ang-(1-7). This mechanism can result in lung injury and vasoconstriction. In addition, Ang II activates pro-inflammatory cascades when binding to the AT1 Receptor. On the other hand, Ang-(1-7) promotes anti-inflammatory effects through its interactions with the Mas Receptor. These molecules might be possible therapeutic targets for treating COVID-19. Thus, the understanding of SARS-CoV-2 intracellular pathways and interactions with the RAS may clarify COVID-19 physiopathology and open perspectives for new treatments and strategies.
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AIMS: Angiotensin-1-7 [Ang-(1-7)] is an essential peptide of the renin-angiotensin system that promotes benefits modulating effects in different tissues. Similarly, interleukin-10 (IL-10) exhibits an immunomodulatory action on the vasculature. This study aimed to evaluate whether Ang-(1-7) levels attenuates vascular contractile response, mediated by IL-10-pathway (JAK1/STAT3/IL-10). MAIN METHODS: Aortas from male mice C57BL/6J and knockout for IL-10 (IL-10-/-) were incubated with Ang-(1-7) [10 µM] or vehicle, during 5 min, 1 h, 6 h, 12 h, and 24 h. Concentration-response curves to phenylephrine, western blotting, and flow cytometry analysis was performed to evaluate the contractile response, protein expression, and IL-10 levels, respectively. KEY FINDINGS: Incubation with Ang-(1-7) produced a time-dependent increase in Janus kinases 1 (JAK1) expression, as well as increased expression and activity of the signal transducer and activator of transcription 3 (STAT3) protein. However, this effect was not observed in knockout animals for IL-10. After 12 h of Ang-(1-7) treatment, arteries from control mice displayed decreased vascular reactivity to phenylephrine, but this effect was not observed in the absence of endogenous IL-10. Additionally, incubation with Ang-(1-7) augments IL-10 levels after 6 h, 12 h, and 24 h of incubation. SIGNIFICANCE: These results demonstrated the role of Ang-(1-7) in the IL-10 signaling pathway and its effects in the vascular contractility response. Thus, these findings suggest a new synergic action where Ang-(1-7) and IL-10 converge into a protective mechanism against vascular dysfunction.
Assuntos
Angiotensina I/metabolismo , Interleucina-10/genética , Janus Quinase 1/metabolismo , Fragmentos de Peptídeos/metabolismo , Fator de Transcrição STAT3/metabolismo , Vasoconstrição/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenilefrina/farmacologia , Fatores de Tempo , Vasoconstrição/efeitos dos fármacosRESUMO
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.
Assuntos
Angiotensina II/farmacologia , Angiotensina I/farmacologia , Hipertensão Renovascular/tratamento farmacológico , Bulbo/metabolismo , Fragmentos de Peptídeos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Anti-Hipertensivos/farmacologia , Modelos Animais de Doenças , Frequência Cardíaca , Hipertensão Renovascular/metabolismo , Hipertensão Renovascular/patologia , Masculino , Bulbo/efeitos dos fármacos , Ratos , Vasoconstritores/farmacologiaRESUMO
Renin-Angiotensin System (RAS) is an important peptide cascade involved in physiological processes. RAS homeostasis disruption produces several cardiovascular and metabolic disorders, such as arterial hypertension, atherosclerosis, acute myocardial infarct, obesity, diabetes, metabolic syndrome and increases gastrointestinal tract (GIT) cell proliferation. Angiotensin (Ang)-(1-7) peptide is the main RAS counter-regulatory axis effector. It is formed from ACE2 enzyme and acts mainly through Mas receptor (MasR). In this context, the aim of the present study was to evaluate alterations in small intestine morphology and intestinal microbiota composition in MasR knockout C57BL/6 mice. We analyzed glucose tolerance; insulin sensitivity and blood collected for biochemical parameters as well as small intestine tissues samples for immunohistochemistry. mRNA and bacteria gDNA expression evaluation. mRNA expression was evaluated by qRT-PCR for TLR4, PI3K and AKT. The main results showed that Mas-R-knockout mice presented lower body weight. MasR-knockout mice also presented increased fasted blood glucose and total cholesterol with reduced HDL, lower glucose tolerance and impaired insulin sensitivity. Increased intestinal mucosa length, increased intestinal villi, reduced Lieberkühn crypt depth. The increased expression of cell proliferation markers Ki-67 and Cyclin D1 and increased TLR4, PI3K and AKT expressions were observed with augmented Bacteroidetes and decreased amount of Firmicutes. That results suggests that MasR deletion generated changes in intestinal microbiota, possibly due to a lower neutral amino acids absorption followed by a compensatory increase in intestinal villi length associated with disbiosis and LPS overproduction that ultimately lead to proliferation and cell inflammation.
