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1.
Toxicol Lett ; 321: 44-53, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31811911

RESUMO

This study was aimed to investigate the effect of prenatal ethanol exposure (PEE) on the susceptibility of offspring rats to glomerulosclerosis and to explore the mechanism. Pregnant Wistar rats were intragastrically administered ethanol (4g/kg·d) from gestational day (GD) 9 to GD 20, and the control group was given equal volume of normal saline. The offspring rats were all fed with high-fat diet after weaning, and were sacrificed at postnatal week 24 (PW24). The results revealed that the adult offspring kidneys in the male and female PEE groups exhibited higher glomerulosclerosis index and interstitial fibrosis index compared with the high-fat diet control groups, accompanied by elevated serum creatinine level. The protein expression of Nephrin and WT1, which were the marker genes of podocytes, was significantly decreased, whereas the protein expression of desmin and α-SMA, the marker genes of mesenchymal cells, was remarked enhanced in the male and female PEE groups. Compared with the high-fat diet control groups, the mRNA and protein expressions of renal angiotensin II receptor type 2 (AT2R) were decreased in the male PEE group, but increased in the female PEE group. PEE increased the mRNA and protein expressions of glucocorticoid (GC) activation system and inhibited the expression of insulin-like growth factor 1 (IGF1) signaling pathway in male offspring kidney; on the contrary, in female offspring kidney, PEE inhibited the mRNA and protein expression of glucocorticoid activation system and increased the expression of IGF1 signaling pathway. Taken together, PEE increased the susceptibility of the adult offspring to glomerulosclerosis, and the programming of renal AT2R or GC-IGF1 is respectively involved in the toxicity of PEE to the male or female offspring.


Assuntos
Dieta Hiperlipídica , Etanol/toxicidade , Glomerulonefrite/etiologia , Glomérulos Renais/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Transdução de Sinais/efeitos dos fármacos , Animais , Feminino , Fibrose , Regulação da Expressão Gênica , Idade Gestacional , Glomerulonefrite/genética , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Glucocorticoides/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Masculino , Gravidez , Ratos Wistar , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Transdução de Sinais/genética
2.
Anticancer Res ; 39(10): 5525-5530, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570446

RESUMO

BACKGROUND/AIM: Basal cell carcinoma (BCC) has been genetically associated with an increased expression of angiotensin-converting enzyme (ACE), an important factor of the renin-angiotensin system which produces vasoconstrictor angiotensin II. Other factors of this system include angiotensinogen (AGT) and angiotensin receptors AGTR1, AGTR2. We investigated the possible association of BCC with genetic variability in the AGT, AGTR1 and AGTR2 genes. MATERIALS AND METHODS: DNA samples of 190 Greeks were studied, including 91 patients with BCC and 99 matched healthy controls. Molecular genotyping of patients and controls was performed for the polymorphisms AGT M235T, AGTR1 A1166C and AGTR2 G1675A. RESULTS: The mutant T allele that increases AGT gene expression was detected in two-fold increased frequency in BCC patients in comparison to healthy controls (p <0.001). On the contrary, no significant difference was observed in AGTR1 and AGTR2 variants between patients and controls. CONCLUSION: Increased expression of AGT may be associated with BCC.


Assuntos
Carcinoma Basocelular/genética , Predisposição Genética para Doença/genética , Polimorfismo Genético/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Angiotensinogênio/genética , Estudos de Casos e Controles , Linhagem Celular Tumoral , Feminino , Frequência do Gene/genética , Humanos , Masculino , Pessoa de Meia-Idade , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/genética
3.
Lupus ; 28(2): 223-233, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30621494

RESUMO

BACKGROUND: There are no reports about the association of angiotensin II type 2 receptor ( AT2R) gene polymorphisms and susceptibility to systemic lupus erythematosus (SLE) in children. OBJECTIVE: The objective of this research is to study AT2R gene polymorphisms in exon 3 (C1593A) and intron 1 (A1675G) in Egyptian children with SLE and its correlation with disease manifestations and serum angiotensin-converting enzyme (ACE) level. METHODS: Typing of AT2R gene polymorphisms was conducted in 123 children with SLE in comparison with 100 healthy controls using the restriction fragment length polymorphism method. RESULTS: Significant differences were found between SLE patients and controls for A-containing genotypes (CA + AA) and A-allele frequencies of AT2R in exon 3 (C1593A) ( p = 0.01, odds ratio (OR) = 2.5, 95% confidence interval (CI) = 1.3-5.05; p = 0.01, OR = 2.2, 95% CI = 1.2-4.1, respectively). G-containing genotypes (AG + GG) and G allele of AT2R in intron 1 (A1675G) were more frequent in SLE patients compared to controls ( p = 0.01, OR = 2.3, 95% CI = 1.2-4.5; p = 0.02, OR = 2.1, 95% CI = 1.2-3.7, respectively). Serum ACE level was significantly higher in SLE patients than in controls ( p < 0.001). There was no association between AT2R gene polymorphisms and ACE level in serum. Moreover, there was no association between AT2R gene polymorphisms and SLE clinical manifestations. CONCLUSION: AT2R gene polymorphisms can be considered risk factors for SLE development in Egyptian children.


