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Modèle expérimental de fibrose rénale interstitielle induite par les acides aristolochiques («plantes chinoises»)Debelle, Frédéric 01 February 2005 (has links)
La néphropathie aux plantes chinoises (CHN) est une maladie rénale grave qui a été décrite pour la première fois en 1993 chez des patientes ayant suivi un régime amaigrissant à base d’extraits de plantes chinoises (Aristolochia fangchi) contenant des acides aristolochiques (AA). Cette néphropathie se caractérise par une atrophie tubulaire et une fibrose interstitielle aboutissant à l’urémie terminale et se complique fréquemment de cancers des voies urinaires. Au moment d’initier ce travail, il subsistait toujours un large débat quant au rôle étiologique réel des acides aristolochiques dans la genèse de cette maladie. En effet, les gélules à visée amaigrissante contenaient d’autres substances potentiellement néphrotoxiques. Mais surtout, il n’existait aucune preuve expérimentale que les AA pouvaient induire une fibrose rénale interstitielle.
Dans la première partie de ce travail, nous démontrons que l’injection par voie sous-cutanée d’AA à la dose de 10 mg/Kg/jour à des rats Wistar mâles en déplétion sodée entraîne l’apparition au 35ème jour d’une atrophie tubulaire, d’une fibrose interstitielle et d’une insuffisance rénale, reproduisant ainsi les anomalies caractéristiques de la CHN. Nous avons ensuite montré que la dexfenfluramine, substance anorexigène à action de type sérotoninergique prise concomitamment par les patientes atteintes de CHN, ne potentialise pas la toxicité rénale des AA. Enfin, la stimulation du système rénine angiotensine (SRA) par la déplétion sodée ou l’inhibition de celui-ci par un traitement pharmacologique ne modifie pas la fibrose interstitielle ni l’insuffisance rénale induite par les AA.
En conclusion, nous avons réussi à développer un modèle in vivo de fibrose rénale interstitielle induite par les AA. Dès lors nous avons apporté la preuve expérimentale de l’implication des AA dans le développement de la CHN. Ce modèle a permis de démontrer que les autres éléments potentiellement néphrotoxiques contenues dans la cure d’amaigrissement (dexfenfluramine, diurétique, laxatif) n’influençaient pas l’évolution de la fibrose interstitielle, ce qui confirme que la prise isolée d’AA suffit à expliquer le développement de la CHN. Cette confirmation à d’importantes implications en santé publique dans la mesure où des plantes contenant des acides aristolochiques font toujours partie des phytothérapies traditionnelles. De plus, il est apparu que, dans ce modèle, les mécanismes de la fibrose rénale interstitielle pouvaient être largement indépendants du SRA. Enfin, de par sa durée limitée et sa grande reproductibilité, ce modèle constitue un outil expérimental d’avenir pour l’étude des mécanismes physiopathologiques de la fibrose rénale interstitielle en général.
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Development of Salt-Sensitive Hypertension in HydronephrosisCarlström, Mattias January 2008 (has links)
<p>Hydronephrosis, due to ureteropelvic junction obstruction, is a common condition in infants with an incidence of approximately 0.5-1%. During the last decade, the surgical management of non-symptomatic hydronephrosis has become more conservative, and the long-term physiological consequences of this new policy are unclear. The overall aim of this thesis was to determine whether there is a link between hydronephrosis and the development of hypertension. Hydronephrosis was induced by partial ureteral obstruction in 3-week old rats or mice. In the adult animals, blood pressure was measured telemetrically during different sodium conditions and the renal function was evaluated. Both species developed salt-sensitive hypertension and histopathological changes (i.e. fibrosis, inflammation, glomerular and tubular changes) that correlated with the degree of hydronephrosis. An abnormal renal excretion pattern with increased diuresis and impaired urine concentrating ability was observed in hydronephrosis. The mechanisms were primarily located to the diseased kidney, as relief of the obstruction attenuated blood pressure and salt-sensitivity. Increased renin angiotensin system activity, due to ureteral obstruction, might be involved in the development but not necessary the maintenance of hypertension. Hydronephrotic animals displayed reduced nitric oxide availability, which might be due to increased oxidative stress in the diseased kidney. Renal nitric oxide deficiency and subsequent resetting of the tubuloglomerular feedback mechanism, appeared to have an important role in the development of hypertension. In conclusion, experimental hydronephrosis, induced by partial ureteral obstruction, provides a new model for studies of salt-sensitive hypertension. Furthermore, the new findings imply that the current conservative treatment strategy in hydronephrosis should be reconsidered in favour of treatment that is more active, in order to prevent the development of renal injury and hypertension in later life.</p>
