Papel dos receptores farmacológicos AT1 e AT2 da Angiotensina II em doença periodontal induzida: aspectos moleculares / Role of pharmacological receptors AT1 and AT2 of Angiotensin II in caused periodontal disease: molecular aspects

O sistema renina angiotensina (SRA) é de grande importância para o equilíbrio hídrico e regulação da pressão arterial do organismo, além de estar associado ao estimulo de vias próinflamatórias. Seu principal peptídeo é a angiotensina II, que interage principalmente com os receptores do tipo 1 (AT1) e do tipo 2 (AT2). Foi encontrado interrelação entre as doenças cardiovasculares e a periodontite. Este estudo teve como objetivo avaliar os aspectos moleculares em camundongos submetidos a um modelo experimental de periodontite, observando a influência dos receptores de Ang II tipo 1 (AT1(-)) e Ang II tipo 2 (AT2(-)) na periodontite. Métodos: A periodontite experimental foi induzida colocando-se uma ligadura com fio de nylon 5.0 ao redor do segundo molar superior esquerdo de camundongos knockoutAT1(-), AT2(-) e selvagem (WT), subdivididos 2 grupos para cada linhagem: sem ligadura e ligadura, totalizando seis grupos: três controles e três experimentais. Após 15 dias da indução da doença os animais foram submetidos à eutanásia. Com o intuito de avaliar se as variações genéticas teriam influência sobre a periodontite foram realizadas as análises de citocinas, peptídeos e enzimas foram analisados a partir de tecidos gengivais por ELISA e RT-PCR. Resultados: Os animais WT e AT2(-) apresentaram resultados semelhantes em relação às citocinas IL-1ß, IL-6, TNF-α, com aumento dos níveis em relação aos saudáveis (p < 0,001). Houve diferenças significativas em IL-ß entre os grupo AT1(-)-L e WT-L (p < 0,05), e em IL-6 e TNF-α os grupos AT1(-)-L apresentaram diferenças significativas (p < 0,001) tanto quando comparado aos grupo WT-L quanto aos grupos AT2(-)-L. Os níveis de IL-10 foram maiores em WT-L (p < 0,01), enquanto os grupos AT2(-) e AT1(-) não apresentaram alterações significativas em relação a essa citocina. Houve diferenças significativas em Angiotensina II entre os grupos AT2(-)-NL e AT2(-)-L (p < 0,01); e em Angiotensina 1-7 entre os grupos AT1(-)-L e AT2(-)-L (p < 0,05). Para TLR2 houve diferenças entre os grupos WT-NL/WT-L (p < 0,05); AT1(-)-NL/AT1(-)-L (p < 0,01) e AT2(-)-NL/AT2(-) - L (p < 0,01). Para o receptor MAS houve diferenças entre os grupos WT-NL/WT-L (p < 0,001) e AT2(-)-NL/AT2(-)-L (p < 0,001), e também em relação ao grupo WT-L/AT1(-)-L (p < 0,001) e AT1(-)-L/AT2(-)-L (p < 0,001). Para a expressão dos peptídeos ECA e ECA2, houve diferença estatística apenas para ECA entre os tipos de grupos WT-NL/WT-L (p < 0,001). Conclusão: Os animais do grupo AT1(-) apresentaram menor inflamação que as demais linhagens doentes, assim como uma menor expressão do receptor Mas e Ang 1-7. Além disso os animais dos grupos WT e AT2(-) demonstraram resultados próximos em diversas análises, evidenciando que o bloqueio do receptor AT1, sobre os efeitos moleculares, é mais positiva (AU).