Assuntos
Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Peptidil Dipeptidase A/sangue , Receptor Tipo 2 de Angiotensina/genética , Adolescente , Estudos de Casos e Controles , Criança , Estudos Transversais , Egito , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo Genético , Fatores de Risco
4.
Oncogene ; 38(13): 2320-2336, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30478450

RESUMO

Despite emergence of new systemic therapies, metastatic melanoma remains a challenging and often fatal form of skin cancer. The renin-angiotensin system (RAS) is a major physiological regulatory pathway controlling salt-water equilibrium, intravascular volume and blood pressure. Biological effects of the RAS are mediated by the vasoactive hormone angiotensin II (AngII) via two receptor subtypes, AT1R (encoded by AGTR1) and AT2R (encoded by AGTR2). We report decreasing expression and increasing CpG island methylation of AGTR1 in metastatic versus primary melanoma and detection in serum of methylated genomic DNA from the AGTR1 CpG island in metastatic melanoma implying that AGTR1 encodes a tumour suppressor function in melanoma. Consistent with this hypothesis, antagonism of AT1R using losartan or shRNA-mediated knockdown in melanoma cell lines expressing AGTR1 resulted in acquisition of the ability to proliferate in serum-free conditions. Conversely, ectopic expression of AGTR1 in cell lines lacking endogenous expression inhibits proliferation irrespective of the presence of AngII implying a ligand-independent suppressor function for AT1R. Treatment of melanoma cell lines expressing endogenous AT2R with either AngII or the AT2R-selective agonist Y6AII induces proliferation in serum-free conditions whereas the AT2R-specific antagonists PD123319 and EMA401 inhibit melanoma growth and angiogenesis and potentiate inhibitors of BRAF and MEK in cells with BRAF V600 mutations. Our results demonstrate that the RAS has both oncogenic and tumour suppressor functions in melanoma. Pharmacological inhibition of AT2R may provide therapeutic opportunities in melanomas expressing this receptor and AGTR1 CpG island methylation in serum may serve as a novel biomarker of metastatic melanoma.


Assuntos
Proliferação de Células , Melanoma/patologia , Melanoma/terapia , Terapia de Alvo Molecular , Sistema Renina-Angiotensina/fisiologia , Amidas/farmacologia , Amidas/uso terapêutico , Angiotensina II/farmacologia , Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Células Cultivadas , Metilação de DNA/efeitos dos fármacos , Embrião não Mamífero , Fumaratos/farmacologia , Fumaratos/uso terapêutico , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Melanoma/genética , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Metástase Neoplásica , Piridinas/farmacologia , Piridinas/uso terapêutico , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
5.
Kidney Int ; 95(1): 138-148, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30442332

RESUMO

Vascular calcification is a common finding in atherosclerosis and in patients with chronic kidney disease. The renin-angiotensin system plays a role in the pathogenesis of cardiovascular remodeling. Here, we examined the hypothesis that angiotensin II type 2 receptor (AT2) stimulation has inhibitory effects on phosphate-induced vascular calcification. In vivo, calcification of the thoracic aorta induced by an adenine and high-phosphate diet was markedly attenuated in smooth muscle cell-specific AT2-overexpressing mice (smAT2-Tg) compared with wild-type and AT2-knockout mice (AT2KO). Similarly, mRNA levels of relevant osteogenic and vascular smooth muscle cell marker genes were unchanged in smAT2-Tg mice, while their expression was significantly altered in wild-type mice in response to high dietary phosphate. Ex vivo, sections of thoracic aorta were cultured in media supplemented with inorganic phosphate. Aortic rings from smAT2-Tg mice showed less vascular calcification compared with those from wild-type mice. In vitro, calcium deposition induced by high-phosphate media was markedly attenuated in primary vascular smooth muscle cells derived from smAT2-Tg mice compared with the two other mouse groups. To assess the underlying mechanism, we investigated the effect of PPAR-γ, which we previously reported as one of the possible downstream effectors of AT2 stimulation. Treatment with a PPAR-γ antagonist attenuated the inhibitory effects on vascular calcification observed in smAT2-Tg mice fed an adenine and high-phosphate diet. Our results suggest that AT2 activation represents an endogenous protective pathway against vascular calcification. Its stimulation may efficiently reduce adverse cardiovascular events in patients with chronic kidney disease.


