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1.
Life Sci ; 235: 116840, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494171

RESUMO

AIMS: Ovarian ischemia as a consequence of torsion constitutes a gynecologic emergency affecting females during reproductive age. Its management by detorsion results in ovarian ischemia-reperfusion (IR) injury. Thus, a conservative treatment with detorsion is highly recommended. Therefore, we attempted to investigate the effect and underlying mechanisms of angiotensin 1-7 (Ang-(1-7)) treatment against ovarian IR injury. MAIN METHODS: Female rats were included into: Sham group; Ang-(1-7) (300 µg/kg, i.p.) group; ovarian IR groups with and without Ang-(1-7) treatment. We determined ovarian Ang-(1-7), malondialdehyde (MDA) and nitric oxide (NO) in addition to serum total anti-oxidant capacity (TAC) levels. Ovarian gene expressions of angiotensin converting enzyme 2 (ACE2), Mas receptor, tumor necrosis factor alpha (TNF-α) and B-cell leukemia/lymphoma-2 (BCL-2) were estimated. Furthermore, histopathological changes and ovarian expressions of nuclear factor kappa B (NF-κB), inducible and endothelial nitric oxide synthases (iNOS and eNOS) were done. KEY FINDINGS: Treatment of ovarian IR rats with Ang-(1-7) led to marked improvement of ovarian damage through histological examination which was accompanied with marked increase in ovarian Ang-(1-7) level and expressions of ACE2 and Mas receptor, decrease in MDA and NO levels and expressions of NF-kB, iNOS and TNF-α with increase in serum TAC levels and ovarian expressions of eNOS and BCL-2. SIGNIFICANCE: Our results proved the protective effect of Ang-(1-7) against ovarian IR injury in rats and this may be attributed to ACE2/Ang (1-7)/Mas axis which showed anti-oxidant, anti-inflammatory and anti-apoptotic effects. Therefore, Ang-(1-7) can be used in the future for treatment of ovarian IR injury.


Assuntos
Angiotensina I/farmacologia , Ovário/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Antioxidantes/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Malondialdeído/metabolismo , NF-kappa B/biossíntese , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo III/biossíntese , Ovário/lesões , Ovário/metabolismo , Peptidil Dipeptidase A/biossíntese , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Ratos , Receptores Acoplados a Proteínas-G/biossíntese , Soro/metabolismo , Fator de Necrose Tumoral alfa/biossíntese
2.
Oxid Med Cell Longev ; 2019: 5868935, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396301

RESUMO

In prevention studies of metabolic syndrome (MetS), Ang-(1-7) has shown to improve the insulin signaling. We evaluated the HPßCD/Ang-(1-7) treatment on lipid metabolism, renin-angiotensin system (RAS) components, oxidative stress, and insulin pathway in the liver and gastrocnemius muscle and hepatic steatosis in rats with established MetS. After 7 weeks of high-fat (FAT) or control (CT) diets, rats were treated with cyclodextrin (HPßCD) or HPßCD/Ang-(1-7) in the last 6 weeks. FAT-HPßCD/empty rats showed increased adiposity index and body mass, gene expression of ACE/ANG II/AT1R axis, and oxidative stress. These results were accompanied by imbalances in the insulin pathway, worsening of liver function, hyperglycemia, and dyslipidemia. Oral HPßCD/Ang-(1-7) treatment decreased ACE and AT1R, increased ACE2 gene expression in the liver, and restored thiobarbituric acid reactive substances (TBARS), catalase (CAT), superoxide dismutase (SOD), insulin receptor substrate (Irs-1), glucose transporter type 4 (GLUT4), and serine/threonine kinase 2 (AKT-2) gene expression in the liver and gastrocnemius muscle improving hepatic function, cholesterol levels, and hyperglycemia in MetS rats. Overall, HPßCD/Ang-(1-7) treatment restored the RAS components, oxidative stress, and insulin signaling in the liver and gastrocnemius muscle contributing to the establishment of blood glucose and lipid homeostasis in MetS rats.


Assuntos
Angiotensina I/farmacologia , Antioxidantes/farmacologia , Síndrome Metabólica/patologia , Fragmentos de Peptídeos/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Administração Oral , Animais , Catalase/genética , Catalase/metabolismo , Ciclodextrinas/farmacologia , Dieta Hiperlipídica , Regulação da Expressão Gênica/efeitos dos fármacos , Insulina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/veterinária , Músculo Esquelético/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Ratos , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
3.
Biomed Pharmacother ; 117: 109193, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31387171