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Single Nucleotide Polymorphisms Linked to Essential Hypertension in Kasigau, KenyaFreeman, Julia Carol 01 December 2013 (has links)
Hypertension, or high blood pressure (BP), is an ever-growing epidemic in the developing world. Understanding the genetics behind essential hypertension (EH), or hypertension with no known cause, is especially important. In this study, three single nucleotide polymorphisms (SNPs) known to be linked to an increase in susceptibility to EH were quantified from a cohort of Kenyans living in the Kasigau region. The SNPs are located in three genes that are part of the renin angiotensin system, the primary regulatory pathway in humans controlling BP. They include: AGT (rs699), AGTR1 (rs5186), and HSD11β2 (rs5479). Overall, by using a fluorescent-based RT-PCR technique, the genotype distribution of AGT (rs699) was 0.63 C/C, 0.34 C/T, and 0.03 T/T. When evaluated as normotensive, prehypertensive, Stage I, or Stage II categories the allele frequencies for f(C)= 0.77,0.85,0.81, 0.77, respectively, and demonstrated Hardy Weinberg Equilibrium (HWE) as assessed by Χ2, p < 0.05. The genotype distribution of AGTR1 (rs5186) was 0.96 A/A, 0.03 A/C, and 0.00 C/C and the genotype distribution of HSD11β2 (rs5479) was 0.46 A/A, 0.46 A/C, and 0.08 C/C. The majority of genotype frequencies for each SNP were in HWE, with the exception of the AGT (rs699) SNP found in the sublocation of Bughuta suggesting other evolutionary selective pressures may be at work in this subpopulation. The high prevalence of the susceptible C allele for AGT (rs699) likely implies it is a critical factor in the high prevalence of EH observed in this population.
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Modèles murins de prééclampsie et effets préventifs de l’entraînement physiqueFalcao, Stéphanie 01 1900 (has links)
La prééclampsie est la première cause de mortalité et de morbidité périnatale et aucun traitement, mis à part l’accouchement, n’est connu à ce jour. Pour mieux comprendre cette maladie, nous avons utilisé trois modèles animaux. Dans un premier temps, nous avons voulu confirmer la présence de prééclampsie chez les souris déficientes en p57kip2, une protéine impliquée dans le cycle cellulaire des trophoblastes. Contrairement au groupe japonais, l’hypertension et la protéinurie au cours de la gestation ne survenaient pas, malgré une perte de structure des trophoblastes dans le labyrinthe ainsi qu’une microcalcification au niveau de leurs placentas. Nous avons alors observé que la diète japonaise induisait à elle seule une diminution de la croissance fœtale, ainsi qu’une dysfonction endothéliale chez ces souris. Nos résultats démontrent que ni les altérations placentaires, ni la génétique ne sont suffisantes pour induire les symptômes de la prééclampsie dans ce modèle, et que la diète peut avoir des effets délétères chez la souris gestante peu importe le génotype. Ensuite, nous avons démontré que les souris hypertendues surexprimant la rénine et l’angiotensinogène humaine développent de la protéinurie et une augmentation de la pression artérielle au cours de la gestation. Leurs placentas sont affectés par de la nécrose et une perte de structure des trophoblastes du labyrinthe en plus de surexprimer le gène du récepteur sFlt-1. Ces souris représentent le premier modèle animal de prééclampsie superposée à de l’hypertension chronique. Finalement, en utilisant des femelles normotendues surexprimant l’angiotensinogène humaine qui développent les symptômes de la prééclampsie lorsqu’elles sont accouplées à des mâles qui surexpriment la rénine humaine, nous avons établi que l’entraînement physique normalisait la hausse de pression ainsi que l’apparition de protéinurie en fin de gestation. Aussi, l'entraînement améliorait la croissance fœtale et placentaire ainsi que la réponse vasculaire indépendante de l’endothélium, et ce, indépendamment du génotype des souris. La présence d’une prolifération exagérée et désorganisée des trophoblastes dans ce modèle était aussi normalisée. L’entraînement physique prévient donc l’apparition des symptômes de la prééclampsie dans ce modèle. Mis ensemble, nos