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Design And Synthesis Of Novel Angiotensin Converting Enzyme (ACE) Inhibitors Having Antioxidant ActivityBhuyan, Bhaskar Jyoti 07 1900 (has links) (PDF)
Angiotensin converting enzyme (ACE) catalyzes the conversion of angiotensin I (Ang I) to angiotensin II (AngII). ACE also cleaves the terminal dipeptide of vasodilating hormone bradykinin (a nonapeptide) to its inactive form. Therefore, inhibition of ACE is one of the treatments of hypertension. A number of ACE inhibitory antihypertensive drugs are known. ‘Oxidative stress’ is another disease state caused by an imbalance in the production of oxidants and antioxidants in the body. A number of studies suggest that hypertension and oxidative stress are interdependent. Therefore, ACE inhibitors having antioxidant property are considered beneficial for the treatment of hypertension.
Generally, selenium compounds exhibit better antioxidant behavior than their sulfur analogues. Therefore, we have synthesized a number of selenium analogues of captopril, an ACE inhibitor used as antihypertensive drug. Similar to captopril, the selenium analogues of captopril exhibited excellent ACE inhibition property. It was observed that these compounds are very good scavengers of peroxynitrite (PN), a strong oxidizing as well as nitrating agent found in vivo. The orientation of the chiral centers in these compounds was found to be very important for their ACE inhibition behavior.
A number of selenocysteine- and cysteine-containing dipeptides and tripeptides were synthesized as inhibitors of ACE. It was observed that the ACE inhibition properties of these compounds depend on various factors such as orientation of the amino functionality, substitution at the C-terminal of the inhibitor, ring size of the proline moiety or the availability of the terminal acid group in carboxylate form etc. A structure-function correlation was drawn for the ACE inhibition properties of the peptide-based selenium-or sulfur-containing compounds. These studies reveal that the antioxidant properties do not depend on the side-chain functional groups, but they depend on the availability of selenium or sulfur centers. Selenium-based compounds were found to be better antioxidants than those containing sulfur moieties. In conclusion, the present study reveals that the replacement of sulfur atom in captopril and its analogues by selenium enhances the antioxidant activity.
The reaction products of lactoperoxidase (LPO)-catalyzed iodination of Ang II were separated and characterized. It was observed that LPO-catalyzed iodination of Ang II takes place preferentially at the tyrosine residue. LPO-catalyzed iodination of Ang II is inhibited by commonly used antithyroid drugs such as MMI, MTU, PTU and also by antihypertensive drug captopril. It was also observed that the monoiodo Ang I is a better substrate for ACE compared to the natural substrate Ang I. The site of nitration of Ang II by PN was also determined by MS-MS analyses. This study reveals that the nitration takes place at the tyrosine residue.
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Padrão de expressão gênica e localização tecidual no rato de um novo membro do Cluster gênico da enzima conversora da angiotensina I: variante-4 / Gene and tissue expression pattern of a novel member of the angiotensin converting enzyme-I gene cluster in the rat: variant-4Kátia Regina Maruyama Gomes 31 January 2008 (has links)
O sistema renina-angiotensina (SRA) é de fundamental importância para a manutenção da homeostasia cardiovascular. A enzima conversora de angiotensina I (ECA) é um elemento crítico na cascata de ativação das diversas substâncias ativas do SRA. Evidências obtidas em nosso laboratório por análise de genômica comparativa e confirmadas através de clonagem de segmentos de cDNA sugerem que esta família de proteínas está incompleta. Nossos dados apontam para existência de duas novas isoformas da ECA, que aqui denominaremos Variante-3 (Var-3) e Variante-4 (Var-4), localizadas no mesmo locus da ECA. Neste trabalho, analisamos simultaneamente o padrão de expressão das 4 Variantes da ECA e ECA2 em 30 tecidos do rato utilizando a técnica de qRT-PCR. A Variante 4, cuja ação ainda é desconhecida e está sendo investigada em nosso laboratório, apresenta predominantemente expressão no testículo e em quantidade relativamente baixa no ventrículo esquerdo. Utilizando a técnica de hibridização in situ no testículo, verificamos que a marcação positiva da Var- 4 pode ou não ser co-localizada com a Var-2 dependendo do estágio celular em que se encontra no túbulo seminífero. Verificou-se que as espermátides redondas são as células que expressam a Var-4 nos túbulos seminíferos. Em conjunto, estes dados mostram que as Variantes 1, 2, 3 e 4 da ECA apresentam expressão tecido-específica. O padrão de expressão