RESUMO

Accumulating evidence indicates that angiotensin (1-7) [Ang-(1-7)] protects against idiopathic pulmonary fibrosis (IPF) in animal experiments. However, whether Ang-(1-7) effectively inhibits epithelial-mesenchymal transition (EMT) induced by transforming growth factor-ß1 (TGF-ß1) remains unclear. The aim of this study is to examine the eff ;ects of Ang-(1-7) on TGF-ß1-induced EMT in human alveolar epithelial cells. We found that angiotensin-converting enzyme 2 (ACE2) /Ang-(1-7)/MasR were decreased in the lungs of mice with IPF induced by bleomycin, and were negatively correlated with Tgfb1 mRNA expression. In vitro, our data showed that exogenous Ang-(1-7) restored the expression of E-cadherin and decreased the expressions of α-SMA and Vimentin induced by TGF-ß1 in A549 cells. Ang-(1-7) also reduced TGF-ß1-induced migration and synthesis of the extracellular matrix, such as collagen Ⅰ and collagen Ⅲ. Mechanistically, we observed that Ang-(1-7) directly inhibited TGF-ß1-induced phosphorylation of Smad2 and Smad3, and suppressed the expression of the downstream target gene of TGF-ß1-Smad signaling, including ZEB1, ZEB2, TWIST, and SNAIL1. Additionally, phosphorylation of mTOR induced by TGF-ß1 also been suppressed by Ang-(1-7) treatment in A549 cells. Interestingly, we found that TGF-ß1 strongly suppressed the expression of ACE2 in A549 cells through inhibiting SIRT1. In conclusion, our findings indicate that Ang-(1-7) directly inhibits TGF-ß1-induced EMT in alveolar epithelial cells via disruption of TGF-ß1-Smad signaling pathway, contributing to the protective effect against IPF.


Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Angiotensina I/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Células A549 , Células Epiteliais Alveolares/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
4.
Biomed Environ Sci ; 32(6): 419-426, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31262387

RESUMO

OBJECTIVE: Silicosis, caused by inhalation of silica dust, is the most serious occupational disease in China and the aim of present study was to explore the protective effect of Ang (1-7) on silicotic fibrosis and myofibroblast differentiation induced by Ang II. METHODS: HOPE-MED 8050 exposure control apparatus was used to establish the rat silicosis model. Pathological changes and collagen deposition of the lung tissue were examined by H.E. and VG staining, respectively. The localizations of ACE2 and α-smooth muscle actin (α-SMA) in the lung were detected by immunohistochemistry. Expression levels of collagen type I, α-SMA, ACE2, and Mas in the lung tissue and fibroblasts were examined by western blot. Levels of ACE2, Ang (1-7), and Ang II in serum were determined by ELISA. Co-localization of ACE2 and α-SMA in fibroblasts was detected by immunofluorescence. RESULTS: Ang (1-7) induced pathological changes and enhanced collagen deposition in vivo. Ang (1-7) decreased the expressions of collagen type I and α-SMA and increased the expressions of ACE2 and Mas in the silicotic rat lung tissue and fibroblasts stimulated by Ang II. Ang (1-7) increased the levels of ACE2 and Ang (1-7) and decreased the level of Ang II in silicotic rat serum. A779 enhanced the protective effect of Ang (1-7) in fibroblasts stimulated by Ang II. CONCLUSION: Ang (1-7) exerted protective effect on silicotic fibrosis and myofibroblast differentiation induced by Ang II by regulating ACE2-Ang (1-7)-Mas axis.


Assuntos
Angiotensina II/sangue , Angiotensina I/uso terapêutico , Pulmão/metabolismo , Miofibroblastos/efeitos dos fármacos , Fragmentos de Peptídeos/uso terapêutico , Silicose/prevenção & controle , Actinas/metabolismo , Angiotensina I/sangue , Angiotensina I/farmacologia , Animais , Animais Recém-Nascidos , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Pulmão/patologia , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/farmacologia , Peptidil Dipeptidase A/metabolismo , Ratos Wistar , Silicose/metabolismo , Silicose/patologia
5.
Toxicol Lett ; 313: 30-41, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31181250

RESUMO

The hedgehog (HH) signaling pathway plays an important role in lung development, but its significance in silicosis is unclear. We showed that in human coal pneumoconiosis autopsy specimens, Sonic Hedgehog (SHH) and the Glioma-associated oncogene homolog transcription factors family (GLI) 1 proteins were up-regulated, whereas Patch-1 (PTC) was down-regulated. The protein levels of SHH, smoothened (SMO), GLI1, GLI2, α-smooth muscle actin (α-SMA) and collagen type Ⅰ (Col Ⅰ) were also elevated gradually in the bronchoalveolar lavage fluid (BALF) of different stages of coal pneumoconiosis patients, dynamic silica-inhalation rat lung tissue and MRC-5 cells induced by Ang II at different time points, whereas the PTC and GLI3 levels were diminished gradually. Ac-SDKP, an active peptide of renin-angiotensin system (RAS), is an anti-fibrotic tetrapeptide. Targeting RAS axis also has anti-silicotic fibrosis effects. However, their roles on the HH pathway are still unknown. Here, we reported that Ac-SDKP + Captopril, Ac-SDKP, Captopril, or Ang (1-7) could alleviate silicotic fibrosis and collagen deposition, as well as improve the lung functions of silicotic rat. These treatments decreased the expression of SHH, SMO, GLI1, GLI2, α-SMA, and Col Ⅰ and increased the expression of PTC and GLI3 on both the silicotic rat lung tissue and MRC-5 cells induced by Ang II. We also reported that Ang II may promote myofibroblast differentiation via the GLI1 transcription factor and independently of the SMO receptor.