Assuntos
Doenças da Aorta/tratamento farmacológico , Fosfatos/toxicidade , Receptor Tipo 2 de Angiotensina/metabolismo , Calcificação Vascular/tratamento farmacológico , Adenina/toxicidade , Animais , Aorta Torácica/patologia , Doenças da Aorta/sangue , Doenças da Aorta/etiologia , Doenças da Aorta/patologia , Células Cultivadas , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , PPAR gama/antagonistas & inibidores , PPAR gama/metabolismo , Fosfatos/sangue , Cultura Primária de Células , Receptor Tipo 2 de Angiotensina/agonistas , Receptor Tipo 2 de Angiotensina/genética , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/terapia , Calcificação Vascular/sangue , Calcificação Vascular/etiologia , Calcificação Vascular/patologia
6.
J Cardiovasc Pharmacol ; 72(6): 291-295, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30422889

RESUMO

Antihypertensive pharmacological treatments focus on the use of angiotensin-converting enzyme (ACE) inhibitors, AT1 receptor antagonists, and beta-blockers as single and combined treatments. The effect of single treatments on the mRNA expression of some components of the renin-angiotensin system has been studied, but not the effect of combined treatments. This study determined the expression of the AT1, AT2, B1, and B2 receptors and of the enzymes ACE and ACE2 in hypertensive rats treated with captopril-propranolol or losartan-propranolol. Methods: The mRNA expression of the receptors and enzymes was determined by reverse transcription-quantitative polymerase chain reaction in the aorta of spontaneously hypertensive rats under different treatments. Results: Rats under combined treatments showed a decrease in the expression of AT1 and ACE, and an increase in the expression of the B1 receptor (captopril + propranolol group: 0.43 ± 0.046, 2.243 ± 0.269, 3.356 ± 0.418; Group: losartan + propranolol: 0.727 ± 0.071, 0.852 ± 0.102, 1.277 ± 0.131 compared to the spontaneously hypertensive group: 1 ± 0.212, 1 ± 0.192, 1 ± 0.214). This decrease in the expression of ACE and AT1 suggests a reduction in the expression of Ang II that could be related to a lower response to this vasoconstrictor. An increase in the expression of B1 would improve vasodilation, which would be a beneficial effect of combined therapies for hypertension.


Assuntos
Anti-Hipertensivos/farmacologia , Aorta Torácica/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Sistema Calicreína-Cinina/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Antagonistas Adrenérgicos beta/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Captopril/farmacologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Sistema Calicreína-Cinina/genética , Losartan/farmacologia , Masculino , Propranolol/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Receptor B1 da Bradicinina/genética , Receptor B1 da Bradicinina/metabolismo , Receptor B2 da Bradicinina/genética , Receptor B2 da Bradicinina/metabolismo , Sistema Renina-Angiotensina/genética
7.
Mol Med Rep ; 18(5): 4349-4355, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30221707

RESUMO

Angiotensin II (Ang II) is a principal molecule of the renin­angiotensin system, which promotes hypertrophy and fibrosis. It has been demonstrated that Ang II upregulates the expression of cyclophilin A (CypA), which is a potential myocardial hypertrophy factor. However, the mechanisms by which Ang II induces the expression of CypA in cardiomyocytes remain unclear. In the present study, reactive oxygen species (ROS) were detected by fluorescence microscopy, and western blot analysis and ELISA were used to measure CypA expression. It was identified that Ang II enhanced the production of ROS in rat cardiomyocytes. ROS, in turn, promoted CypA expression and secretion. Notably, the action of Ang II was primarily dependent on the angiotensin type 2 receptor (AT2R), not the type 1 receptor. These results provided an insight into the role of the AT2R signaling pathway in Ang II­induced myocardial hypertrophy.


Assuntos
Angiotensina II/genética , Ciclofilina A/genética , Hipertrofia/genética , Receptor Tipo 2 de Angiotensina/genética , Animais , Regulação da Expressão Gênica , Humanos , Hipertrofia/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Transdução de Sinais
8.
Stem Cells Transl Med ; 7(10): 721-730, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30133167

RESUMO

Although mesenchymal stem cells (MSCs) transplantation has been shown to promote the lung respiration in acute lung injury (ALI) in vivo, its overall restorative capacity appears to be restricted mainly because of low retention in the injured lung. Angiotensin II (Ang II) are upregulated in the injured lung. Our previous study showed that Ang II increased MSCs migration via Ang II type 2 receptor (AT2R). To determine the effect of AT2R in MSCs on their cell migration after systemic injection in ALI mice, a human AT2R expressing lentiviral vector and a lentivirus vector carrying AT2R shRNA were constructed and introduced into human bone marrow MSCs. A mouse model of lipopolysaccharide-induced ALI was used to investigate the migration of AT2R-regulated MSCs and the therapeutic potential in vivo. Overexpression of AT2R dramatically increased Ang II-enhanced human bone marrow MSC migration in vitro. Moreover, MSC-AT2R accumulated in the damaged lung tissue at significantly higher levels than control MSCs 24 and 72 hours after systematic MSC transplantation in ALI mice. Furthermore, MSC-AT2R-injected ALI mice exhibited a significant reduction of pulmonary vascular permeability and improved the lung histopathology and had additional anti-inflammatory effects. In contrast, there were less lung retention in MSC-ShAT2R-injected ALI mice compared with MSC-Shcontrol after transplantation. Thus, MSC-ShAT2R-injected group exhibited a significant increase of pulmonary vascular permeability and resulted in a deteriorative lung inflammation. Our results demonstrate that overexpression of AT2R enhance the migration of MSCs in ALI mice and may provide a new therapeutic strategy for ALI. Stem Cells Translational Medicine 2018;7:721-730.