Assuntos
Disbiose/metabolismo , Intestino Delgado/metabolismo , Intestino Delgado/microbiologia , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Animais , Mucosa Intestinal/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfatidilinositol 3-Quinases/metabolismo , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptor 4 Toll-Like/metabolismoAssuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/complicações , Pneumonia Viral/virologia , Fibrose Pulmonar/etiologia , Sistema Renina-Angiotensina/fisiologia , Células Epiteliais Alveolares/enzimologia , Angiotensina I/metabolismo , Angiotensina I/farmacologia , Angiotensina II/metabolismo , Enzima de Conversão de Angiotensina 2 , Betacoronavirus/fisiologia , COVID-19 , Infecções por Coronavirus/fisiopatologia , Interações entre Hospedeiro e Microrganismos , Humanos , Pulmão/enzimologia , Pulmão/fisiopatologia , Pulmão/virologia , Pandemias , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Peptidil Dipeptidase A/genética , Pneumonia Viral/fisiopatologia , Receptores de Coronavírus , Receptores Virais/genética , Receptores Virais/metabolismo , SARS-CoV-2 , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/metabolismoRESUMO
The current pharmacological strategies for the management of anxiety disorders and depression, serious conditions which are gaining greater prevalence worldwide, depend on only two therapeutic classes of mood-stabilizing drugs: Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs). Although first line agents with proven efficacy, their clinical success in the management of anxiety disorders and depression is still considered highly complex due to the multifaceted nature of such conditions. Several studies have shown a possible therapeutic target could be found in the form of the Angiotensin-Converting Enzyme [ACE] type 2 (ACE2), Angiotensin [Ang]-(1-7) and Mas receptor pathway of the Renin- Angiotensin System (RAS), which as will be discussed, has been described to exhibit promising therapeutic properties for the management of anxiety disorders and depression. In this article, the literature to describe recent findings related to the role of the RAS in anxiety and depression disorders was briefly revised. The literature used covers a time range from 1988 to 2019 and were acquired from the National Center for Biotechnology Information's (NCBI) PubMed search engine. The results demonstrated in this review are promising and encourage the development of new research for the treatment of anxiety and depression disorders focusing on the RAS. In conclusion, the ACE2/Ang-(1-7)/Mas pathway may exhibit anxiolytic and anti-depressive effects through many possible biochemical mechanisms both centrally and peripherally, and result in highly promising mental health benefits which justifies further investigation into this system as a possible new therapeutic target in the management of neuropsychiatric disorders, including any as of yet undescribed risk-benefit analysis compared to currently-implemented pharmacological strategies.
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Transtornos de Ansiedade/metabolismo , Depressão/metabolismo , Transdução de Sinais , Angiotensina I/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transtornos de Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Humanos , Fragmentos de Peptídeos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
In the present study we evaluated the cardiovascular effects produced by microinjection of the new component of the renin-angiotensin system, alamandine, into caudal ventrolateral medulla of urethane-anesthetized normotensive and hypertensive 2K1C rats. The participation of different angiotensin receptors in the effects of alamandine was also evaluated. Microinjection of angiotensin-(1-7) was used for comparison. The microinjection of 4, 40 and 140pmol of alamandine or angiotensin-(1-7) into caudal ventrolateral medulla induced similar hypotensive effects in Sham-operated rats. However, contrasting with angiotensin-(1-7), in 2K1C rats the MAP response to the highest dose of alamandine was similar to that observed with saline. The microinjection of A-779, a selective Mas receptor antagonist, blunted the angiotensin-(1-7) effects but did not block the hypotensive effect of alamandine in Sham or in 2K1C rats. However, microinjection of D-Pro7-angiotensin-(1-7), a Mas/MrgD receptor antagonist, blocked the hypotensive effect induced by both peptides. Furthermore, microinjection of PD123319, a putative AT2 receptor antagonist blocked the hypotensive effect of alamandine, but not of angiotensin-(1-7), in Sham and 2K1C rats. Microinjection of the AT1 receptor antagonist, losartan, did not alter the hypotensive effect of angiotensin-(1-7) or alamandine in both groups. These results provide new insights about the differential mechanisms participating in the central cardiovascular effects of alamandine and angiotensin-(1-7) in normotensive and 2K1C hypertensive rats.