Assuntos
Angiotensina II/farmacologia , Angiotensina I/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Captopril/farmacologia , Diferenciação Celular/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Miofibroblastos/efeitos dos fármacos , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/farmacologia , Fibrose Pulmonar/prevenção & controle , Sistema Renina-Angiotensina/efeitos dos fármacos , Silicose/prevenção & controle , Adulto , Idoso , Animais , Antracose/metabolismo , Antracose/patologia , Linhagem Celular , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Proteínas Hedgehog/metabolismo , Humanos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Silicose/metabolismo , Silicose/patologia
6.
Mediators Inflamm ; 2019: 2401081, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30918468

RESUMO

The renin-angiotensin system (RAS) peptides play an important role in inflammation. Resolution of inflammation contributes to restore tissue homeostasis, and it is characterized by neutrophil apoptosis and their subsequent removal by macrophages, which are remarkable plastic cells involved in the pathophysiology of diverse inflammatory diseases. However, the effects of RAS peptides on different macrophage phenotypes are still emerging. Here, we evaluated the effects of angiotensin-(1-7) (Ang-(1-7)) and the most novel RAS peptide, alamandine, on resting (M0), proinflammatory M(LPS+IFN-γ), and anti-inflammatory M(IL-4) macrophage phenotypes in vitro, as well as on specific immune cell populations and macrophage subsets into the pleural cavity of LPS-induced pleurisy in mice. Our results showed that Ang-(1-7) and alamandine, through Mas and MrgD receptors, respectively, do not affect M0 macrophages but reduce the proinflammatory TNF-α, CCL2, and IL-1ß transcript expression levels in LPS+IFN-γ-stimulated macrophages. Therapeutic administration of these peptides in LPS-induced inflammation in mice decreased the number of neutrophils and M1 (F4/80lowGr1+CD11bmed) macrophage frequency without affecting the other investigated macrophage subsets. Our data suggested that both Ang-(1-7) and alamandine, through their respective receptors Mas and MrgD, promote an anti-inflammatory reprogramming of M(LPS+IFN-γ)/M1 macrophages under inflammatory circumstances and potentiate the reprogramming induced by IL-4. In conclusion, our work sheds light on the emerging proresolving properties of Ang-(1-7) and alamandine, opening new avenues for the treatment of inflammatory diseases.


Assuntos
Angiotensina I/farmacologia , Anti-Inflamatórios/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/farmacologia , Animais , Células Cultivadas , Interleucina-4/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo
7.
Nitric Oxide ; 88: 1-9, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30880106

RESUMO

Enhanced vasoconstriction and decreased vasodilatation due to endothelial dysfunction contribute to the progression of hypertension. Angiotensin (Ang)-(1-7) plays important roles in regulating the cardiovascular activity. The current study aimed to investigate the roles of Ang-(1-7) in modulating blood pressure, vascular tension and its signal pathway in spontaneously hypertensive rats (SHR). The effects of intravenous injection of drugs were determined in rats with anesthesia in vivo. Mesenteric artery (MA), coronary artery (CA) and pulmonary artery (PA) were isolated from rats and isometric tension measurements in arteries were performed. Compared with Wistar-Kyoto rats (WKY), the high K+ induced vasoconstriction was enhanced and acetylcholine-induced vasodilatation were attenuated in the MA, CA and PA in SHR. Intravenous injection of Ang-(1-7) decreased, while A-779 increased mean arterial pressure and abolished the hypotensive effect of Ang-(1-7) in SHR. Ang-(1-7) caused dose-dependent relaxation in MA, CA and PA in SHR, which was inhibited by pretreatment with Mas receptor antagonist A-779, nitric oxide (NO) synthase inhibitor l-NAME, guanylate cyclase inhibitor ODQ and protein kinase G (PKG) inhibitor DT-2. The Mas receptor expression, NO, cGMP and PKG levels of the three above arteries of SHR were lower than that of WKY. Ang-(1-7) increased the NO, cGMP and PKG levels in arteries from SHR, which was blocked by A-779. Activation of the Mas receptor by Ang-(1-7) relaxes the MA, CA, and PA through the NO-cGMP-PKG pathway, which contributes to the decrease of arterial pressure in SHR.