da Var-4, principal objeto deste trabalho, é consistente com a idéia de que esta variante gênica pode estar envolvida com o controle da espermatogênese e em processos cardíacos, até então não caracterizados / The renin-angiotensin system (RAS) is essential to maintain the cardiovascular homeostasis. The angiotensin-converting enzyme (ACE) is a critical point in the biochemical activation of several active substances, notably angiotensin II. Evidence obtained in our laboratory using comparative genomic analysis and confirmed by cDNA cloning suggests that this protein family is incomplete and point to the existence of two new isoforms of ACE that from now on are denominated Variant-3 (Var-3) and Variant-4 (Var-4), located within the same ACE locus. In the present work we simultaneously analyzed the expression pattern of the 4 ACE gene variants in 30 different tissues of rats. The variant 4, whose mechanism of action remains unknown and it is being presently investigated in our laboratory is mainly expressed in testis and in relatively low quantity in left ventricle. Using in situ hybridization technique in testis, we verified that positive labeling of Var-4 is distinct from Var-2, suggesting that they may play distinct functions during the spermatogenesis process. Taking together, we provide direct evidence that the ACE gene locus contain, 4 variants instead of 2 and they show a specific cell tissue pattern of expression. Mostly important, the Var-4 is primarily expressed in testis and the data suggest that it may be involved with spermatogenesis control, and in cardiac processes presently unknown
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Implication du tissu adipeux dans le développement de la prééclampsie et l’effet bénéfique de l’entrainement physiqueCoutu, Kevin 06 1900 (has links)
No description available.
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Účinky L-serinu a vliv anestézie na regulaci krevního tlaku u normotenzních a hypertenzních potkanů / L-serine induced effects on blood pressure in normotensive and hypertensive rats: the influence of anesthesiaBencze, Michal January 2012 (has links)
Anesthetics cause profound alterations in respiratory and cardiovascular systems. Our experiments demonstrated that different anesthetics caused different changes in blood pressure regulating components. The role of particular BP regulating systems was disclosed by their selective inhibition - sympathetic nervous system blocked by pentolinium (peripheral ganglionic blockade), renin-angiotensin system by captopril (angiotensin converting enzyme blocker) and nitric oxide production by L-NAME (nitric oxide synthase blocker). Components of blood pressure regulating mechanisms in conscious normotensive Wistar rats and spontaneously hypertensive rats were compared with four different groups of anesthetized rats by pentobarbital, ketamine-xylazine, chloralose-urethane and isoflurane. Each anesthesia caused different hemodynamic changes. If hemodynamic conditions should be similar to conscious rats, the most suitable anesthetic is pentobarbital. L-serine-induced effects represent endothelium-derived hyperpolarizing factor (EDHF)-mediated response, which is a type of endothelium-dependent regulation of vascular tone, independent of nitric oxide and prostacyclin production. Pronounced L-serine effects on blood pressure were shown in NO-deficient type of hypertension. Our study demonstrated its pronounced effects in...
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Úloha vybraných vazoaktivních systémů v rozvoji chronického onemocnění ledvin / Contribution of particular vasoactive systems in the development of chronic kidney diseaseDrábková, Natálie January 2019 (has links)
Chronic kidney disease (CKD) is a life-threating disease which arises as a frequent consequence of diabetes and hypertension. Since it is going on silently, CKD often progresses to the end-stage renal disease. It is therefore necessary to combat this disease especially due to the fact that the world population is growing old. The aim of this work was to determine the contribution of selected vasoactive systems contributing to the maintenance of high blood pressure in the developmental and established phase of CKD. Two models of CKD were used: 5/6 nephrectomy in Ren-2 transgenic rats (TGR) and stenosis of renal artery (2K1C) in Wistar rats. We demonstrated that renin-angiotensin system does not play so important role in blood pressure maintenance in both CKD models. By contrast, a more important role has sympathetic nervous system. During both the developmental and established phase of CKD, vasoconstrictor systems prevail above vasodilator NO-synthase effects. In fact, the role of NO-dependent vasodilation gradually decreased in nephrectomized TGR rats, while it was unchanged in Wistar rats with 2K1C hypertension.