The renin angiotensin system (RAS) is of great importance for water balance and regulation of blood pressure in the body, in addition to being associated with the stimulation of proinflammatory pathways. Its main peptide is angiotensin II, which interacts mainly with type 1 (AT1) and type 2 (AT2) receptors. An interrelationship was found between cardiovascular diseases and periodontitis. This study aimed to evaluate the molecular aspects in mice subjected to an experimental model of periodontal disease, observing the influence of Ang II type 1 (AT1(-)) and Ang II type 2 (AT2(-)) receptors on periodontitis. Methods: Experimental periodontitis was induced by placing a ligature with 5.0 nylon thread around the upper left second molar of AT1(-), AT2(-) and wild-type (WT) knockout mice, subdivided into 2 groups for each strain: without ligation and ligation, totaling six groups: three controls and three experimental. After 15 days of disease induction, the animals were euthanized. In order to evaluate whether genetic variations would have an influence on periodontal disease, analyzes of cytokines were carried out, peptides and enzymes were analyzed from gingival tissues by ELISA and RT-PCR. Results: WT and AT2(-) animals showed similar results in relation to the cytokines IL-1ß, IL-6, TNF-α, with increased levels compared to healthy ones (p < 0.001). There were significant differences in IL-ß between the AT1(-)-L and WT-L groups (p < 0.05), and in IL-6 and TNF-α the AT1(-)-L groups showed significant differences (p < 0.001) both when compared to the WT-L and AT2(-)-L groups. IL-10 levels were higher in WT-L (p < 0.01), while the AT2(-) and AT1(-) groups did not show significant changes in relation to this cytokine. There were significant differences in Angiotensin II between the AT2(-)-NL and AT2(-)-L groups (p < 0.01); and in Angiotensin 1-7 between the AT1(-)-L and AT2(-)-L groups (p < 0.05). For TLR2 there were differences between the WT-NL/WT-L groups (p < 0.05); AT1(-)-NL/AT1(-)-L (p < 0.01) and AT2(-)-NL/AT2(-)-L (p < 0.01). For the MAS receptor there were differences between the WT-NL/WT-L (p < 0.001) and AT2(-)-NL/AT2(- )-L (p < 0.001) groups, and also in relation to the WT-L group /AT1(-)-L (p < 0.001) and AT1(-)-L/AT2(-)-L (p < 0.001). For the expression of ACE and ACE2 peptides, there was a statistical difference only for ACE between the types of WT-NL/WT-L groups (p < 0.001). Conclusion: The animals in the AT1(-) group showed less inflammation than the other diseased lines, as well as a lower expression of the Mas and Ang 1-7 receptor. Furthermore, animals from the WT and AT2(-) groups demonstrated similar results in several analyses, showing that the blockade of the AT1 receptor, on molecular effects, is more positive (AU).

Participation of hepatic α/β-adrenoceptors and AT1 receptors in glucose release and portal hypertensive response induced by adrenaline or angiotensin II

It has been previously demonstrated that the hemodynamic effect induced by angiotensin II (AII) in the liver was completely abolished by losartan while glucose release was partially affected by losartan. Angiotensin II type 1 (AT1) and adrenergic (∝1- and β-) receptors (AR) belong to the G-proteins superfamily, which signaling promote glycogen breakdown and glucose release. Interactive relationship between AR and AT1-R was shown after blockade of these receptors with specific antagonists. The isolated perfused rat liver was used to study hemodynamic and metabolic responses induced by AII and adrenaline (Adr) in the presence of AT1 (losartan) and ∝1-AR and β-AR antagonists (prazosin and propranolol). All antagonists diminished the hemodynamic response induced by Adr. Losartan abolished hemodynamic response induced by AII, and AR antagonists had no effect when used alone. When combined, the antagonists caused a decrease in the hemodynamic response. The metabolic response induced by Adr was mainly mediated by ∝1-AR. A significant decrease in the hemodynamic response induced by Adr caused by losartan confirmed the participation of AT1-R. The metabolic response induced by AII was impaired by propranolol, indicating the participation of β-AR. When both ARs were blocked, the hemodynamic and metabolic responses were impaired in a cumulative effect. These results suggested that both ARs might be responsible for AII effects. This possible cross-talk between β-AR and AT1-R signaling in the hepatocytes has yet to be investigated and should be considered in the design of specific drugs.