Assuntos
Angiotensina I/farmacologia , Fragmentos de Peptídeos/farmacologia , Vasodilatação/efeitos dos fármacos , Angiotensina II/análogos & derivados , Angiotensina II/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , GMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Óxido Nítrico/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Vascul Pharmacol ; 115: 33-45, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30790705

RESUMO

Perinatal sodium overload induces endothelial dysfunction in adult offspring, but the underlying mechanisms are not fully known. The involvement of tissue renin-angiotensin system on high sodium-programmed endothelial dysfunction was examined. Acetylcholine and angiotensin I and II responses were analyzed in aorta and mesenteric resistance arteries from 24-week-old male offspring of normal-salt (O-NS, 1.3% NaCl) and high-salt (O-HS, 8% NaCl) fed dams. COX-2 expression, O2- production and angiotensin converting enzyme (ACE) activity were determined. A separated O-HS was treated with losartan (15 mg kg-1/day) for eight weeks. Compared to O-NS, O-HS were normotensive. Acetylcholine-induced relaxation was impaired in O-HS arteries, which was improved by tempol, apocynin or indomethacin. The angiotensin I-induced contraction was greater in O-HS arteries, whereas the angiotensin II responses were unchanged. ACE activity, O2- production and COX-2 expression were increased in O-HS arteries. In this group, the increased O2- production was inhibited by apocynin or losartan. Chronic losartan decreased COX-2 expression and restored the endothelium-dependent vasodilation in O-HS. Our findings reiterate that perinatal sodium overload programs endothelial dysfunction in adult offspring through a blood pressure-independent mechanism. Our results also suggest that vascular angiotensin II is the main mediator of high sodium-programmed endothelial dysfunction, promoting COX-2 expression and oxidative stress.


Assuntos
Fenômenos Fisiológicos da Nutrição Animal , Aorta Torácica/fisiopatologia , Endotélio Vascular/fisiopatologia , Fenômenos Fisiológicos da Nutrição Materna , Artérias Mesentéricas/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal , Sistema Renina-Angiotensina , Cloreto de Sódio na Dieta/efeitos adversos , Fatores Etários , Angiotensina I/farmacologia , Angiotensina II/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Ciclo-Oxigenase 2/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Feminino , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Gravidez , Ratos Wistar , Sistema Renina-Angiotensina/efeitos dos fármacos , Superóxidos/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
9.
J Pharmacol Exp Ther ; 369(1): 9-25, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30709867

RESUMO

Increasing evidence indicates that decreased brain blood flow, increased reactive oxygen species (ROS) production, and proinflammatory mechanisms accelerate neurodegenerative disease progression such as that seen in vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's disease and related dementias. There is a critical clinical need for safe and effective therapies for the treatment and prevention of cognitive impairment known to occur in patients with VCID and chronic inflammatory diseases such as heart failure (HF), hypertension, and diabetes. This study used our mouse model of VCID/HF to test our novel glycosylated angiotensin-(1-7) peptide Ang-1-6-O-Ser-Glc-NH2 (PNA5) as a therapy to treat VCID and to investigate circulating inflammatory biomarkers that may be involved. We demonstrate that PNA5 has greater brain penetration compared with the native angiotensin-(1-7) peptide. Moreover, after treatment with 1.0/mg/kg, s.c., for 21 days, PNA5 exhibits up to 10 days of sustained cognitive protective effects in our VCID/HF mice that last beyond the peptide half-life. PNA5 reversed object recognition impairment in VCID/HF mice and rescued spatial memory impairment. PNA5 activation of the Mas receptor results in a dose-dependent inhibition of ROS in human endothelial cells. Last, PNA5 treatment decreased VCID/HF-induced activation of brain microglia/macrophages and inhibited circulating tumor necrosis factor α, interleukin (IL)-7, and granulocyte cell-stimulating factor serum levels while increasing that of the anti-inflammatory cytokine IL-10. These results suggest that PNA5 is an excellent candidate and "first-in-class" therapy for treating VCID and other inflammation-related brain diseases.


Assuntos
Angiotensina I/química , Angiotensina I/farmacologia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/tratamento farmacológico , Demência Vascular/complicações , Memória/efeitos dos fármacos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Proteínas Proto-Oncogênicas/agonistas , Receptores Acoplados a Proteínas-G/agonistas , Angiotensina I/farmacocinética , Angiotensina I/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Biomarcadores/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Eletrocardiografia , Glicosilação , Meia-Vida , Insuficiência Cardíaca/complicações , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/fisiopatologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Fragmentos de Peptídeos/farmacocinética , Fragmentos de Peptídeos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Memória Espacial/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
10.
Pathol Oncol Res ; 25(1): 429-435, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30229380

RESUMO

Glioblastoma multiforme (GBM) is the most primary brain tumor, specially characterized with the damage of blood-brain barrier (BBB). The Ang-(1-7) was proven to have an inhibitory effect on glioblastoma growth. However, its role on blood-brain barrier (BBB) and the underlying molecular mechanism remains unclear. In this study, Ang-(1-7) significantly relieved the damage of blood-brain barrier in rats with intracranial U87 gliomas as evaluated by magnetic resonance imaging (MRI). Furthermore, its treatment attenuated BBB permeability, tumor growth and edema formation. Similarly, Ang-(1-7) also decreased U87 glioma cells barrier permeability in vitro. Further analysis showed that Ang-(1-7) could effectively restore tight junction protein (claudin-5 and ZO-1) expression levels both in rats and U87 glioma cells by affecting the activation of JNK pathway. SP600125, an inhibitor of JNK, significantly enhanced the expression of Claudin-5 and ZO-1, and decreased the disruption of BBB and enhanced the efficiency of Ang-(1-7) in glioma rats. Taken together, this study demonstrated a protective role of Ang-(1-7) in glioma-induced blood-brain barrier damage by regulating tight junction protein expression. Accordingly, Ang-(1-7) may become a promising therapeutic agent against glioma.