Assuntos
Lesão Pulmonar Aguda/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/patologia , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Movimento Celular , Citocinas/análise , Modelos Animais de Doenças , Contagem de Leucócitos , Lipopolissacarídeos/toxicidade , Masculino , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Neutrófilos/citologia , Receptor Tipo 2 de Angiotensina/genética
9.
Proc Natl Acad Sci U S A ; 115(34): E8057-E8066, 2018 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-30082378

RESUMO

Peripheral nerve damage initiates a complex series of structural and cellular processes that culminate in chronic neuropathic pain. The recent success of a type 2 angiotensin II (Ang II) receptor (AT2R) antagonist in a phase II clinical trial for the treatment of postherpetic neuralgia suggests angiotensin signaling is involved in neuropathic pain. However, transcriptome analysis indicates a lack of AT2R gene (Agtr2) expression in human and rodent sensory ganglia, raising questions regarding the tissue/cell target underlying the analgesic effect of AT2R antagonism. We show that selective antagonism of AT2R attenuates neuropathic but not inflammatory mechanical and cold pain hypersensitivity behaviors in mice. Agtr2-expressing macrophages (MΦs) constitute the predominant immune cells that infiltrate the site of nerve injury. Interestingly, neuropathic mechanical and cold pain hypersensitivity can be attenuated by chemogenetic depletion of peripheral MΦs and AT2R-null hematopoietic cell transplantation. Our study identifies AT2R on peripheral MΦs as a critical trigger for pain sensitization at the site of nerve injury, and therefore proposes a translatable peripheral mechanism underlying chronic neuropathic pain.


Assuntos
Dor Crônica/metabolismo , Macrófagos/metabolismo , Neuralgia/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Aloenxertos , Animais , Dor Crônica/genética , Dor Crônica/patologia , Transplante de Células-Tronco Hematopoéticas , Macrófagos/patologia , Camundongos , Neuralgia/genética , Neuralgia/patologia , Receptor Tipo 2 de Angiotensina/genética
10.
J Neurosci ; 38(32): 7032-7057, 2018 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-29976627

RESUMO

Injury, inflammation, and nerve damage initiate a wide variety of cellular and molecular processes that culminate in hyperexcitation of sensory nerves, which underlies chronic inflammatory and neuropathic pain. Using behavioral readouts of pain hypersensitivity induced by angiotensin II (Ang II) injection into mouse hindpaws, our study shows that activation of the type 2 Ang II receptor (AT2R) and the cell-damage-sensing ion channel TRPA1 are required for peripheral mechanical pain sensitization induced by Ang II in male and female mice. However, we show that AT2R is not expressed in mouse and human dorsal root ganglia (DRG) sensory neurons. Instead, expression/activation of AT2R on peripheral/skin macrophages (MΦs) constitutes a critical trigger of mouse and human DRG sensory neuron excitation. Ang II-induced peripheral mechanical pain hypersensitivity can be attenuated by chemogenetic depletion of peripheral MΦs. Furthermore, AT2R activation in MΦs triggers production of reactive oxygen/nitrogen species, which trans-activate TRPA1 on mouse and human DRG sensory neurons via cysteine modification of the channel. Our study thus identifies a translatable immune cell-to-sensory neuron signaling crosstalk underlying peripheral nociceptor sensitization. This form of cell-to-cell signaling represents a critical peripheral mechanism for chronic pain and thus identifies multiple druggable analgesic targets.SIGNIFICANCE STATEMENT Pain is a widespread health problem that is undermanaged by currently available analgesics. Findings from a recent clinical trial on a type II angiotensin II receptor (AT2R) antagonist showed effective analgesia for neuropathic pain. AT2R antagonists have been shown to reduce neuropathy-, inflammation- and bone cancer-associated pain in rodents. We report that activation of AT2R in macrophages (MΦs) that infiltrate the site of injury, but not in sensory neurons, triggers an intercellular redox communication with sensory neurons via activation of the cell damage/pain-sensing ion channel TRPA1. This MΦ-to-sensory neuron crosstalk results in peripheral pain sensitization. Our findings provide an evidence-based mechanism underlying the analgesic action of AT2R antagonists, which could accelerate the development of efficacious non-opioid analgesic drugs for multiple pain conditions.


Assuntos
Angiotensina II/fisiologia , Hiperalgesia/fisiopatologia , Macrófagos Peritoneais/metabolismo , Neuralgia/fisiopatologia , Receptor Tipo 2 de Angiotensina/fisiologia , Células Receptoras Sensoriais/fisiologia , Canal de Cátion TRPA1/fisiologia , Angiotensina II/toxicidade , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Comunicação Celular/fisiologia , Células Cultivadas , Feminino , Gânglios Espinais/citologia , Genes Reporter , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Imidazóis/farmacologia , Ativação de Macrófagos , Macrófagos Peritoneais/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuralgia/tratamento farmacológico , Ativação de Neutrófilo , Oxirredução , Piridinas/farmacologia , Receptor Tipo 2 de Angiotensina/genética , Células Receptoras Sensoriais/química , Pele/citologia , Canal de Cátion TRPA1/deficiência , Tacrolimo/análogos & derivados , Tacrolimo/farmacologia
11.
Nat Struct Mol Biol ; 25(7): 570-576, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29967536