résultats aideront à mieux comprendre les mécanismes à l’origine de la prééclampsie et de sa prévention. / Preeclampsia is the primary cause of maternal and foetal mortality and morbidity and no treatment, apart from delivery are known to date. To better understand this pathology, we investigated three different animal models. First, we needed to confirm preeclampsia-like symptoms in p57kip2 deficient mice, a protein implicated in the trophoblast cell cycle. Conversely to the Japanese group, we observed neither hypertension nor proteinuria in this model. However their placentas showed labyrinthine trophoblast structure loss as well as microcalcification. We therefore studied the impact of Japanese diet, which induced foetal growth restriction and endothelial dysfunction independently from genotype. Our results demonstrate that placental alterations and genetics are not sufficient to induce preeclampsia-like symptoms in this model, and that diet can have deleterious effects on pregnant mice, independently from genotype. We then demonstrated that hypertensive mice overexpressing human angiotensinogen and renin developed de novo proteinuria and had a significant increase of their hypertension during gestation. Their placentas are affected by necrosis and labyrinthine trophoblast structure loss as well as an overexpression of sFlt-1 receptors. These mice represent the first animal model of superimposed preeclampsia on chronic hypertension. Finally, we used normotensive females overexpressing human angiotensinogen, which develop preeclampsia-like symptoms when they are mated with males overexpressing human rennin, to establish that exercise training normalised hypertension and proteinuria at the end of gestation. Moreover, exercise training ameliorates foetal and placental growth as well as endothelium-independent relaxation, independently from the genotype. Exaggerated and disorganised proliferation of trophoblasts in this model is also normalised. Exercise training prevents preeclampsia-like symptoms in this model. Taken together, our results will help a better understanding of this disease and its prevention.
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Effet du bosentan sur les niveaux d'inflammation systémique et rénale chez des patients avec néphropathie diabétique traités par bloqueurs de récepteurs de l'angiotensine IITubail, Zead 05 1900 (has links)
Outre les facteurs métaboliques et hémodynamiques, l’inflammation est actuellement considérée comme un facteur pathogénique potentiel de la néphropathie diabétique (ND), pouvant contribuer à l’initiation et à la progression de la maladie. Les mécanismes menant au développement de l’inflammation rénale dans la ND sont encore peu connus, bien qu’une augmentation d’activité des systèmes rénine angiotensine (RAS) et de l’endothéline (ET) semble y contribuer. L’objectif général de cette étude mono-centre, à double aveugle, randomisée et incluant un groupe placebo était de démontrer que l’inhibition simultanée du RAS et du système de l’ET chez des patients avec ND induisait des effets rénoprotecteurs et anti-inflammatoires supérieurs à ceux observés par blocage du RAS seul. L’objectif spécifique de notre étude était d’évaluer la possibilité que l’administration d’un bloqueur des récepteurs de l’ET-1, le bosentan, à des patients atteints de ND et traités par bloqueurs des récepteurs de l’angiotensine II (BRA), réduisait, chez ces derniers, la protéinurie et les marqueurs inflammatoires systémiques et rénaux. Ce travail constitue un rapport d’un cas clinique et illustre les résultats obtenus suite à l’administration pendant 16 semaines du bosentan chez un patient diabétique de type 2 avec néphropathie clinique traité au long cours par BRA. Le protocole de recherche comprenait 6 visites médicales à 4 semaines d’intervalle, la première visite (V1) correspondant au recrutement du patient, la deuxième visite (V2) constituant le temps 0 de l’étude et la dernière visite (V6) représentant la fin de l’étude. Des échantillons de sang et d’urine étaient prélevés à 3 reprises soit à V2, V4 c’est-à-dire 8 semaines après le début du traitement et à V6 soit 16 semaines après le début du traitement pour mesure des taux sériques et urinaires de divers facteurs pro-inflammatoires incluant l’ET-1, le facteur de nécrose tumorale alpha (TNF-α), l’interleukine-6 (IL-6), le facteur chémoattractant des monocytes-1 (MCP-1), la molécule d’adhésion intracellulaire-1 (ICAM-1), la molécule d’adhésion vasculaire-1 (VCAM-1) et la protéine C-réactive (CRP). Un profil lipidique était aussi déterminé au début et à la fin de l’étude. La fonction rénale était mesurée aux