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Effects of exercise training on intrauterine growth restriction in an animal modelKasaei Roodsari, Aida 09 1900 (has links)
No description available.
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Caractérisation du gène de l'enzyme de conversion de l'angiotensine-2 dans le rein diabétique et implication dans le développement de la néphropathie diabétique et de l'hypertensionShi, Yixuan 07 1900 (has links)
De nombreuses études ont bien démontré que l’activation du système rénine-angiotensine (RAS) joue un rôle important dans le développement de l’hypertension et de la néphropathie diabétique (DN). La découverte de l’enzyme de conversion de l’angiotensine-2 (ACE2) et l’identification du récepteur MAS, spécifique pour l’angiotensine 1-7 (Ang 1-7), ont permis d’identifier deux nouveaux membres du RAS. L’axe ACE2/Ang 1-7/MAS contrebalance les effets de l’axe ACE/Ang II/AT1. Plusieurs évidences impliquent la contribution du RAS intrarénal dans la DN. Des études réalisées dans notre laboratoire avec des souris transgéniques surexprimant l’angiotensinogène de rat dans les cellules de leurs tubules proximaux rénaux (RPTCs) ont permis de démontrer l’importance du RAS intrarénal dans l’induction de l’hypertension et les dommages rénaux. Nous avons également observé que l’expression rénale de l’ACE2 et les niveaux urinaires d’ANG 1-7 sont plus faibles chez les souris Akita (diabète de type 1) et qu’un traitement avec des bloqueurs du RAS permet de normaliser l’expression de l’ACE2 et de prévenir le développement de l’hypertension dans le modèle des souris Akita. Dans un milieu diabétique, à la fois la glycémie et l’angiotensine II (Ang II) peuvent induire la génération des espèces réactives de l’oxygène (ROS), contribuant ainsi aux dommages rénaux. Afin d’explorer la relation entre les ROS, ACE2 et la DN, nous avons créé des souris Akita transgéniques surexprimant la catalase (Cat) dans les RPTCs, en croisant des souris Akita diabétique de type 1 à notre modèle de souris transgéniques surexprimant la Cat de rat dans les RPTCs. Dans une seconde étude, des souris Akita ont été traitées avec l’Ang 1-7 ou une combinaison d’Ang 1-7 et de son antagoniste, A779, afin d’étudier la relation entre l’action de l’Ang 1-7, l’hypertension systolique (sHTN), le stress oxydatif, les dommages rénaux, ACE2 et l’expression du récepteur Mas.
Nos résultats ont montré que la surexpression de Cat atténue le stress oxydatif rénal; prévient l’hypertension, améliore le taux de filtration glomérulaire, l’albuminurie, l’hypertrophie rénale, la fibrose tubulo-interstitielle et l’apoptose tubulaire; et supprime l’expression des gènes profibrotiques et proapoptotiques dans les RPTCs des souris Akita Cat-Tg lorsque comparées aux souris Akita. De plus, la surexpression de Cat dans les RPTC des souris Akita normalise l’expression rénale de l’ACE2 et les niveaux urinaires d’Ang 1-7.
D’autre part, l’administration d’Ang 1-7 prévient l’hypertension systémique, normalise le ratio albumine/créatinine urinaire et atténue l’hyperfiltration glomérulaire des souris Akita, sans affecter la glycémie sanguine. De plus, le traitement avec l’Ang 1-7 atténue aussi le stress oxydatif et l’expression de la NADPH oxydase, Agt, ACE, TGF-β1 (transforming growth factor-β1) et collagène IV, tout en augmentant l’expression de l’ACE2 et du récepteur Mas dans les reins des souris Akita. Ces effets sont renversés par la co-admininstration d’A779.