Assuntos
Angiotensina I/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Edema Encefálico/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Permeabilidade da Membrana Celular/efeitos dos fármacos , Glioma/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioma/metabolismo , Glioma/patologia , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Ratos , Ratos Sprague-Dawley , Junções Íntimas , Células Tumorais Cultivadas
11.
Eur J Pain ; 23(4): 739-749, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30421564

RESUMO

BACKGROUND: We have recently reported that the spinal angiotensin (Ang) converting enzyme (ACE)/Ang II/AT1 receptor axis and downstream p38 MAPK phosphorylation are activated in streptozotocin (STZ)-induced diabetic mice and lead to tactile hypersensitivity. Moreover, our previous results suggested that the intrathecal (i.t.) administration of Ang (1-7), an N-terminal fragment of Ang II, may attenuate the Ang II-induced nociceptive behaviour through the inhibition of p38 MAPK phosphorylation via Mas receptors. Here, we investigated whether the i.t. administration of Ang (1-7) can attenuate STZ-induced diabetic neuropathic pain. METHODS: Tactile and thermal hypersensitivities were determined using the von Frey filament and Hargreaves tests, respectively. The protein expression of ACE2, Mas receptors and phospho-p38 MAPK was measured by western blotting. Spinal ACE2 activity was determined using ACE2 activity assay kit. RESULTS: The i.t. administration of Ang (1-7) significantly reduced the tactile and thermal hypersensitivities on day 14 after STZ injection, and these effects were significantly prevented by the Mas receptor antagonist A779. The expression of ACE2 and Mas receptors in the plasma membrane fraction of the lumbar dorsal spinal cord was both significantly decreased in STZ mice. Spinal ACE2 activity was also decreased while p38 MAPK phosphorylation was increased in the lumbar dorsal region of these mice. This phosphorylation was attenuated by the injection of Ang (1-7), whose effect was reversed by A779. CONCLUSIONS: Our data demonstrate that Ang (1-7) attenuates STZ-induced diabetic neuropathic pain and that this occurs through a mechanism involving spinal Mas receptors and he inhibition of p38 MAPK phosphorylation. SIGNIFICANCE: The ACE2/Ang (1-7)/Mas receptor axis was down-regulated in the spinal cord of STZ mice and the i.t. administration of Ang (1-7) attenuated the STZ-induced diabetic neuropathic pain via Mas receptors. Therefore, the activation of this axis could be an effective therapeutic target to alleviate the neuropathic pain in diabetic patients.


Assuntos
Angiotensina I/farmacologia , Diabetes Mellitus Experimental/metabolismo , Neuropatias Diabéticas/metabolismo , Hiperestesia/metabolismo , Neuralgia/metabolismo , Percepção da Dor/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Vasodilatadores/farmacologia , Angiotensina II/análogos & derivados , Angiotensina II/farmacologia , Animais , Diabetes Mellitus Experimental/complicações , Neuropatias Diabéticas/etiologia , Hiperestesia/etiologia , Masculino , Camundongos , Neuralgia/etiologia , Peptidil Dipeptidase A/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
12.
Peptides ; 112: 78-84, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30529303

RESUMO

Native angiotensin-(1-7) exerts many therapeutic effects. However, it is rapidly degraded by ACE and other peptidases. This drawback is largely eliminated for lanthionine-stabilized angiotensin-(1-7), termed cAng-(1-7), which is fully resistant to ACE and has strongly increased resistance to other peptidases. Goal of the present study was to test whether cAng-(1-7) has therapeutic activity in diabetes mouse models: in a multiple low dose streptozotocin-induced model of type I diabetes and / or in a db/db model of type II diabetes. In the type I diabetes model cAng-(1-7) caused in an increase in the insulin level of 133% in week 4 (p < 0.001) compared to vehicle, and in the type II diabetes model an increase of 55% of the insulin level in week 8 (p < 0.05) compared to vehicle. cAng-(1-7) reduced blood glucose levels in the type I model by 37% at day 22 (p < 0.001) and in the type II diabetes model by 17% at day 63 of treatment (p < 0.001) and in an oral glucose tolerance test in a type II diabetes model, by 17% at week 4 (p < 0.01). cAng-(1-7) also caused a reduction of glycated hemoglobin levels in the type II diabetes model of 21% in week 6 (p < 0,001). These data are consistent with therapeutic potential of cAng-(1-7) in type I and II diabetes.