visites V1, V2, V4 et V6 par détermination du taux de filtration glomérulaire (TFG) et de l’excrétion urinaire d’albumine (UAE). Des tests biochimiques de routine étaient aussi faits à chaque visite. La corrélation entre les paramètres inflammatoires et rénaux sous étude et la filtration glomérulaire était enfin déterminée. Nos résultats chez ce sujet ont démontré que le bosentan réduisait l’UAE de 32 % et 35% aux semaines 8 et 16, et ce, sans affecter la pression artérielle ou la filtration glomérulaire. L'effet anti-protéinurique du bosentan était associé à une réduction des concentrations urinaires de VCAM-1, ICAM-1, IL-6, TNF-α et d’ET-1 ainsi qu’à une diminution des concentrations sériques de TNF-α. Le changement dans la protéinurie était corrélé de manière positive avec les changements des niveaux urinaires de VCAM-1 (r=0.86), ICAM-1 (r=0.88), ET-1 (r=0.94), et du TNF-α (r=0.96) ainsi qu’avec les changements des niveaux sériques de TNF-α (r=0.98). Ces données suggèrent que l’inhibition du système de l’ET induit dans la ND des effets rénoprotecteurs additifs à ceux observés par blocage du RAS seul. Ils supportent le concept que l’activation du système de l’ET au niveau rénal, par ses effets inflammatoires, puisse jouer un rôle important dans la pathogenèse de la ND. L’effet anti-inflammatoire et anti-protéinurique du bosentan constitue une découverte intéressante susceptible d’engendrer dans le futur une alternative thérapeutique et préventive dans la prise en charge de la ND. / Apart from metabolic and hemodynamic factors, inflammation has recently been introduced as a potential key pathogenic mechanism involved in the development and progression of diabetic nephropathy (DN). The mechanisms by which renal inflammation occurs in DN are still poorly understood, yet increased renal activity of the renin-angiotensin system (RAS) and endothelin (ET) system may play a key role. The main objective of this mono-centre, double blind, randomized, placebo-controlled study was to demonstrate that concomitant blockade of the RAS and ET system in patients with DN produces greater renal protective effects and exerts greater anti-inflammatory changes than those seen with blockade of the RAS system alone. The specific aim of the study was to evaluate whether administration of bosentan to patients with DN on angiotensin II receptor blockers (ARB) reduces systemic and renal inflammation and improves glomerular filtration. The work presented herein illustrates the results obtained in one type 2 diabetic patient with clinical DN and treated with ARB following the administration of bosentan for 16 weeks. The study protocol included 6 medical visits at 4 weeks interval, with the first visit (V1) being the screening visit and the second visit (V2) being the baseline and randomization visit. Blood and urine samples were taken at V2, after 8 weeks of treatment (V4), and at the end of the study (V6) for determination of serum and urinary inflammatory markers including ET-1, tumour necrosis factor alpha (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and C-reactive protein (CRP). Lipid profile was done at the beginning and end of the study. Renal function was assessed at V1, V2, V4 and V6 by determination of glomerular filtration rate and urinary albumin excretion (UAE). Routine biochemical analyses were done at each visit. Correlation between serum and urinary inflammatory markers and UAE was determined. Our results demonstrated that bosentan administration to this patient reduced UAE by 32% and 35% at weeks 8 and 16, respectively, without affecting blood pressure and glomerular filtration. The anti-proteinuric effect of bosentan was associated with a reduction in urinary levels of VCAM-1, ICAM-1, IL-6, TNF- and ET-1 and a reduction in serum TNF- levels. Change in UAE was positively correlated with changes in urinary levels of VCAM-1 (r=0.86), ICAM-1 (r=0.88), ET-1 (r=0.94), and TNF- (r=0.96) and with change in serum TNF- levels (r=0.98). Our data suggest that blockade of the ET system in top of RAS inhibition exerts additive renoprotective effects in DN. They support the notion that activation of the ET system, by promoting renal inflammation, may play a role in the pathogenesis of DN. The anti-inflammatory and anti-proteinuric effect of bosentan represents an interesting finding which may leads in the future to an alternate therapeutic and preventive for the treatment of DN.
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Dissection du rôle fondamental de l'hyperglycémie sur la morphogenèse rénaleTran, Stella Lê Minh January 2008 (has links)
Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.