RESUMO

Angiotensin II (AngII) plays a central role in regulating human blood pressure, which is mainly mediated by interactions between AngII and the G-protein-coupled receptors (GPCRs) AngII type 1 receptor (AT1R) and AngII type 2 receptor (AT2R). We have solved the crystal structure of human AT2R binding the peptide ligand [Sar1, Ile8]AngII and its specific antibody at 3.2-Å resolution. [Sar1, Ile8]AngII interacts with both the 'core' binding domain, where the small-molecule ligands of AT1R and AT2R bind, and the 'extended' binding domain, which is equivalent to the allosteric modulator binding site of muscarinic acetylcholine receptor. We generated an antibody fragment to stabilize the extended binding domain that functions as a positive allosteric modulator. We also identified a signature positively charged cluster, which is conserved among peptide-binding receptors, to locate C termini at the bottom of the binding pocket. The reported results should help with designing ligands for angiotensin receptors and possibly to other peptide GPCRs.


Assuntos
Angiotensina II/análogos & derivados , Receptor Tipo 2 de Angiotensina/química , Sítio Alostérico , Sequência de Aminoácidos , Angiotensina II/química , Angiotensina II/metabolismo , Cristalografia por Raios X , Endotelina-1/química , Endotelina-1/metabolismo , Humanos , Fragmentos de Imunoglobulinas , Cinética , Ligantes , Modelos Moleculares , Conformação Proteica , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Transdução de Sinais , Eletricidade Estática
12.
Lipids Health Dis ; 17(1): 178, 2018 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-30055626

RESUMO

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) can develop in prenatal stages and can be exacerbated by exposure to a postnatal high-fat (HF) diet. We investigated the protective effects of resveratrol on prenatal and postnatal HF diet-induced NAFLD. METHODS: Male Sprague-Dawley rat offspring were placed in five experimental groups (n = 10-12 per group): normal diet (VNF), maternal HF diet (ONF), postnatal HF diet (VHF), and maternal HF diet/postnatal HF diet (OHF). A therapeutic group with resveratrol for maternal HF diet/postnatal HF diet (OHFR) was used for comparison. Resveratrol (50 mg/kg/day) was dissolved in drinking water for offspring from post-weaning to postnatal day (PND) 120. RESULTS: We found that HF/HF-induced NAFLD was prevented in adult offspring by the administration of resveratrol. Resveratrol administration mediated a protective effect on rats on HF/HF by regulating lipid metabolism, reducing oxidative stress and apoptosis, restoring nutrient-sensing pathways by increasing Sirt1 and leptin expression, and mediating the renin-angiotensin system (RAS) to decrease angiotensinogen, renin, ACE1, and AT1R levels and increased ACE2, AT2R and MAS1 levels compared to those in the OHF group. CONCLUSION: Our results suggest that a maternal and post-weaning HF diet increases liver steatosis and apoptosis via the RAS. Resveratrol might serve as a therapeutic target by mediating protective actions against NAFLD in offspring exposed to a combination of maternal and postnatal HF diet.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Hipolipemiantes/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Estilbenos/farmacologia , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Animais , Animais Recém-Nascidos , Dieta Hiperlipídica/efeitos adversos , Feminino , Leptina/genética , Leptina/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Renina/genética , Renina/metabolismo , Resveratrol , Sirtuína 1/genética , Sirtuína 1/metabolismo , Desmame
13.
Hypertens Pregnancy ; 37(2): 87-92, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29714512

RESUMO

OBJECTIVES: To investigate the association of polymorphisms and haplotypes of angiotensin receptor 2 (AT2R) gene with pregnancy induced hypertension (PIH) in Chinese Han women. METHODS: A case-control study was designed with 446 cases (gestational hypertension, GH: 124; pre-eclampsia, PE + eclampsia, E: 322) and 650 controls. rs5193, rs1403543 and rs12710567 of AT2R gene were genotyped. A logistic regression approach was applied to estimate the relationship between the polymorphisms and haplotypes of AT2Rgene with PIH risk. RESULTS: No relationship between AT2R gene polymorphisms and PIH was detected. The haplotype analysis also showed a negative result. CONCLUSIONS: rs5193, rs1403543 and rs12710567 of AT2R gene might have no effect on PIH risk among Chinese Han women.


