No description available.

The prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) quickly reached pandemic proportions, and knowledge about this virus and coronavirus disease 2019 (COVID-19) has expanded rapidly. This review focuses primarily on mechanisms that contribute to acute cardiac injury and dysfunction, which are common in patients with severe disease. The etiology of cardiac injury is multifactorial, and the extent is likely enhanced by pre-existing cardiovascular disease. Disruption of homeostatic mechanisms secondary to pulmonary pathology ranks high on the list, and there is growing evidence that direct infection of cardiac cells can occur. Angiotensin converting enzyme 2 (ACE2) plays a central role in COVID-19 and is a necessary receptor for viral entry into human cells. ACE2 normally not only eliminates angiotensin II (Ang II) by converting it to Ang (1-7), but also elicits a beneficial response profile counteracting that of Ang II. Molecular analyses of single nuclei from human hearts have shown that ACE2 is most highly expressed by pericytes. Given the important roles that pericytes have in the microvasculature, infection of these cells could compromise myocardial supply to meet metabolic demand. Furthermore, ACE2 activity is crucial for opposing adverse effects of locally generated Ang II, so virus-mediated internalization of ACE2 could exacerbate pathology by this mechanism. While the role of cardiac pericytes in acute heart injury by SARS-CoV-2 requires investigation, expression of ACE2 by these cells has broader implications for cardiac pathophysiology.

No description available.

No description available.

Congestive heart failure is commonly treated with a low sodium diet and diuretic. The purpose of this treatment is the reduction of preload, or blood volume presented to the diseased cardiac muscle. The purpose of this study was to assess the roles of dietary sodium and furosemide on cardiac function, plasma electrolyte concentrations, and the renin-angiotensin-aldosterone system, in healthy canines. Twenty mixed-breed canines were allotted to one of four groups, Group I - Dogs fed low sodium diet (0.08% sodium), Group II - Dogs fed high sodium diet (1.0% sodium), Group III - Dogs fed low sodium (0.08%) and treated with furosemide (2 mg/kg orally (PO) every twelve hours (BID)), and Group IV - Dogs fed high sodium (1.0%) and furosemide ( 2 mg/kg PO BID). Cardiac function was assessed via echocardiography on days 0, 21,and 53. Plasma electrolyte concentrations were measured on days 0, 21, and 35. Activation of the renin-angiotensin-aldosterone system was evaluated on days 0, 21, 35, and 53. Low and high sodium diet with and without furosemide treatment did not alter cardiac function, plasma sodium, or plasma potassium concentrations. However, furosemide treatment combined with a low sodium diet resulted in the lowest plasma chloride concentrations, on days 21 and 35 (p<0.05). Furthermore, furosemide treatment resulted in significant alterations in the renin-angiotensin-aldosterone system, on days 21, 35, and 53, (p < 0.0001). Furosemide treatment significantly increased renin activity and aldosterone concentration. The interaction between furosemide and the low sodium diet yielded a greater increase in plasma renin activity and plasma aldosterone concentrations than furosemide administration with the high sodium diet. These results suggest direct activation of the renin-angiotensin-aldosterone system by furosemide. Future research is warranted in congestive heart failure subjects, due to the adverse affects of decreased plasma chloride concentrations and activation of the renin-angiotensin-aldosterone system. / Master of Science