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Avaliação da influência do tecido adiposo perivascular (PVAT) na reatividade vascular da aorta de ratos com insuficiência cardíaca submetidos ao treinamento físico aeróbio e resistido. / Evaluation of the influence of perivascular adipose tissue on the vascular reactivity of the aorta of rats with heart failure submitted to aerobic and resistance training.Fontes, Milene Tavares 15 February 2019 (has links)
O tecido adiposo perivascular (PVAT) libera substâncias dilatadoras e constritoras, sendo que as dilatadoras se sobrepõem, exercendo efeito anticontrátil. Esse efeito está prejudicado na presença de algumas doenças cardiovasculares. Na insuficiência cardíaca (IC) ocorrem danos ao sistema vascular, todavia nenhum estudo avaliou a função do PVAT na IC. A utilização do treinamento físico (TF) tem sido recomendada com terapia não farmacológica eficiente em promover benefícios ao sistema cardiovascular. As recomendações sugerem que o exercício resistido seja adicionado aos programas de TF para pacientes com IC, podendo, assim, o treinamento combinado (TC; aeróbio e resistido) fornecer benefícios adicionais à saúde cardiovascular. Com isso, o objetivo do presente trabalho foi avaliar o papel do PVAT na reatividade vascular da aorta torácica dos ratos com IC e, após, avaliar a influência do TC na resposta anticontrátil do PVAT da aorta torácica e abdominal de ratos saudáveis e com IC. Ratos Wistar foram submetidos à oclusão da artéria coronária descendente ou falso operado (SO). Após 4 semanas, para o estudo sem TC os animais foram mantidos sem intervenção, e para o estudo que envolvia o TC foram divididos em sedentários (SOs e ICs) e treinados (SOt e ICt, esteira e escada, 5 x/sem., 8 sem.). Anéis da aorta torácica e/ou abdominal com (E+) e sem endotélio (E-), na presença (PVAT+) ou na ausência do PVAT (PVAT-), foram montados em miógrafo de arame e curvas concentração-resposta à fenilefrina (FEN, 10-910-5M) foram realizadas. A IC promoveu aumento da contração FEN nos anéis E+/PVAT- da aorta torácica quando comparado aos SO, e o efeito anticontrátil do PVAT foi prejudicado pela IC nos anéis E+/PVAT+ e E-/PVAT+. O prejuízo no efeito anticontrátil do PVAT foi acompanhado por maior atividade da ECA1 e da expressão dos AT1R, AT2R e MASR no PVAT dos animais com IC. O antagonismo dos AT1R, AT2R e MASR promoveram redução da resposta contrátil nos anéis E+/PVAT- nos IC, nos anéis E+/PVAT+ essa redução foi superior apenas para o antagonismo do AT1R e AT2R. A produção de espécies reativas de oxigênio (ERO) na aorta torácica e PVAT dos animais IC foi maior que nos SO, acompanhada por uma menor biodisponibilidade de NO. O TC aumentou a capacidade física nos SOt e ICt. Na aorta torácica o TC reverteu parte do prejuízo da função anticontrátil do PVAT, aumentou a expressão do PRDM-16 e ESPST-1 que estavam reduzidos na IC, além disso, melhorou a biodisponibilidade de NO no PVAT pela maior expressão da eNOS, β3-AR e AMPk1/2α, aumentou a concentração de adiponectina e reduziu marcadores pró-inflamatórios. Na aorta abdominal, o efeito anticontrátil do PVAT não estava presente e o TC reverteu a disfunção endotelial dos animais com IC, aumentando a biodisponibilidade de NO e a expressão da eNOS na aorta. Em conclusão, na IC os AT1R e AT2R contribuem tanto para a disfunção endotelial quanto do PVAT, reduzindo a biodisponibilidade de NO e aumentando a produção de ERO. O TC melhorou a função anticontrátil na aorta torácica, por benefícios na via de sinalização α3-AR/Adiponectina/AMPK/eNOS, modificando o perfil morfológico e inflamatório do PVAT. Já na aorta abdominal, o TC melhorou a função vascular, aumentando a biodisponibilidade de NO. / Perivascular adipose tissue (PVAT) releases dilating and constricting substances, and the dilators overlap, exerting an anti-contractile effect. This effect is impaired in the presence of some cardiovascular diseases. In heart failure (HF) damage to the vascular system occurs, however, no study has evaluated the function of PVAT in HF. The use of physical training (PT) has been recommended with non-pharmacological therapy effective in promoting cardiovascular system benefits. The recommendations suggest that resistance exercise be added to the PT programs for patients with HF, thus, combined training (CT, aerobic and resisted) may provide additional cardiovascular health benefits. The objective of the present study was to evaluate the role of PVAT in the vascular reactivity of the thoracic aorta of HF rats and, after that, to evaluate the influence of CT in the anti-contractile response of PVAT of the thoracic and abdominal aorta of healthy and HF rats. Wistar rats were submitted to descending coronary artery occlusion or false operated (SO). After 4 weeks, for the study without CT, the animals were kept without intervention, and for the study involving the CT were divided into sedentary (SOs and HFs) and trained (SOt and HFt, treadmill and ladder, 