Assuntos
Alanina/análogos & derivados , Angiotensina I/farmacologia , Glicemia/análise , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina/sangue , Fragmentos de Peptídeos/farmacologia , Sulfetos/química , Alanina/química , Angiotensina I/química , Angiotensina I/uso terapêutico , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/induzido quimicamente , Feminino , Insulina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/uso terapêutico , Estreptozocina/toxicidade , Resultado do Tratamento
13.
Oxid Med Cell Longev ; 2018: 1841046, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30425780

RESUMO

Aims: The goal of this study was to evaluate the effects of long-term (16 weeks) administration of angiotensin (1-7) [A(1-7)] on kidney function in db/db mice and to identify the protective mechanisms of this therapy. Methods: db/db mice and heterozygous controls were treated with A(1-7) or vehicle daily, subcutaneously for up to 16 weeks. Kidney injury was assessed by measuring blood flow in renal arteries, plasma creatinine levels, and proteinuria. Effects of treatment on oxidative stress were evaluated by histological staining and gene expression. Results: 16 weeks of daily administration of A(1-7) to a mouse model of severe type 2 diabetes (db/db) prevented the progression of kidney damage. Treatment with A(1-7) improved blood flow in the renal arteries, as well as decreased plasma creatinine levels and proteinuria in diabetic mice. Reduction of oxidative stress was identified as one of the mechanisms of the renoprotective action of A(1-7). Treatment prevented formation of nitrotyrosine residues, a marker of oxidative stress damage. A(1-7) also reduced the expression of two enzymes involved in formation of nitrotyrosine, namely, eNOS and NOX-4. A(1-7) regulated the phosphorylation pattern of eNOS to enhance production of NO in diabetic animals, possibly through the Akt pathway. However, these elevated levels of NO did not result in increased nitrosylation, possibly due to reduced NOX-4 levels. Conclusions: Long-term administration of A(1-7) improved kidney function and reduced oxidative stress damage in db/db mice.


Assuntos
Angiotensina I/administração & dosagem , Angiotensina I/farmacologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Rim/patologia , Rim/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/farmacologia , Animais , Diabetes Mellitus Experimental/genética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Rim/efeitos dos fármacos , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/patologia , Glomérulos Renais/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação/efeitos dos fármacos , Resistência ao Cisalhamento , Tirosina/análogos & derivados , Tirosina/metabolismo
14.
J Mol Med (Berl) ; 96(12): 1407-1418, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30374682

RESUMO

The highest incidence of nasopharyngeal carcinoma (NPC) is in southeast China, including Taiwan. Many side effects have been observed following radiation therapy with chemotherapy; hence, exploring new treatment modalities for NPC is an important future direction. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous heptapeptide hormone and important component of the renin-angiotensin system that acts through both the Mas receptor and AT2 receptor, exhibiting anti-proliferative and anti-angiogenic properties in cancer cells. However, the anti-cancer activity of Ang-(1-7) related to autophagy in NPC remains largely debated. The effects and signaling pathway(s) involved in the Ang-(1-7)/Mas receptor axis in NPC were investigated both in vitro and in vivo. Ang-(1-7) inhibited cell proliferation, migration, and invasion in NPC-TW01 cells. Ang-(1-7) induced autophagy by increasing the levels of the autophagy marker LC3-II and by enhancing p62 degradation via activation of the Beclin-1/Bcl-2 signaling pathway with involvement of the PI3K/Akt/mTOR and p38 pathways in vitro study. In addition, pre-treatment with Ang-(1-7) inhibited tumor growth in NPC xenografts by inducing autophagy, suggesting a correlation between PI3K/Akt/mTOR pathway inhibition and the abovementioned anti-cancer activities. However, no autophagy was observed following Ang-(1-7) post-treatment. Taken together, these data indicate that Ang-(1-7) plays a novel role in autophagy downstream signaling pathways in NPC, supporting its potential as a therapeutic agent for alleviation the incidence of NPC and preventive treatment of recurrent NPC. KEY MESSAGES: Ang-(1-7) inhibits cell proliferation, migration, and invasion by activating autophagy Ang-(1-7)pre-treatment inhibits tumor growth via autophagy by suppressing PI3K/Akt/mTOR pathway. Ang-(1-7) may provide a novel preventative treatment for NPC and recurrent NPC.


Assuntos
Angiotensina I/farmacologia , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Fragmentos de Peptídeos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Angiotensina I/uso terapêutico , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Humanos , Masculino , Camundongos Nus , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/patologia , Fragmentos de Peptídeos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Sci Rep ; 8(1): 15772, 2018 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-30361641