Assuntos
Predisposição Genética para Doença , Hipertensão Induzida pela Gravidez/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 2 de Angiotensina/genética , Adulto , Estudos de Casos e Controles , Feminino , Genótipo , Haplótipos , Humanos , Pré-Eclâmpsia/genética , Gravidez , Adulto Jovem
14.
Biomed Pharmacother ; 102: 947-958, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29710550

RESUMO

In the present study, we investigated the effects of angiotensin (Ang II) receptor blockers in cerebral ischemia by administration of telmisartan (AT1 blocker) and/or PD123319 (AT2 blocker) in global ischemic mice model. The neuroprotective effect of AT antagonists was evaluated through monitoring muscle co-ordination and cerebral blood perfusion in ischemic mice. Gene expression studies (NF-κB, GSK-3ß, EAAT-2, AT1 & AT2 receptors) and staining of brain regions with cresyl violet, GFAP, synaptophysin and NSE methods were carried out in to understand the molecular mechanisms. Further, the brain glutamate, cytokines, and Ang II peptide levels were evaluated and their correlation with EAAT-2 mRNA expression was performed. Our results indicate that the induction of ischemia elevates brain Ang II, cytokines, and glutamate levels and reduced muscle co-ordination and cerebral blood perfusion. The expressions of NF-κB, GSK-3ß and AT1 were significantly increased, whereas, EAAT-2 expression was decreased. Blocking of AT1 receptors by telmisartan (TM) reversed the detrimental responses of cerebral ischemia and restored the cerebral blood flow denoting blockade of Ang II/AT1 pathway is beneficial in ischemia, whereas, blockade of AT2 receptors by PD123319 (PD) increased the ischemic injury in mice. This vulnerable effect of PD may be attributed through augmenting the Ang II/AT1 dependent cytokines mediated glutamate transporter (EAAT-2) dysfunction. Interestingly, the beneficial effects of AT1 blocker was remarkably antagonized by AT2 blocker in most of the parameters studied in ischemic conditions. Also, the expression of AT2 receptors was significantly increased compared to that of AT1 receptors upon ischemic induction. It denotes that the endogenous Ang II predominantly acts on AT2 receptor, thereby promoting its own mRNA transcription. Hence, the increased expression of AT2 receptors in ischemic condition could be used as target protein for therapeutic benefit.


Assuntos
Isquemia Encefálica/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Glutamina/metabolismo , Inflamação/patologia , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Angiotensina II/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/fisiopatologia , Circulação Cerebrovascular , Citocinas/metabolismo , Ácido Glutâmico/metabolismo , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Fluxometria por Laser-Doppler , Masculino , Camundongos , Músculos/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Perfusão , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/genética , Transdução de Sinais/efeitos dos fármacos
15.
Toxicol In Vitro ; 50: 373-382, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29665408

RESUMO

There is evidence to support that ROSs are increased in Parkinson's disease (PD). Our recent research showed that angiotensin II (Ang II) participated in the pathogenesis of PD by triggering oxidative stress. Angiotensin-(1-7)[Ang-(1-7)] has been shown to moderate the adverse effects of the Ang II in many diseases. The purpose of the present study was to determine whether the Ang-(1-7) could have similar effects in CATH.a neurons. We used rotenone-induced neuron injury models to evaluate changes in cultured CATH.a cell lines levels of SOD, GSH and ROS. We also evaluated the expression of AT1, AT2, Mas receptors and Nox1, Nox2, P47phox, Hsp70 in treated with PBS, rotenone, Ang-(1-7), or Mas receptor antagonist A-779, alone and combined. The qRT-PCR and western blot were used to detect mRNA and protein levels of the AT1, AT2, Mas receptors and Nox1, Nox2, P47phox, Hsp70. The levels of SOD and GSH were determined by using commercial kits. The ROS generation was measured by the fluorescent probe assay. Ang-(1-7) in our current study significantly decreased rotenone-induced oxidative damage and increased the SOD and GSH generation. In addition, Ang-(1-7) significantly elevated Mas receptor expression and reduced NADPH oxidase activation, and these effects were completely eliminated by the A-779. Our findings suggest that Ang-(1-7) attenuates rotenone-induced oxidative damage in CATH.a neurons by activating the Mas receptor expression and inhibiting NADPH oxidase.


Assuntos
Angiotensina I/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Rotenona/toxicidade , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Glutationa/metabolismo , Camundongos , NADPH Oxidases/metabolismo , Neurônios/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Superóxido Dismutase/metabolismo
16.
J Sports Sci ; 36(20): 2327-2332, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29561708

RESUMO

The main purpose of this study was to investigate if the rs11091046 (A>C) polymorphism in AGTR2 gene is associated with athletic status in top-level athletes from Brazil. Since the AGTR2 gene is located on the X chromosome, the case-control association study was done separately for women and men. The female cohort was composed of 205 athletes and 241 non-athletes, and the male cohort was composed of 419 athletes and 490 non-athletes. We did not identify an association between the C-allele and the endurance phenotype. However, power athletes had a higher frequency of the A-allele. In women, A/A genotype was overrepresented in international-level power group compared with non-athletes or international-level endurance athletes (23.2% vs. 16.6% or 8.8%, respectively; p < 0.05). In men, the A-allele frequency observed in power athletes or international-level power athletes was statistically different from that observed in non-athletes (51.6% or 57.8% vs. 40.4%; p < 0.009). Furthermore, men sprinters with the A-allele showed significantly faster personal best times for the 100 m than those with the C-allele (10.56 ± 0.32 s vs. 10.93 ± 0.49 s; p < 0.02). In conclusion, it was found that the AGTR2 A-allele is a candidate genetic marker for top-level power athletes.