La stimulation du récepteur de la rénine/prorénine [(P) RR], un membre récemment découvert du système rénine-angiotensine (SRA), augmente l'activité du SRA et des voies de signalisation angiotensine II-indépendante. Pour étudier l'impact potentiel du (P)RR dans le développement de l`obésité, nous avons émis l'hypothèse que les souris déficientes en (P)RR uniquement dans le tissus adipeux (KO) auront une diminution du poids corporel en ciblant le métabolisme du tissu adipeux, l'activité locomoteur et/ou la prise alimentaire. Ainsi, des souris KO ont été générées en utilisant la technologie Cre/Lox. Le gain de poids et la prise alimentaire ont été évalués hebdomadairement dans les mâles et femelles KO et de type sauvage (WT) pendant 4 semaines alors qu’ils étaient maintenu sur une diète normal. De plus, un groupe de femelles a été placé pour 6 semaines sur une diète riche en gras et en glucides (HF/HC). La composition corporelle et l'activité ambulatoire ont été évaluées par l’EchoMRI et à l’aide de cages Physioscan, respectivement. Les tissus adipeux ont été prélevés et pesés. De plus, les gras péri-gonadaux ont été utilisés pour le microarray. Finalement, le niveaux d'expression d'ARNm du (P)RR ont été évalués. Comme le gène du (P)RR est situé sur le chromosome X, les mâles étaient des KOs complets et les femelles étaient des KOs partielles. Les souris KO avaient un poids corporel significativement plus petit par rapport à WT, les différences étant plus prononcées chez les mâles. De plus, les femelles KOs étaient résistantes à l'obésité lorsqu'elles ont été placées sur la diète HF/HC et donc elles avaient significativement moins de masse grasse par rapport aux WTs. L’analyse histologique des gras péri-gonadaux des KOs nous ont dévoilés qu’il avait une réduction du nombre d'adipocytes mais de plus grande taille. Bien qu'il n'y ait eu aucun changement dans la consommation alimentaire, une augmentation de près de 3 fois de l'activité ambulatoire a été détectée chez les mâles. De plus, nous avons observé que leurs tibias étaient de longueur réduite ce qui suggère fortement l'affection de leur développement. Les gras péri-gonadaux des souris KO avaient une expression réduite de l`ABLIM2 (Actin binding LIM protein family, member 2) qui est associé avec le diabète de type II chez l'humain. Ainsi, les données recueillies suggèrent fortement que le (P)RR est impliquée dans la régulation du poids corporelle. / Stimulation of the (pro)renin receptor [(P)RR], a recently discovered member of the renin-angiotensin system (RAS), increases the activity of the RAS and stimulates angiotensin II-independent signaling pathways. To investigate the possible impact of the (P)RR on obesity development, we hypothesized that mice deficient in the (P)RR specifically in their adipose tissue (KO) would have a decrease in body weight by targeting adipose tissue metabolism, locomotor activity and/or food intake. As such, KO mice were generated using the Cre/Lox technology. Weekly weight gain and food intake were assessed in both male and female KO and wild-type (WT) littermates for 4 weeks on a normal diet. A group of females were also placed for an additional 6 weeks on a high-fat/high-carbohydrate diet (HF/HC). Body composition and physical activity were evaluated using EchoMRI and Physioscan cages, respectively. Adipose tissues were collected and weighed at sacrifice. Moreover, perigonadal fat was used for Gene assay and histological analysis. (P)RR mRNA expression levels were evaluated using real-time PCR. Different circulating metabolites and proteinuria were measured by ELISA kits. As the (P)RR gene is located on the X chromosome, males were complete KOs and females were partial KOs. KO body weights were significantly lower compared to WTs, the differences being more pronounced in males. Female KOs were resistant to obesity development when placed on a HF/HC diet and as such, had significantly smaller fat mass as well as lower circulating leptin levels compared to WTs. All KO perigonadal fat had a reduced number of adipocytes but of bigger size. Although there were no changes in food intake, an almost 3-fold increase in activity was detected in males. Moreover, they presented with shorter tibial length which strongly suggests that they may have developmental issues. Gonadal fat of KO mice showed a reduced expression of ABLIM2 gene (Actin binding LIM protein family, member 2) which is associated with type II diabetes in humans. Conversely, no obvious changes in glycemia were detected while tendencies for lower proteinuria could be observed. The data collected thus strongly suggests that the (P)RR is implicated in body weight regulation.