RESUMO

Angiotensin 1-7 (Ang1-7) is an endogenous bioactive component of the renin-angiotensin system (RAS). In addition to its cardiovascular properties, its anti-proliferative and anti-angiogenic traits are believed to play important roles in carcinogenesis. The present study examines the influence of Ang1-7 on processes associated with development and progression of prostate cancer cells. Our findings indicate that while Ang1-7 (1 nM; 48 h) can effectively reduce cell proliferation in DU-145, it can induce a significant decrease in the expression of MKI67 in LNCaP. In both cell lines we also observed a reduction in colony size in soft agar assay. A various changes in gene expression were noted after exposure to Ang1-7: those of anti- and pro-apoptotic agents and the NF-kB family of transcription factors, as well as mesenchymal cell markers and vascular endothelial growth factor A (VEGFA). In addition, Ang1-7 was found to modulate cell adhesion and matrix metallopeptidase (MMP) activity. Changes were also observed in the levels of angiotensin receptors and sex steroid hormone receptors. Ang1-7 reduced the levels of estrogen receptor alpha gene (ESR1) and increased the expression of estrogen receptor beta gene (ESR2) in all prostate cancer cells; it also up-regulated androgen receptor (AR) expression in androgen-sensitive cells but contradictory effect was observed in androgen- irresponsive cell lines. In summary, the results confirm the existence of complex network between the various elements of the local RAS and the molecular and cellular mechanisms of prostate cancerogenesis. The response of cancer cells to Ang1-7 appears to vary dependently on the dose and time of incubation as well as the aggressiveness and the hormonal status of cells.


Assuntos
Angiotensina I/farmacologia , Fragmentos de Peptídeos/farmacologia , Neoplasias da Próstata/genética , Adesão Celular/efeitos dos fármacos , Contagem de Células , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Proteínas da Matriz Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Invasividade Neoplásica , Neoplasias da Próstata/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
16.
Crit Care ; 22(1): 269, 2018 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-30367644

RESUMO

BACKGROUND: Sepsis and related multiple organ dysfunction result in high morbidity and mortality. Angiotensin (Ang)-(1-7), a biologically active peptide, has various opposing effects of Ang II. Because the effect of Ang-(1-7) on sepsis is unknown, in this study we aimed to determine the impact of Ang-(1-7) on pathophysiologic changes in a clinically relevant model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). METHODS: Sepsis was induced by CLP in rats under anesthesia. Rats were randomized to one of the following five groups: (1) sham-operated group, (2) Ang-(1-7) (1 mg/kg intravenously infused for 1 h) at 3 h and 6 h after sham operation, (3) CLP, (4) Ang-(1-7) at 3 h after CLP, and (5) Ang-(1-7) at 3 h and 6 h after CLP. Rats were observed for 24 h after CLP surgery and then killed for subsequent histological examination. RESULTS: Ang-(1-7) significantly improved the survival of septic rats (83.3% vs. 36.4% at 24 h following CLP; p = 0.009). Ang-(1-7) attenuated the CLP-induced decreased arterial pressure and organ dysfunction, indicated by diminished biochemical variables and fewer histological changes. Ang-(1-7) significantly reduced the level of plasma interleukin-6 and pulmonary superoxide production (p < 0.05). Moreover, caspase-3 and cytoplasmic IκB expression in liver was significantly lower in the Ang-(1-7)-treated CLP rats (p < 0.05). CONCLUSIONS: In this clinically relevant model of sepsis, Ang-(1-7) ameliorates CLP-induced organ dysfunction and improves survival, possibly through suppressing the inflammatory response, oxidative stress, and apoptosis, suggesting that Ang-(1-7) could be a potential novel therapeutic approach to treatment of peritonitis and polymicrobial sepsis.


Assuntos
Angiotensina I/farmacologia , Fragmentos de Peptídeos/farmacologia , Sepse/mortalidade , Sobrevivência de Tecidos/fisiologia , Angiotensina I/uso terapêutico , Animais , Apoptose/fisiologia , Biomarcadores/análise , Biomarcadores/sangue , Coinfecção/mortalidade , Modelos Animais de Doenças , Interleucina-6/análise , Interleucina-6/sangue , Escores de Disfunção Orgânica , Estresse Oxidativo , Fragmentos de Peptídeos/uso terapêutico , Ratos , Ratos Wistar , Estatísticas não Paramétricas , Superóxidos/análise , Superóxidos/sangue
17.
J Renin Angiotensin Aldosterone Syst ; 19(3): 1470320318789332, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30024321

RESUMO

The vasodilatory effect of angiotensin-(1-7) seems to vary between sexes, and estradiol (E2) can modulate the magnitude of the Ang-(1-7) vasodilatory response in female rats. However, there are few studies addressing the influence of sex on the age-related vasodilatory effect of Ang-(1-7). Here, we evaluated the vasodilatory response to Ang-(1-7) on vascular ageing. Ang-(1-7) dose-response curves were determined in mice aortic rings from males (old and young) and females (E2 treated/non-treated old and young) mounted in an isolated organ chamber. Abdominal aortic rings were used for protein expression analysis and determination of reactive oxygen species (ROS) and nitric oxide (NO) production. Our results showed that the Ang-(1-7) vasodilatory effect was absent in aorta from old females, contrasting with a full response in vessels from young females. The Ang-(1-7) vasodilatory effect was restored by E2 replacement in old females. A robust increase in Mas receptor, SOD2, NRF-2 and NOX2 expression was observed in aorta from old females, which was normalized by E2. This effect of E2 was also associated with lower production of ROS and normal levels of NO. In conclusion, our data demonstrated that pathways involved in the Ang-(1-7) vasodilatory response in female mice is affected by hormonal changes in ageing and rescued by E2.