Ces résultats démontrent que la surexpression de Cat prévient l’hypertension et la progression de la néphropathie, en plus de mettre en lumière l’importance du stress oxydatif intrarénal et l’expression de l’ACE2 comme facteurs contribuant à l’hypertension et les dommages rénaux observés dans le diabète. En outre, nos données suggèrent que l’Ang 1-7 joue un rôle protecteur dans l’hypertension et les dommages aux RPTC dans le diabète, principalement en réduisant les voies de signalisations du stress oxydatif dans les reins et en normalisant l’expression de l’ACE2 et du récepteur Mas. Nos résultats indiquent aussi que l’Ang 1-7 pourrait agir comme un agent thérapeutique potentiel dans le traitement de l’hypertension systémique et les dommages rénaux observés dans le diabète. En conséquence, l’Ang 1-7 est responsable du rôle protecteur de l’ACE2 dans l’hypertension et la DN. / It is well accepted that renin-angiotensin system (RAS) activation plays an important role in the development of hypertension and diabetic nephropathy (DN). With the discovery of angiotensin-converting enzyme-2 (ACE2) and recognition of MAS as the receptor of Angiotensin 1-7 (Ang 1-7), new players in RAS, ACE2/Ang 1-7/MAS axis, have been identified to counteract the effect of ACE/Ang II/ AT1 axis. Evidence implicates the intrarenal RAS’s contribution to DN. Previous studies from our laboratory using transgenic mice overexpressing rat Angiotensinogen (Agt) in their renal proximal tubular cells (RPTCs) have demonstrated the importance of the intrarenal RAS in renal damage and the induction of hypertension. We also recently observed that renal ACE2 expression and urinary Ang 1–7 were lower in type 1 diabetic Akita mice and that treatment with RAS blockers normalized ACE2 expression and prevented hypertension development in these Akita mice. In the diabetic milieu, both glycemia and angiotensin II (Ang II) can induce reactive oxygen species (ROS) generation, which contributes to kidney injury. To explore the relationship among ROS, ACE2 and DN, we created Akita transgenic mice overexpressing catalase (Cat) in RPTCs by crossbreeding type I diabetic Akita mice with our established transgenic mice overexpressing rat Cat in RPTCs. In another study, Akita mice were treated with Ang 1-7 or combination of Ang 1-7 and its antagonist, A779, to investigate the relations between Ang 1-7 action, systolic hypertension (sHTN), oxidative stress, kidney injury, ACE2 and Mas receptor expression.
Our results showed that overexpression of Cat attenuated renal oxidative stress; prevented hypertension; ameliorated glomerular filtration rate, albuminuria, kidney hypertrophy, tubulointerstitial fibrosis, and tubular apoptosis; and suppressed profibrotic and proapoptotic gene expression in RPTCs of Akita Cat-Tg mice compared with Akita mice. Furthermore, overexpression of Cat in RPTCs of Akita mice normalized renal ACE2 expression and urinary Ang 1–7 levels.
On the other hand, Ang 1-7 administration prevented systemic hypertension, normalized urinary albumin/creatinine ratio and attenuated glomerular hyperfiltration without affecting blood glucose levels in Akita mice. Furthermore, Ang 1-7 treatment also attenuated oxidative stress and the expression of NADPH oxidase 4, Agt, ACE, transforming growth factor-β1 (TGF-β1) and collagen IV, and increased the expression of ACE2 and Mas receptor in Akita mouse kidneys. These effects were reversed by co-administration of A779.
These data demonstrated that Cat overexpression prevents hypertension and progression of nephropathy and highlight the importance of intrarenal oxidative stress and ACE2 expression contributing to hypertension and renal injury in diabetes. Furthermore, our data suggest that Ang 1-7 plays a protective role in hypertension and RPTC injury in diabetes, predominantly through decreasing renal oxidative stress-mediated signaling and normalizing ACE2 and Mas receptor expression. Our results also indicate Ang 1-7 as a potential therapeutic agent for treatment of systemic hypertension and kidney injury in diabetes. Therefore, Ang 1-7 mediates the major protective role of ACE2 in the hypertension and DN.