Assuntos
Desempenho Atlético/fisiologia , Polimorfismo de Nucleotídeo Único , Receptor Tipo 2 de Angiotensina/genética , Adulto , Brasil , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Força Muscular/fisiologia , Resistência Física/fisiologia
17.
Int J Mol Med ; 41(4): 2375-2388, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29393347

RESUMO

Hypertension is one of the most common complications following renal transplantation, and it increases the risk of graft loss and other cardiovascular diseases. Previous studies have revealed that the use of angiotensin II (Ang II) blockers for preventing and treating hypertension is closely associated with higher survival following renal transplantation. However, the cellular and molecular mechanisms by which the vascular contractility of the recipient is altered in response to Ang II following renal transplantation have not been fully elucidated. In the present study, using the Fisher­Lewis rat kidney transplantation model, the blood pressure (BP) of the conscious transplant recipient was measured following the intravenous administration of Ang II. In addition, the mechanisms underlying the Ang II-mediated vascular contractility via the type 1 and type 2 Ang II receptors (AT1R and AT2R, respectively) in large and small-resistance blood vessels were determined in the recipient after renal transplantation. The results showed that renal transplantation significantly increased the Ang II-stimulated BP of the rats. Additionally, ex vivo contractility experiments using aorta and mesenteric arteries revealed that the contractions induced by Ang II were significantly strengthened in the recipient following renal transplantation, and were associated with an increased intracellular Ca2+ concentration. Losartan almost eradicated the Ang II-induced contractions whereas PD-123319 had no apparent effects on the Ang II-induced contractions in the aorta and mesenteric arteries of the recipient. Furthermore, the expression levels of AT1R but not AT2R were significantly increased in the vasculature of the recipient following renal transplantation, which exhibited a close association with selective DNA demethylation detected in the promoter region of the vascular AT1aR gene. These results indicate that changes of recipient vascular AT1R gene expression, occurring through a mechanism involving DNA methylation, increase the vascular contractility in response to Ang II. This may lead to the increased risk of hypertension following renal transplantation.


Assuntos
Aorta/fisiologia , Epigênese Genética , Transplante de Rim , Artérias Mesentéricas/fisiologia , Receptor Tipo 2 de Angiotensina/metabolismo , Vasoconstrição , Angiotensina II/metabolismo , Animais , Pressão Sanguínea , Metilação de DNA , Transplante de Rim/métodos , Masculino , Regiões Promotoras Genéticas , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/genética
18.
Mol Med Rep ; 17(4): 5184-5192, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29393490

RESUMO

Activation of renin-angiotensin system (RAS) is one of the pathological mechanisms associated with myocardial ischemia-reperfusion injury following resuscitation. The present study aimed to determine whether erythropoietin (EPO) improves post­resuscitation myocardial dysfunction and how it affects the renin­angiotensin system. Sprague­Dawley rats were randomly divided into sham, vehicle, epinephrine (EP), EPO and EP + EPO groups. Excluding the sham group, all groups underwent cardiopulmonary resuscitation (CPR) 4 min after asphyxia­induced cardiac arrest (CA). EP and/or EPO was administrated by intravenous injection when CPR began. The results demonstrated that the vehicle group exhibited lower mean arterial pressure, left ventricular systolic pressure, maximal ascending rate of left ventricular pressure during left ventricular isovolumic contraction and maximal descending rate of left ventricular pressure during left ventricular isovolumic relaxation (+LVdP/dt max and ­LVdP/dt max, respectively), and higher left ventricular end­diastolic pressure, compared with the sham group following return of spontaneous circulation (ROSC). Few significant differences were observed concerning the myocardial function between the vehicle and EP groups; however, compared with the vehicle group, EPO reversed myocardial function indices following ROSC, excluding­LVdP/dt max. Serum renin and angiotensin (Ang) II levels were measured by ELISA. The serum levels of renin and Ang II were significantly increased in the vehicle group compared with the sham group, which was also observed for the myocardial expression of renin and Ang II receptor type 1 (AT1R), as determined by reverse transcription­quantitative polymerase chain reaction and western blotting. EPO alone did not significantly reduce the high serum levels of renin and Ang II post-resuscitation, but changed the protein levels of renin and AT1R expression in myocardial tissues. However, EPO enhanced the myocardial expression of Ang II receptor type 2 (AT2R) following ROSC. In conclusion, the present study confirmed that CA resuscitation activated the renin­Ang II­AT1R signaling pathway, which may contribute to myocardial dysfunction in rats. The present study confirmed that EPO treatment is beneficial for protecting cardiac function post­resuscitation, and the roles of EPO in alleviating post­resuscitation myocardial dysfunction may potentially be associated with enhanced myocardial expression of AT2R.