5 x/8 sem.). In the presence (PVAT+) or in the absence of the PVAT (PVAT-), thoracic and/or abdominal aorta with (E+) and without endothelium (E-), were mounted on wire myograph and concentration-response curves to phenylephrine, (PHE, 10-9-10-5M) were performed. HF promoted an increase in PHE contraction in the E+/PVAT- rings of the thoracic aorta when compared to SO, and the ani-contratile effect of PVAT was impaired by HF in the E+/PVAT+ and E-/PVAT+ rings. The impairment in the anti-contratile effect of PVAT was accompanied by increased activity of ECA1 and the expression of AT1R, AT2R and MASR in the PVAT of animals with HF. The AT1R, AT2R and MASR antagonism promoted a reduction of the contractile response in the E+/PVAT- rings in the HF, in the E+/PVAT+ rings, this reduction was superior only to the antagonism of AT1R and AT2R. The production of reactive oxygen species (ROS) in the thoracic aorta and PVAT of the HF animals was higher than in the SO, accompanied by a lower NO bioavailability. CT increased physical capacity in SOt and HFt. In the thoracic aorta CT reversed part of the impairment of PVAT anti-contratile function, increased the expression of PRDM-16 and ESPST-1 that were reduced in HF, in addition, it improved the bioavailability of NO in PVAT by the greater expression of eNOS, β3-AR and AMPk1/2 α, increased the concentration of adiponectin and reduced proinflammatory markers. In the abdominal aorta, the anti-contratile effect of PVAT was not present and CT reversed the endothelial dysfunction of HF animals, increasing NO bioavailability and eNOS expression in the aorta. In conclusion, in HF, AT1R and AT2R contribute to both endothelial and PVAT dysfunction, reducing NO bioavailability and increasing ROS production. CT improved the anti-contractile function in the thoracic aorta due to benefits in the β3-AR/Adiponectin/AMPK/eNOS signaling pathway, modifying the morphological and inflammatory profile of PVAT. Already in the abdominal aorta, the CT improved the vascular function, the CT improved the vascular function, increasing the bioavailability of NO.
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Efeitos crônicos da angiotensina II sobre a atividade e expressão da isoforma 3 do trocador Na+/H+. / Chronic effects of angiotensin II on the isoform 3 of Na+/H+ exchanger (NHE3).Leite, Gabriella Duarte Queiroz 23 March 2011 (has links)
NHE3 reabsorve a maior parte de Na+ em túbulos proximais e é agudamente modulado por Ang II de forma bimodal. O objetivo deste trabalho foi avaliar os efeitos crônicos da Ang II sobre a atividade, expressão e atividade promotora de NHE3. A atividade de NHE3 foi avaliada na presença de veículo, inibidor de NHE1, 2 e 3 e H+ ATPase. Houve redução da recuperação do pHi na presença do inibidor de NHE3. Células foram expostas por 24h a Ang II de 10-7M a 10-12 M e houve aumento de atividade com Ang II 10-11 M. Houve aumento na expressão de NHE3 e no seu RNAm. Actinomicina D não mostrou diferença entre os tempos de ½ vida do RNAm. Transfecções transitórias de fragmentos do promotor de NHE3 de rato mostraram que a atividade do fragmento -65/+31 aumentou na presença de Ang II. Mutações em sítios para a ligação de Sp1/Egr-1 e AP2 mostraram que o sítio Sp1/Egr-1 é fundamental para esse efeito. As vias que envolvem o citocromo P450, PI3K, PKA e MAPK são ativadas, porém, as vias da PLC e JAK/STAT não. Losartan aboliu os efeitos observados. Conclui-se que a exposição crônica à baixa concentração de Ang II promoveu aumento na atividade, expressão, nível de RNAm e atividade promotora do gene NHE3 via AT1R. O sítio de ligação para os fatores de transcrição Sp1/Egr-1 está envolvido nessa resposta. / NHE3 is the major responsible for the sodium reabsorption in proximal tubules and it is Ang II acutely modulated in a bimodal fashion. The aim of this study was to evaluate the chronic effects of Ang II on NHE3 activity, transcription and expression. The NHE3 activity was evaluated in the presence of vehicle, NHE1, 2 and 3 and H+ ATPase inhibitors. Presence of NHE3 inhibitor reduced the rate of pHi recovery. Cells were treated with Ang II 10-7M to 10-12 M for 24h and Ang II 10-11 M increased the pHi recovery rate. NHE3 protein and mRNA were increased in Ang II presence. NHE3 mRNA ½ life in Actinomycin D incubated cells was not affected by Ang II treatment. Transient transfections of fragments of rat NHE3 promoter showed that the activity of -65/+31 was increased in Ang II presence. Mutation at Sp1/Egr-1 and AP2 sites in the -60/+31 fragment showed that Sp1/Egr-1 integrity is required. Cytochrome P450, PI3K, PKA and MAPK signaling pathways are related with this effect, while PLC and JAK/STAT are not. Losartan abolished the observed effects. In conclusion, chronic treatment with low concentration of Ang II resulted in increase of NHE3 activity, protein expression, mRNA levels and promoter activity of NHE3 gene through AT1R. Sp1/Egr-1 site seems to be involved in this effect.