Assuntos
Envelhecimento/metabolismo , Angiotensina I/farmacologia , Vasos Sanguíneos/metabolismo , Fragmentos de Peptídeos/farmacologia , Animais , Aorta/metabolismo , Vasos Sanguíneos/patologia , Estradiol/farmacologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Superóxidos/metabolismo , Vasodilatação/efeitos dos fármacos
19.
Pharmacol Res ; 135: 112-121, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30048754

RESUMO

Angiotensin-(19), a peptide of the non-classical renin angiotensin system, has been shown to prevent and revert hypertension and cardiac hypertrophy. We hypothetized that systemic delivery of angiotensin-(1-9) following myocardial infarction will also be protective and extend to provide protection during reperfusion of the ischemic heart. Adult Sprague Dawley rats were subjected to left anterior descending artery ligation and treated with angiotensin-(1-9) via osmotic mini-pump for 2 weeks in the presence or absence of Mas receptor or AT2R antagonists (A779 and PD123319, respectively). Myocardial death and left ventricular function were evaluated after infarction. Infarct size and functional parameters were determined in isolated rat hearts after global ischemia/reperfusion in the presence of angiotensin-(1-9) plus receptor antagonists or Akt inhibitor at reperfusion. in vitro, neonatal rat ventricular cardiomyocytes underwent simulated ischemia/reperfusion and angiotensin-(1-9) was co-incubated with A779, PD123319 or Akt inhibitor. Systemic delivery of angiotensin-(1-9) significantly decreased cell death and improved left ventricular recovery after in vivo myocardial infarction. Perfusion with the peptide reduced the infarct size and improved functional recovery after ex vivo ischemia/reperfusion. In vitro, angiotensin-(1-9) decreased cell death in isolated neonatal rat ventricular cardiomyocytes subjected to simulated ischemia/reperfusion. The cardioprotective effects of angiotensin-(1-9) were blocked by PD123319 and Akti VIII but not by A779. Angiotensin-(1-9) limits reperfusion-induced cell death by an AT2R- and Aktdependent mechanism. Angiotensin-(1-9) is a novel strategy to protect against cardiac ischemia/reperfusion injury.


Assuntos
Angiotensina I/uso terapêutico , Cardiotônicos/uso terapêutico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fragmentos de Peptídeos/uso terapêutico , Angiotensina I/farmacologia , Animais , Animais Recém-Nascidos , Cardiotônicos/farmacologia , Células Cultivadas , Coração/efeitos dos fármacos , Coração/fisiologia , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Fragmentos de Peptídeos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Receptor Tipo 2 de Angiotensina/metabolismo
20.
Clin Sci (Lond) ; 132(11): 1117-1133, 2018 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-29685981

RESUMO

Patients with hyperthyroidism exhibit increased risk of development and progression of cardiac diseases. The activation of the renin-angiotensin system (RAS) has been indirectly implicated in these cardiac effects observed in hyperthyroidism. Angiotensin-(1-7) (Ang-(1-7)) has previously been shown to counterbalance pathological effects of angiotensin II (Ang II). The aim of the present study was to investigate the effects of elevated circulating Ang-(1-7) levels on cardiac effects promoted by hyperthyroidism in a transgenic rat (TG) model that constitutively overexpresses an Ang-(1-7)-producing fusion protein [TGR(A1-7)3292]. TG and wild-type (WT) rats received daily injections (i.p.) of triiodothyronine (T3; 7 µg/100 g of body weight (BW)) or vehicle for 14 days. In contrast with WT rats, the TG rats did not develop cardiac hypertrophy after T3 treatment. Indeed, TG rats displayed reduced systolic blood pressure (SBP) and cardiac hyperdynamic condition induced by hyperthyroidism. Moreover, increased plasma levels of Ang II observed in hyperthyroid WT rats were prevented in TG rats. TG rats were protected from glycogen synthase kinase 3ß (GSK3ß) inactivation and nuclear factor of activated T cells (NFAT) nuclear accumulation induced by T3. In vitro studies evidenced that Ang-(1-7) prevented cardiomyocyte hypertrophy and GSK3ß inactivation induced by T3. Taken together, these data reveal an important cardioprotective action of Ang-(1-7) in experimental model of hyperthyroidism.


Assuntos
Angiotensina I/fisiologia , Cardiomegalia/etiologia , Glicogênio Sintase Quinase 3 beta/fisiologia , Hipertireoidismo/complicações , Fatores de Transcrição NFATC/fisiologia , Fragmentos de Peptídeos/fisiologia , Angiotensina I/sangue , Angiotensina I/farmacologia , Animais , Cardiomegalia/sangue , Cardiomegalia/diagnóstico por imagem , Células Cultivadas , Ecocardiografia , Hipertireoidismo/sangue , Hipertireoidismo/induzido quimicamente , Masculino , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/farmacologia , Ratos Sprague-Dawley , Ratos Transgênicos , Ratos Wistar , Sistema Renina-Angiotensina/fisiologia , Transdução de Sinais/fisiologia , Tri-Iodotironina/farmacologia
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