Assuntos
Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Eritropoetina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Miocárdio/metabolismo , Receptor Tipo 2 de Angiotensina/genética , Angiotensina II/sangue , Angiotensina II/metabolismo , Animais , Biomarcadores , Cardiomiopatias/fisiopatologia , Reanimação Cardiopulmonar , Feminino , Parada Cardíaca , Masculino , Ratos , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Renina/sangue , Renina/genética , Renina/metabolismo
19.
Clin Sci (Lond) ; 132(6): 627-640, 2018 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-29436482

RESUMO

The angiotensin II (Ang II) type 2 receptor (AT2R) and the angiotensin-(1-7) (Ang-(1-7)) receptor (MasR) play a cardiovascular protective role by counter-regulating Ang II type 1 receptor (AT1R)-mediated effects, but whether this involves blunting of adrenocortical hormone secretion is unknown. We investigated the presence of AT1R, AT2R, and MasR in aldosterone-producing adenoma (APA), a condition featuring hyperaldosteronism, and in APA-adjacent tissue. The effect of Compound 21 (C21), an AT2R agonist, on CYP11B1 (cortisol synthase) and CYP11B2 (aldosterone synthase) gene expression in NCI-H295R and HAC15 cell lines, and in APA and APA-adjacent tissue, was also assessed using the AT1R antagonist irbesartan to ascertain the specificity of C21 effect. We found that the AT1R, AT2R, and MasR were expressed in APA and APA-adjacent tissue, albeit heterogeneously. The gene expression of AT1R and AT2R was lower, and that of the MasR higher in APAs than in APA-adjacent tissue. In steroid-producing NCI-H295R and HAC15 cell lines, and in APA and APA-adjacent tissue, C21 was ineffective at nanomolar concentrations, but increased CYP11B1 and CYP11B2 gene expression at micromolar concentrations through AT1R, as this effect was blunted by irbesartan. The scant expression of the AT2R, along with the lack of any effect of C21 at low concentrations on CYP11B2, do not support the contention that the protective arm of renin-angiotensin system (RAS) blunts aldosterone synthase in the normal adrenal cortex and primary aldosteronism.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/metabolismo , Aldosterona/metabolismo , Hiperaldosteronismo/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Sistema Renina-Angiotensina , Zona Glomerulosa/metabolismo , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/patologia , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/patologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Estudos de Casos e Controles , Linhagem Celular , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Humanos , Hiperaldosteronismo/genética , Hiperaldosteronismo/patologia , Irbesartana/farmacologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/agonistas , Receptor Tipo 2 de Angiotensina/genética , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/genética , Esteroide 11-beta-Hidroxilase/genética , Esteroide 11-beta-Hidroxilase/metabolismo , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Zona Glomerulosa/efeitos dos fármacos , Zona Glomerulosa/patologia
20.
J Am Heart Assoc ; 7(3)2018 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-29431106

RESUMO

BACKGROUND: The classical renin-angiotensin system is known as the angiotensin (Ang)-converting enzyme/Ang II/Ang type 1 receptor axis, which induces various organ damage including cognitive decline. The angiotensin-converting enzyme 2/Ang-(1-7)/Mas axis is known to exert antagonistic actions against the classical renin-angiotensin system axis in the cardiovascular system. However, its roles in the brain remain unclear. We examined possible roles of the angiotensin-converting enzyme 2/Ang-(1-7)/Mas axis in cognitive function, employing vascular cognitive impairment model mice. METHODS AND RESULTS: Male 10-week-old C57BL6 (wild-type mice, Mas1 knockout mice, Ang II type 2 receptor knockout mice, and Ang II type 2 receptor/Mas1 double knockout mice were subjected to bilateral carotid artery stenosis (BCAS) surgery. Six weeks after treatment, they were subjected to cognitive tasks. Brain samples were used for histopathological analysis. Cognitive function was significantly impaired in wild-type and double knockout mice after BCAS. On the other hand, the cognitive function of Mas1 knockout mice was maintained in spite of the reduction of cerebral blood flow with BCAS. Total cell number in the dentate gyrus region was significantly reduced after BCAS in wild-type but not in Mas1 knockout mice. The number of doublecortin-positive cells in the subgranular zone was not significantly different between wild-type and Mas1 knockout mice. Ang-(1-7) administration did not improve cognitive function in all mice after BCAS surgery. CONCLUSIONS: Lack of the Mas receptor may have a protective effect against chronic brain ischemia when the Ang II type 2 receptor exists.


Assuntos
Comportamento Animal , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Estenose das Carótidas/complicações , Circulação Cerebrovascular , Transtornos Cognitivos/prevenção & controle , Cognição , Demência Vascular/prevenção & controle , Proteínas Proto-Oncogênicas/deficiência , Receptor Tipo 2 de Angiotensina/deficiência , Receptores Acoplados a Proteínas-G/deficiência , Animais , Encéfalo/patologia , Estenose das Carótidas/metabolismo , Estenose das Carótidas/fisiopatologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/psicologia , Demência Vascular/etiologia , Demência Vascular/metabolismo , Demência Vascular/psicologia , Modelos Animais de Doenças , Predisposição Genética para Doença , Masculino , Aprendizagem em Labirinto , Memória de Curto Prazo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Atividade Motora , Neuropeptídeos/metabolismo , Fenótipo , Proteínas Proto-Oncogênicas/genética , Receptor Tipo 2 de Angiotensina/genética , Receptores Acoplados a Proteínas-G/genética
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