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Avaliação da contribuição do receptor AT1 de angiotensina II e do papel da via de sinalização AKT/GSK-3/mTOR no processo de hipertrofia do cardiomiócito induzido pelo hormônio tiroideano / Angiotensin type 1 receptor mediates Thyroid Hormone-induced cardiomyocyte hypertrophy through the Akt/GSK-3ß/mTOR signaling pathwayDiniz, Gabriela Placoná 12 February 2010 (has links)
O presente estudo avaliou o papel do receptor AT1 de Angiotensina II no desenvolvimento da hipertrofia dos cardiomiócitos promovida pelo T3, bem como a participação dos mecanismos intracelulares deflagrados pelo receptor AT1 neste modelo de hipertrofia cardíaca. O silenciamento do receptor AT1 com RNA de interferência preveniu totalmente o desenvolvimento da hipertrofia dos cardiomiócitos induzida pelo T3. Os cardiomiócitos tratados com T3 demonstraram uma rápida ativação da via da Akt/GSK-3/mTOR, a qual foi atenuada ou prevenida pelo silenciamento do receptor AT1. Ainda, a expressão de Angiotensina I/II no lisado celular e a expressão do receptor AT1 foram rapidamente aumentados pelo T3. Esses dados demonstram pela primeira vez que o receptor AT1 é um mediador crítico da hipertrofia dos cardiomiócitos induzida pelo T3, bem como para a ativação da via da Akt, sugerindo que a via Ang I/II-AT1-Akt/GSK-3/mTOR corresponde a um potencial mediador dos efeitos tróficos exercidos pelo T3 nessas células. / The present study investigated the role of Angiotensin type 1 receptor (AT1R) in T3-induced cardiomyocyte hypertrophy, as well as the participation of the intracellular mechanisms mediated by AT1R in this cardiac hypertrophy model. The AT1R silencing using small interfering RNA totally prevented the development of T3-induced cardiomyocyte hypertrophy. The cardiomyocytes treated with T3 demonstrated a rapid activation of Akt/GSK-3/mTOR signaling pathway, which was attenuated or prevented by the AT1R silencing. In addition, local Angiotensin I/II (Ang I/II) levels and the AT1R expression were rapidly increased by T3 treatment. These data demonstrate for the first time that the AT1R is a critical mediator to the T3-induced cardiomyocyte hypertrophy, as well as to the activation of the Akt signaling, suggesting that the Ang I/II-AT1R-Akt/GSK-3/mTOR pathway corresponds to a potential mediator of the trophic effect exerted by T3 in cardiomyocytes.