Assuntos
Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Angiotensina I/toxicidade , Hipertensão/induzido quimicamente , Oligopeptídeos/toxicidade , Fragmentos de Peptídeos/toxicidade , Animais , Imidazóis/farmacologia , Masculino , Piridinas/farmacologia , Ratos , Receptor Tipo 2 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
INTRODUCTION: The Renin-Angiotensin System (RAS) has emerged as being related to vascular disease. Recently the RAS has been associated with obesity, diabetes, and even cancer. OBJECTIVE: This review and Bioinformatics analyses focuses on the investigation of Angiotensinconverting enzymes (ACE and ACE2) as therapeutical targets for Malignant Epithelial Neoplasia, specifically for Oral Squamous Cell Carcinoma (OSCC). CONCLUSION: The literature review and Bioinformatics analyses showed that ACE and ACE2 are interesting targets for OSCC treatment. Studies involving RAS and OSCC should be encouraged for experimental validation.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Bucais/tratamento farmacológico , Peptidil Dipeptidase A/metabolismo , Enzima de Conversão de Angiotensina 2 , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Biologia Computacional , Humanos , Terapia de Alvo Molecular , Neoplasias Bucais/metabolismo , Peptidil Dipeptidase A/química , Sistema Renina-Angiotensina/fisiologiaRESUMO
We aimed to study the renal injury and hypertension induced by chronic intermittent hypoxia (CIH) and the protective effects mediated by angiotensin 1-7 [Ang(1-7)]. We randomly assigned 32 male Sprague-Dawley rats (body weight 180-200 g) to normoxia control, CIH, Ang(1-7)-treated normoxia, and Ang(1-7)-treated CIH groups. Systolic blood pressure (SBP) was monitored at the start and end of each week. Renal sympathetic nerve activity (RSNA) was recorded. CTGF and TGF-β were detected by immunohistochemistry and western blotting. Tissue parameters of oxidative stress were also determined. In addition, renal levels of interleukin-6, tumor necrosis factor-α, nitrotyrosine, and hypoxia-inducible factor-1α were determined by immunohistochemistry, immunoblotting, and ELISA. TUNEL assay results and cleaved caspase 3 and 12 were also determined. Ang(1-7) induced a reduction in SBP together with a restoration of RSNA in the rat model of CIH. Ang(1-7) treatment also suppressed the production of reactive oxygen species, reduced renal tissue inflammation, ameliorated mesangial expansion, and decreased renal fibrosis. Thus, Ang(1-7) treatment exerted renoprotective effects on CIH-induced renal injury and was associated with a reduction of oxidative stress, inflammation and fibrosis. Ang(1-7) might therefore represent a promising therapy for obstructive sleep apnea-related hypertension and renal injury.
Assuntos
Animais , Masculino , Ratos , Injúria Renal Aguda/tratamento farmacológico , Angiotensina I/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/administração & dosagem , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Interleucina-6/metabolismo , Rim/metabolismo , Rim/patologia , Ratos Sprague-DawleyRESUMO
Renin-angiotensin system (RAS) is an important factor in the pathophysiology of hypertension. Mas receptor, Angiotensin-(1-7) [Ang-(1-7)]-activated receptor, is an important RAS component and exerts protective effects in the vasculature. Ang-(1-7) vascular effects and Mas receptor expression in carotid from renovascular hypertensive (2K-1C) rats is not clear. In the present study we investigated Mas receptor vasodilator response activated by Ang-(1-7) in the carotid rings from sham and 2K-1C rats. Changes in isometric tension were recorded on organ chamber. Mas receptors expression was investigated in carotid by Western blot. Nitric oxide production was evaluated by 2,3-diaminonaphthalene (DAN) and eNOS expression and activity by immunofluoresce and western blot, respectively. Ang-(1-7) induced concentration-dependent vasodilator effect in carotid rings from sham and 2K-1C, which the hypertension increased vasodilatation response. In the 2K-1C carotid rings, A-779 (Mas receptor antagonist) reduced but not abolish the vasodilator effect of Ang-(1-7). Corroborating, Mas receptor protein expression was significantly increased in the 2K-1C rats. L-NAME and ibuprofen decreased Ang-(1-7) vasodilator response and L-NAME plus ibuprofen practically abolish the remaining vasodilatation response. Nitric oxide production is increased due increased of eNOS expression and pSer(1177) activity. Our results demonstrated that renovascular hypertension increased Mas receptors expression and nitric oxide production in the rats carotid which, consequently increased Ang-(1-7)-vasorelaxant response.