L'obésité est une maladie associée à de nombreuses complications comme le diabète de type 2, l'hypertension et le cancer. De nos jours, les modifications au mode de vie, tels l’alimentation et le niveau d’activité physique, ne sont pas suffisants pour combattre les effets délétères de l'obésité. La pharmacothérapie est un traitement alternatif bien que les effets bénéfiques soient temporaires et ne peuvent être maintenus à long terme. Le besoin pour un traitement bénéfique à long terme sans effet secondaire n'est pas comblé. Mieux connu pour son rôle dans la régulation de la pression artérielle, le système rénine-angiotensine favorise l'entreposage du gras. Le récepteur à la prorénine et à la rénine est une composante du système rénine-angiotensine. Ainsi, le récepteur qui amplifie l'activation de celui-ci pourrait avoir un rôle clé dans le gain de masse grasse. Le but de ce projet de thèse est d'évaluer le rôle du récepteur à la prorénine et à la rénine dans le développement de l'obésité et de ses complications chez la souris et ce, en utilisant une combinaison de diète riche en gras et en hydrates de carbone et du handle region peptide, un bloqueur du récepteur à la prorénine à la rénine. Après une période de 10 semaines, nous avons constaté que l'expression et la protéine du récepteur à la prorénine et à la rénine augmentent spécifiquement dans le tissu adipeux sous-cutané et viscéral des souris obèses. Lorsqu'administré en concomitance avec une diète riche en gras et en hydrates de carbone, le handle region peptide favorise chez la souris des diminutions des gains des masses corporelles et adipeuses viscérales. Une diminution de l'expression de l'enzyme catalysant la dernière étape de la lipogenèse pourrait être responsable de la réduction de gras viscéral. Chez les mêmes animaux, l'expression de plusieurs adipokines est également diminuée dans le tissu adipeux suggérant une réduction de la résistance à l'insuline, de l'inflammation et de l'infiltration des macrophages localement dans le gras sous-cutané et viscéral. L'augmentation de l'expression d’un marqueur de l'adipogenèse dans le tissu adipeux sous-cutané pourrait suggérer un plus grand nombre d'adipocytes. Cela pourrait tamponner l'excès d'acides gras libres circulants puisque nous avons constaté une diminution de ce paramètre chez les souris ayant une diète riche en gras et en hydrates de carbone et traitées avec le peptide. Nous avons émis l'hypothèse qu'un cycle futile pourrait être activé dans le gras sous-cutané car nous avons observé une augmentation de l'expression de plusieurs enzymes impliquées dans la lipogenèse et dans la lipolyse. Le ''brunissement'' du tissu adipeux est la présence de cellules similaires aux adipocytes bruns dans le tissu adipeux qui sont caractérisés par une grande densité mitochondriale et la thermogenèse. L'augmentation de l'expression des marqueurs de ''brunissement'' et de biogenèse de mitochondrie dans le gras sous-cutané suggère que le ''brunissement'' pourrait également être activé dans ce dépôt de gras. La sensibilité à l'insuline chez ces animaux pourrait être améliorée telle que suggérée en circulation par la diminution de l'insuline, par le glucose qui change peu, par l'augmentation du ratio glucose sur insuline ainsi que par un changement potentiel dans la corrélation entre le poids corporel de la souris et les niveaux d’adiponectine circulante. Nos travaux suggèrent que le handle region peptide pourrait augmenter la capacité du tissu adipeux sous-cutané à métaboliser les lipides circulants avec l'activation potentielle d'un cycle futile et le ''brunissement''. Cela préviendrait le dépôt ectopique de lipides vers les compartiments viscéraux comme le suggère la réduction de masse adipeuse viscérale chez les souris ayant une diète riche en gras et en hydrates de carbone et traitées avec le peptide. Utilisant un modèle de souris, cette étude démontre le potentiel pharmacologique du handle region peptide comme un nouveau traitement pour prévenir l'obésité. / Obesity is a disease associated with multiple complications such as type 2 diabetes, hypertension and cancer. Nowadays, lifestyle modifications, such as eating habits and physical activity, are simply not enough to counter the deleterious effects of obesity. Pharmacotherapy is used as an alternative treatment although beneficial effects are temporary and cannot be maintained in the long run. The current medical need for a treatment with long term beneficial outcomes devoid of side effects is unmet. Best known for its role in blood pressure regulation, the renin-angiotensin system has recently been attributed a role in favouring fat storage. The prorenin and renin receptor is a component of renin-angiotensin system that amplifies its activation. Thus, the prorenin and renin receptor might play a key role in gaining fat mass. The aim of this thesis is to investigate the role of the prorenin and renin receptor in the development of obesity and its complications in mice using a combination of high-fat and high carbohydrate diet and the handle region peptide, a blocker of the prorenin and renin receptor. After a period of 10 weeks, we have found that the prorenin and renin receptor is increased specifically in subcutaneous and visceral adipose tissue of obese mice. When administered simultaneously with a high-fat and high-carbohydrate diet, the handle region peptide reduced body weight gain in mice with similar decrease in visceral fat mass. Decreased expression of the enzyme catalyzing the last step of lipogenesis could be responsible for the reduction in visceral fat mass. In the same animals, the expressions of several adipokines were also decreased in adipose tissue suggesting reduced insulin resistance, inflammation and macrophage infiltration locally in subcutaneous and visceral fat. Increased expression of a marker of adipogenesis in subcutaneous adipose tissue could suggest higher adipocyte number. This would buffer excess circulating free fatty acid since we have noticed a reduction in the latter in mice on a high-fat and high-carbohydrate diet and treated with the peptide. We hypothesized that a futile cycle could be activated in subcutaneous fat because we have observed increased expression of several enzymes implicated in lipogenesis and lipolysis. « Beiging » is defined as the presence of brown-like adipocytes in adipose tissue which is characterized by high mitochondrial density and thermogenesis. Increased expression of markers for « beiging » and mitochondrial biogenesis in subcutaneous fat suggests that « beiging » could also be activated in this fat pad. Insulin sensitivity in these animals could be improved as suggested in the circulation by decreased insulin, similar glucose, increased glucose on insulin ratio as well as a possible change in the correlation between mouse body weight and circulating adiponectin levels. Our work suggests that the handle region peptide could increase the capacity of subcutaneous adipose tissue to metabolize circulating lipids with a potential activation of a futile cycle and « beiging ». This would prevent ectopic deposition of fat in visceral compartments as suggested by the reduction in visceral fat mass in mice on high-fat and high-carbohydrate diet and treated with the peptide. Using a mice model, this study demonstrates the pharmacological potential of the handle region peptide as a novel treatment to prevent obesity.