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Alterações do Sistema Renina-Angiotensina na artéria carótida contralateral à lesão por cateter balão / Alterations in the Renin-Angiotensin System in the contralateral carotid artery after balloon catheter injuryOlivon, Vania Claudia 20 April 2010 (has links)
Quinze dias após a lesão por cateter balão, observou-se que o efeito máximo da Ang II na artéria contralateral à lesão está aumentado em relação aos valores obtidos em artérias de animais intactos. Esse aumento do Emax da Ang II não é modificado na ausência do endotélio. A lesão por cateter balão não acarreta alterações morfológicas e morfométricas da artéria contralateral à lesão quando comparadas àquelas observadas na artéria de animais controle. A desenervação simpática com 6-hidrodopamina e a desnervação sensorial com capsaicina revertem o aumento do Emax da Ang II na artéria contralateral à lesão por cateter balão. As curvas concentração-efeito para o angiotensinogênio e para Ang I apresentam o mesmo perfil na artéria contralateral à lesão por cateter balão e na artéria de animais controle. Na presença do endotélio, o losartan (antagonista do receptor AT1) e PD 123,319 (antagonista do receptor AT2) antagonizaram de forma não-superável os efeitos contráteis da Ang II em artérias de animais controle e contralateral à lesão. Observou-se, ainda, que o efeito vasorelaxante de altas concentrações de Ang II é revertido para efeitos vasoconstrictores na presença dos antagonistas seletivos dos receptores AT1, Mas e B2, tanto em artérias de animais controle quanto em artérias contralaterais à lesão. Entretanto, o Emax da Ang II nessas condições é maior na artéria contralateral à lesão. Em artéria contralateral à lesão observou-se aumento na expressão dos receptores AT2 e Mas, enquanto receptores AT1 apresenta o mesmo perfil de expressão daquele observado em artéria de animais controle. A Ang (1-7) induz relaxamento em artérias com e sem endotélio. O parâmetro de Emax da Ang (1-7) está significativamente aumentado na artéria contralateral na presença e ausência de endotélio. O Emax da Ang II, em artérias controle com endotélio, na presença de inibidores da enzima NOS, está aumentada, enquanto que na artéria contralateral este parâmetro não sofre alteração. A produção dos metabólitos do óxido nítrico (nitrito e nitrato) está reduzida na artéria contralateral à lesão quando comparado ao observado em artérias de animais controle, bem como a expressão de todas as isoformas da NOS. A lesão por cateter balão promove aumento na formação de EROs na artéria contralateral à lesão, que desaparece na presença de tiron (seqüestrador de EROs). A lesão também induz aumento na expressão da enzima p22phox, subunidade do sistema NADPH oxidase. O Emax da Ang II em artéria contralateral à lesão na presença de Tiron é semelhante ao observado em artérias de animais controle na ausência do seqüestrador. Em conclusão, a lesão por cateter balão promove respostas neurocompensatórias e aumento do estresse oxidativo em artéria contralateral à lesão. Estas alterações podem influenciar a expressão do receptor AT2 e Mas, e também mecanismos intracelulares desencadeados pela ativação de receptores AT1 e Mas. / Fifteen days after balloon catheter injury Emax of Ang II was increased in the contralateral artery as compared to values obtained in arteries from intact animals. This increase in Ang II Emax was not modified in the absence of the endothelium. The morphological and morphometric characteristics in the contralateral artery were not altered as compared to control animals. The sympathetic desnervation and sensory desnervation abolished the increase Emax of Ang II in the contralateral artery. The concentration-effect curves to angiotensinogen and Ang I were similar in contralateral arteries and in control arteries. In the presence of endothelium, losartan (AT1 antagonist receptor) and PD 123,319 (AT2 antagonist receptor) showed noncompetitive antagonistic characteristics in control arteries and contralateral artery. It was also observed that vasorelaxant effect of high concentrations of Ang II was reversed to vasoconstrictors effects in the presence of selective antagonists of AT1 receptors, Mas receptors and B2 receptors in the control arteries and contraalteral arteries. However, Emax of Ang II in these conditions was greater in contralateral artery. Contralateral artery showed increased expression of AT2 and Mas receptors, while AT1 have the same expression when compared to control arteries. Ang (1-7) triggered concentration response curves in arteries with and without endothelium. However, was observed Emax Ang (1-7) values was significantly increased in the contralateral artery in presence or absence of endothelium. Emax of Ang II in control arteries with endothelium in the presence of NOS isoforms inhibitors was increased, whereas the contralateral artery this parameter was the same. Nitrite and nitrate production was reduced in the contralateral artery when compared to control artery. NOS isoforms expression were reduced in contralateral artery. Balloon catheter injury increased ROS formation in contralateral artery, which abolished in the presence of tiron (ROS scavenger). The injury also induced increased p22phox enzyme expression, subunit of the NADPH oxidase system. Ang II Emax in the contralateral artery in the presence of tiron was similar as obtained in control arteries without tiron. In conclusion, the balloon catheter injury promoted neurocompensatory responses and increased oxidative stress in the contralateral artery. These changes increased AT2 and Mas receptor expression and also intracellular mechanisms triggered by activation of AT1 receptors.
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