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Déterminer les mécanismes impliqués dans les effets du récepteur à la rénine et prorénine dans l’obésité et dans le diabète = Determining mechanisms implicated in the effects of the renin and prorenin receptor in the development of obesity and diabetesShamansurova Akhmedova, Zulaykho 11 1900 (has links)
L'obésité est une épidémie mondiale qui augmente le risque de développer un diabète de type 2 ainsi que ses complications. Chez les individus obèses, le tissu adipeux sécrète de grandes quantités d'hormones et de cytokines qui affectent négativement le métabolisme du glucose et des lipides, ce qui provoque l'inflammation et la résistance à l'insuline. L'obésité augmente également l'activité du système rénine-angiotensine (RAS) localement au niveau de différents tissus et de façon systémique dans la circulation. L’angiotensinogène est convertie en angiotensine I par la rénine, ainsi que par la prorénine uniquement quand la prorénine est liée au récepteur de la rénine et prorénine [(P)RR] 1 . Ceci est la voie angiotensine-dépendante (Ang-D) du (P)RR. La liaison de la rénine et de la prorénine avec le (P)RR active également une voie angiotensine-indépendante (Ang-ND), ce qui produit une signalisation intracellulaire comportant la mitogen activated protein kinase (MAPK), la extracellular regulatory kinase 1/2 (ERK1/2), la promyelocytic leukemia zinc finger protein (PLZF) et le tumor necrosis factor alpha (TNF-a). Ceux-ci peuvent provoquer la croissance et la prolifération cellulaire, l'apoptose et la fibrose et pourraient donc être reliés aux dommages tissulaires et aux complications associées à l'obésité 1, 2. Plusieurs effets bénéfiques d’un blocage pharmacologique du (P)RR ont été rapportés tels la prévention du développement d'une fibrose cardiaque et rénale ainsi que la prévention de la néphropathie et de la rétinopathie diabétique. Cependant, les effets du (P)RR dans le tissu adipeux ont été peu étudiés.
Par conséquent, notre objectif était d'étudier le rôle du (P)RR dans le développement de l'obésité et de la résistance à l'insuline par : 1) l'administration de HRP (un peptide bloquant l’effet du (P)RR) chez un modèle de souris obèse par l’administration d’une diète riche en gras (HFD), et 2) l’évaluation de souris ayant une délétion (KO) du gène (P)RR spécifiquement dans le tissu adipeux, qui a été généré dans notre laboratoire par la technologie Cre-LoxP.
L'expression du gène et de la protéine du (P)RR dans les tissus adipeux était augmentée chez les souris nourries avec une HFD indépendamment du traitement au HRP. Le traitement par le HRP a réduit le poids corporel et la masse adipeuse chez les souris nourries avec une HFD alors qu’une tendance pouvait être observée chez les souris sur diète normale (ND). De façon similaire, les souris (P)RR KO spécifiquement dans le tissu adipeux avaient une réduction du poids corporel et de la masse adipeuse, même sur ND, ce qui suggère fortement l'implication du (P)RR dans le tissu adipeux dans le développement de l'obésité.
Le phénotype des souris KO incluait une augmentation de l'activité horizontale uniquement dans leur période active, ce qui pourrait contribuer à augmenter leur métabolisme énergétique et ainsi réduire leur poids corporel et leur masse adipeuse. De plus, les souris KO homozygotes mâles avaient un métabolisme de base plus élevé car nous avons observé une augmentation de la consommation d'oxygène et de la production de dioxyde de carbone pendant leur période active et de sommeil. Cette augmentation du métabolisme pourrait résulter, en partie, d'une augmentation de la thermogenèse comme en témoigne l’expression accrue du gène de brunissement, PRDM16, dans le tissu adipeux péri-rénale de souris mâles KO. Conformément à cela, des résultats récents provenant de notre laboratoire ont également démontré que le HRP pouvait induire du brunissement au niveau du tissu adipeux sous-cutanée 3.
