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The role of the (pro)renin receptor in the development of neurogenic hypertensionBloch, Catherine 11 June 2020 (has links)
Despite the number of therapeutic interventions currently available for treating hypertension, approximately one-third of adult patients in the United States currently being treated remain hypertensive (43). As the number of hypertensive patients continues to grow, it is becoming increasingly important to investigate the different types of hypertension in order to have a greater understanding of the pathogenesis and identify potential targets for treatment. Neurogenic hypertension refers to hypertension resulting from a centrally mediated mechanism, likely involving a sustained increase in sympathetic nervous system activity. The renin-angiotensin aldosterone system (RAAS) is a physiological cascade responsible for restoring blood pressure when it drops. The rate-limiting step involves the enzyme renin. Although there is evidence of local RAAS activity in the brain, expression of renin in the brain is very low (125). The (pro)renin receptor ((P)RR) is able to bind and activate both renin and (pro)renin. Because the (P)RR and (pro)renin expression is high in the brain, it is possible that local RAAS activity is orchestrated by the (P)RR. In this study, we investigated if neuroinflammatory conditions could foster an environment that would allow for a rise in sympathetic nervous system activity (SNA) resulting from brain RAAS activity and the (P)RR. By treating neuronal cell cultures with proinflammatory cytokines, an anti-inflammatory agent, and (pro)renin, we explored any changes or differences in mRNA expression levels. Additionally, the effects of antioxidants were investigated. The results of this study showed that cells lacking antioxidants were more vulnerable to cellular stress and inflammation in the presence of increased (pro)renin. Proinflammatory stress was correlated with increased mRNA expression of proinflammatory and immune system regulatory genes in addition to increased expression of angiotensin II type I receptor, a vital component of RAAS. This could indicate that neuroinflammatory stress can be exacerbated and contribute to increased RAAS activity in the brain mediated by the (P)RR.
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Hipertensão arterial e disfunção autonômica induzidas por dieta hiperlipídica: papel do CART e de fatores inflamatórios em núcleos autonômicos do sistema nervoso central. / High blood pressure and autonomic dysfunction induced by high-fat diet: role of CART and inflammatory factors in central autonomic network.Chaar, Laiali Jurdi El 27 June 2016 (has links)
Obesidade é fator de risco para a hipertensão arterial e os mecanismos envolvidos nesta doença não são totalmente esclarecidos. Camundongos C57BL/6J e transgênicos com com deleção em neurônios e glia da via inflamatória do receptor toll-like-NFκB foram submetidos à dieta hiperlipídica (HL) por 8 e 15 semanas e avaliados parâmetros metabólicos, pressão arterial, frequência cardíaca, atividade do sistema nervoso autônomo, fatores inflamatórios e neuropeptídeos no hipotálamo e no tronco encefálico. Os camundongos expostos HL desenvolveram hipertensão arterial acompanhada de disfunção autonômica e aumento de CART no DMH. Os animais transgênicos quando submetidos à dieta HL desenvolveram um quadro de obesidade, porém não apresentaram hipertensão arterial e disfunção autonômica. Além disso, o grupo de animais HL aumentou o RNAm de CCL5 no hipotálamo e de CD86 no tronco-encefálico e a densidade de microglia no NTS caudal. Os resultados sugerem novos mecanismos para a hipertensão e disfunção autonômica secundárias à ingestão de dieta hiperlipídica mostrando o papel do CART o DMH e o envolvimento da via inflamatória do TLR-NFκB em neurônios e glia nos mecanismos desta patologia. / Obesity is a risk factor for high blood pressure and the mechanisms involved in this disease are not fully clarified. C57BL/6J and transgenic mice with toll-like-NFκB receptor inflammatory- pathway deletion in neurons and glia were fed with high-fat diet (HL) for 8 or 15 weeks and assessed metabolic parameters, blood pressure, heart rate, autonomic nervous system activity, inflammatory factors and neuropeptides in the hypothalamus and brainstem. The HL mice developed hypertension accompanied with autonomic dysfunction and increased CART in DMH. Transgenic animals when submitted to HL diet developed obesity, but not showed high blood pressure and autonomic dysfunction. In addition, HL animals had increased CCL5 mRNA in hypothalamus, CD86 mRNA in brainstem and micróglia density in caudal NTS. The results suggest new mechanisms for hypertension and autonomic dysfunction secondary to intake of high-fat diet by showing CART role in DMH and the involvement of the inflammatory pathway TLR-NFκB in neurons and glia.
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Hipertensão arterial e disfunção autonômica induzidas por dieta hiperlipídica: papel do CART e de fatores inflamatórios em núcleos autonômicos do sistema nervoso central. / High blood pressure and autonomic dysfunction induced by high-fat diet: role of CART and inflammatory factors in central autonomic network.Laiali Jurdi El Chaar 27 June 2016 (has links)
Obesidade é fator de risco para a hipertensão arterial e os mecanismos envolvidos nesta doença não são totalmente esclarecidos. Camundongos C57BL/6J e transgênicos com com deleção em neurônios e glia da via inflamatória do receptor toll-like-NFκB foram submetidos à dieta hiperlipídica (HL) por 8 e 15 semanas e avaliados parâmetros metabólicos, pressão arterial, frequência cardíaca, atividade do sistema nervoso autônomo, fatores inflamatórios e neuropeptídeos no hipotálamo e no tronco encefálico. Os camundongos expostos HL desenvolveram hipertensão arterial acompanhada de disfunção autonômica e aumento de CART no DMH. Os animais transgênicos quando submetidos à dieta HL desenvolveram um quadro de obesidade, porém não apresentaram hipertensão arterial e disfunção autonômica. Além disso, o grupo de animais HL aumentou o RNAm de CCL5 no hipotálamo e de CD86 no tronco-encefálico e a densidade de microglia no NTS caudal. Os resultados sugerem novos mecanismos para a hipertensão e disfunção autonômica secundárias à ingestão de dieta hiperlipídica mostrando o papel do CART o DMH e o envolvimento da via inflamatória do TLR-NFκB em neurônios e glia nos mecanismos desta patologia. / Obesity is a risk factor for high blood pressure and the mechanisms involved in this disease are not fully clarified. C57BL/6J and transgenic mice with toll-like-NFκB receptor inflammatory- pathway deletion in neurons and glia were fed with high-fat diet (HL) for 8 or 15 weeks and assessed metabolic parameters, blood pressure, heart rate, autonomic nervous system activity, inflammatory factors and neuropeptides in the hypothalamus and brainstem. The HL mice developed hypertension accompanied with autonomic dysfunction and increased CART in DMH. Transgenic animals when submitted to HL diet developed obesity, but not showed high blood pressure and autonomic dysfunction. In addition, HL animals had increased CCL5 mRNA in hypothalamus, CD86 mRNA in brainstem and micróglia density in caudal NTS. The results suggest new mechanisms for hypertension and autonomic dysfunction secondary to intake of high-fat diet by showing CART role in DMH and the involvement of the inflammatory pathway TLR-NFκB in neurons and glia.
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