Chez les souris traitées avec le HRP, bien que la glycémie eût été similaire aux souris recevant le placebo, l'insuline plasmatique et le rapport insuline/glucose était plus faible indépendamment de la diète. De façon similaire, les souris (P)RR KO avaient une insulinémie et un taux de peptide C plus faibles par rapport aux souris contrôles, sans aucune différence dans les courbes de la glycémie au cours d'un test de tolérance au glucose par voie orale. Les niveaux d'insuline dans l’état basal et stimulé étaient significativement plus faibles chez les souris KO, sans aucune modification du contenu pancréatique en insuline et du ratio insuline/peptide-C, ceci indique donc qu’il n’y a pas eu d’altération du niveau du métabolisme pancréatique de l'insuline. L’augmentation de l'adiponectine plasmatique chez les souris KO pourrait, entre autres, contribuer à une meilleure sensibilité à l'insuline observée. De plus, dans les groupes traités aux HRP, nous avons observé une amélioration du profil d'expression des gènes des transporteurs de glucose GLUT1 et GLUT4, du TNF-alpha, MCP-1, F4/80 et de la leptine dans le tissu adipeux ce qui pourrait contribuer à la meilleure sensibilité à l'insuline. Comme une meilleure sensibilité à l'insuline a été observée chez la souris suite au blocage pharmacologique et à la suppression génétique du (P)RR, ceci suggère que le (P)RR est impliqué dans la régulation de l’homéostasie du glucose.
De plus, un taux circulant réduit des triglycérides (TG) a été observé chez les souris traitées au HRP, alors que des niveaux inférieurs de TG ont été trouvés seulement dans les muscles squelettiques chez les souris KO. Ces modifications du métabolisme des lipides et des taux circulants d'adiponectine résultent probablement d'un tissu adipeux plus sain tel que révélé par nos analyses histologiques démontrant une réduction de la taille des adipocytes chez les souris KO et traitées au HRP 3.
Nos résultats démontrent que le (P)RR, en particulier dans le tissu adipeux, est impliqué dans la régulation du poids corporel et de l'homéostasie du glucose probablement par la modulation de la morphologie et de la fonction des adipocytes. Le développement d'une nouvelle stratégie clinique axée sur le blocage du (P)RR pourrait aider à traiter l'obésité et ses pathologies associées telles la résistance à l'insuline et le diabète de type 2. / Obesity is a worldwide epidemic and increases the risk of developing type 2 diabetes and its complications. In obesity, adipose tissue secretes large amounts of hormones and cytokines that negatively regulate glucose and lipid metabolism, causing inflammation and insulin resistance. Obesity also increases the activity of both local (tissue-specific) and circulating renin-angiotensin system (RAS). Angiotensinogen is converted to angiotensin I by renin, whereas prorenin may only do so upon binding to the (pro)renin receptor [(P)RR] 1. This is thus the angiotensin-dependent (Ang-D) pathway of the (P)RR. The binding of renin and prorenin with the (P)RR also activates an angiotensin-independent pathway (Ang-ND), leading to intracellular signaling involving, for instance, the mitogen activated protein kinase (MAPK), the extracellular regulatory kinase ½ (Erk1/2), the promyelocytic leukemia zinc finger protein (PLZF) and tumor necrosis factor alpha (TNF-a) 1, 2. These can produce cell growth and proliferation, apoptosis and fibrosis 1, 2, and as such may contribute to tissue damage and complications associated with obesity. The beneficial effects of pharmacological blockade of the (P)RR include prevention of the development of cardiac and renal fibrosis, as well as of diabetes-associated nephropathy and retinopathy. However, effects of the (P)RR in adipose tissue have been poorly investigated. Hence, our objective was to study the role of the (P)RR in the development of obesity and insulin resistance by: 1) administering HRP (a (P)RR blocker peptide) to mice fed a high-fat diet (HFD), and 2) in knock-out (KO) mice with adipose tissue-specific (P)RR gene deletion, which were generated in our laboratory by cre-loxp technology.
(P)RR gene and protein expression in adipose tissue were increased in mice fed a HFD independently of HRP treatment. HRP treatment also reduced mice body weight and fat masses in HFD-fed mice while they only tended to be lower in mice on normal diet (ND). Similarly, the adipose tissue specific (P)RR KO mice had reduced body weight and fat masses, even on ND, and as such confirmed the involvement of adipose tissue (P)RR in the development of obesity.
The KO phenotype included increased horizontal activity, only in the dark cycle (active period), which would increase energy expenditure and could contribute to their lower body weight and fat mass. Male hemizygous KO mice had higher basal metabolic rate as they had increased oxygen consumption and carbon dioxide production during both their active and inactive period. This increased basal metabolism may result in part from an increase in thermogenesis as increased “beiging” gene expression, PRDM16, was observed in peri-renal fat of male KO mice. In line with this, recent results from our laboratory have also shown that HRP may induce “beiging” in subcutaneous fat 3.
In mice treated with the HRP, although glycemia was similar to placebo treated mice, plasma insulin and the insulin to glucose ratio were lower compared to untreated groups on both HFD or ND. Similarly, (P)RR KO mice had lower plasma insulin and C-peptide levels compared to controls, without any differences in the glycemia curves during an oral glucose tolerance test. Given that the basal and stimulated insulin levels were significantly lower in KO mice, without any changes in total pancreatic insulin content and with similar insulin to C-peptide ratio, this suggests that pancreatic insulin metabolism was not modified. The increased circulating adiponectin levels observed in KO mice may have contributed to the better insulin sensitivity present in the mice. In the HRP treated mice, we observed an improved gene expression profile of glucose transporters GLUT1 and GLUT4, TNF-alpha, MCP-1, F4/80 and leptin in adipose tissue, which may also contribute to the increased insulin sensitivity. Given that better insulin sensitivity was observed in mice with both (P)RR pharmacological blockade and genetic suppression, this suggests that the (P)RR is involved in the regulation of glucose homeostasis.
In addition, lower circulating triglycerides (TG) levels were found in mice treated with HRP, whereas lower TG levels were observed only in skeletal muscles in (P)RR KO mice. Put altogether, the lower lipid content and higher plasma adiponectin levels likely result from a healthier fat tissue as revealed by histological analysis which showed a reduction in adipocytes size in KO mice and was recently revealed in HRP treated HFD fed mice 3.
Our results demonstrate that the (P)RR, particularly in adipose tissue, is implicated in the regulation of body weight and glucose homeostasis via modulation of adipocytes morphology and function. The development of a new clinical strategy focused on blockade of the (P)RR specifically in adipose tissue could help to treat obesity and its associated pathologies such as insulin resistance and type 2 diabetes.
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Mécanisme(s) d'action de l'insuline dans la prévention de l'hypertension et la progression de la tubulopathie dans le diabète : rôle de hnRNP F, Nrf2 et BmfGhosh, Anindya 08 1900 (has links)
No description available.
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Avaliação dos eventos envolvidos na evolução crônica da lesão renal aguda pós isquêmica em ratos com deficiência de vitamina D / Assessment of the events involved in chronic evolution of acute kidney injury in a murine ischemia/reperfusion model after vitamin D deficiencyGonçalves, Janaína Garcia 08 August 2014 (has links)
Na maioria dos países, a incidência e prevalência da doença renal crônica (DRC) vem aumentando ao longo dos anos. Embora tenha havido uma melhora significativa no manejo da DRC com os inibidores do sistema renina-angiotensina-aldosterona, a doença ainda é progressiva, levando a necessidade do surgimento de novas estratégias protetoras. A fibrose renal progressiva está presente na DRC e envolve a participação de várias citocinas, com destaque para o fator Transforming growth factor- beta1 (TGF-beta1). Tem sido demonstrado que a mortalidade de pacientes com DRC está diretamente relacionada à função renal e está associada a riscos tradicionais como cardiovasculares e infecções. Entretanto, esses riscos tradicionais explicam apenas metade das causas de mortalidade nesses pacientes. Evidências crescentes mostram que o status de vitamina D pode ser um fator de risco não tradicional para a evolução da DRC. Tendo em vista o importante papel da vitamina D na manutenção das funções fisiológicas essenciais e a observação da queda dos níveis deste hormônio na DRC, torna-se relevante o estudo da deficiência de vitamina D nos eventos envolvidos na evolução crônica da lesão renal aguda em modelo experimental de isquemia/reperfusão renal. Ratos Wistar foram divididos em quatro grupos: controle, animais que receberam dieta padrão; dVD, animais que receberam dieta depletada em vitamina D; Isq, animais que receberam dieta padrão e foram submetidos ao insulto de isquemia/reperfusão renal bilateral no 28º dia; Isq+dVD, animais que receberam dieta depletada em vitamina D e foram submetidos ao insulto de isquemia/reperfusão bilateral no 28º dia. Ao final dos 90 dias do protocolo, os animais foram submetidos à eutanásia, amostras de sangue, urina e o tecido renal foram coletados para a análise dos mecanismos de lesão renal. Os animais submetidos ao insulto de isquemia/reperfusão renal apresentaram hipertrofia renal, aumento dos níveis de pressão arterial média, colesterol e de PTH plasmático. Além disso, foi observada expansão da área intersticial, aumento do infiltrado de macrófagos/monócitos, da expressão de colágeno IV, fibronectina, vimentina e alfa-actina e redução da expressão da proteína Klotho. A deficiência de vitamina D contribuiu para a elevação dos níveis plasmáticos de PTH e aumento da proteinúria assim como para as alterações túbulo-intersticiais crônicas importantes (fibrose e infiltrado inflamatório do interstício, dilatação e atrofia tubular), aumento da expressão da citocina TGF-beta1 expressão do receptor de vitamina D (VDR) e da proteína Klotho, observados nos animais deficientes em vitamina D submetidos ao insulto de isquemia/reperfusão renal. Portanto, através de vias inflamatórias e com participação do fator de crescimento TGF-beta1 ê um fator agravante para o dano túbulo-intersticial e formação de fibrose intersticial nesse modelo experimental de isquemia/reperfusão renal / In most countries, the incidence and prevalence of chronic kidney disease (CKD) has been increasing over the years. Although there was a significant improvement in the management of CKD with renin-angiotensin-system inhibitors, the disease is still progressive, leading to the need of emergence of new protective strategies. The progressive renal fibrosis is present in CKD and involves the participation of several cytokines, especially the Transforming growth factor-beta1 (TGF-beta1). It has been shown that the mortality of patients with CKD is directly related to renal function, which is associated to traditional risk factors such as cardiovascular diseases and infections. However, these traditional risk factors explain only half of the causes of mortality in these patients. Growing evidence shows that vitamin D status may be a non-traditional risk factor for the progression of CKD. Considering the important role of vitamin D in the maintenance of essential physiological functions and the observation of low levels of this hormone in CKD, the study of vitamin D deficiency in the events involved in chronic evolution of acute kidney injury in an experimental model of ischemia/reperfusion becomes relevant. Wistar rats were divided into four groups : control, animals received a standard diet ; dVD, animals received a vitamin D-depleted diet ; Isq, animals received a standard diet and were subjected to bilateral renal ischemia/reperfusion injury on day 28; Isq +dVD, animals received a vitamin D-depleted diet and were subjected to bilateral renal ischemia/reperfusion injury on day 28 . At the end of the 90 days of the protocol, the animals were euthanized and samples of blood, urine and kidney tissue were collected for analysis of the mechanisms of renal injury. The animals subjected to the insult of ischemia/ reperfusion showed renal hypertrophy, increased levels of mean blood pressure, cholesterol and plasma PTH. Furthermore, expansion of the interstitial area, increased infiltration of macrophages/monocytes, increased expression of collagen IV, fibronectin, vimentin and alpha-actin, and reduced expression of Klotho protein were observed. The vitamin D deficiency contributed to the elevation of plasma PTH levels and increased proteinuria as well as for important chronic tubulo-interstitial changes (fibrosis and inflammatory infiltration of the interstitium, tubular dilation and atrophy), increased expression of cytokine TGF-beta1 vitamin D receptor (VDR) and Klotho protein observed in vitamin D-deficient animals subjected to the insult of renal ischemia/reperfusion. Therefore, through inflammatory pathways and involvement of TGF-beta1 w y aggravating factor in tubulointerstitial damage and formation of interstitial fibrosis in this experimental model of renal ischemia/reperfusion
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