Background. The kidney is one of the major organs involved in whole-body homeostasis and it is well understood that chronic renal impairment is further complicated with deranged carbohydrate metabolism, dyslipidemia, altered abdominal fat distribution and the activation of renin-angiotensin system (RAS). Recently, RAS blockades of angiotensinconverting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB) have been noticed for their potential effects on improve glucose and lipid metabolisms and lowering the risk of new-onset diabetes. However, underlying cellular and molecular mechanisms are not fully established. / Conclusions. (1) UNX induces progressive renal impairment and dysregulation of pancreatic and renal RAS in rats. (2) Pancreatic RAS activation leads to intra-islet fibrosis, insulin-secreting beta-cell deficit and insulin secretory deficiency. (3) Renal cortex RAS dysregulation induces ectopic adipocyte differentiation and lipid infiltration, in combination with lipodystrophy and lipid peroxidation, results to insulin resistance. (4) Pancreatic insulin-secretion deficit and insulin resistance contribute to the development of glucose intolerance and hyperglycemia. (5) Kidney impacting on glucose and lipid metabolism by affecting pancreatic islet and adipocyte, suggesting an essential role of the kidney in maintaining the whole-body homeostasis. (6) RAS blockade with ACEI or ARB may prevent the development of chronic renal impairment and glucose and lipid dysmetabolisms in UNX rats. (7) Common pathways modulating blood pressure, glucose and lipid metabolism warrant future studies for the better management of the global epidemic of metabolic syndrome. / Materials and methods. Chronic renal impairment and RAS disturbance were induced by unilateral nephrectomy (UNX) in adult Sprague-Dawley rats undergoing as long as 10 months of observation. Three-month old male rats were randomized into 4 groups: (1) sham operated control rats (n=10), (2) untreated UNX model rats (n=10), (3) ACEI---lisinopril treated UNX rats (n=10), and (4) ARB-olmesartan treated UNX rats (n=10). Blood glucose levels during fasting and oral glucose tolerance test (OGTT) conditions, lipids, insulin and renal function were measured at 3, 6, 8 and 10 months after operation. Histological changes of kidney, pancreas, liver, and adipose tissue were examined at 10 months post-operation. / Objectives. (1) To set up a rat model with persistent chronic renal impairment and RAS activation. (2) To examine changes of fasting blood glucose, glucose tolerance, blood lipids and insulin sensitivity. (3) To examine changes of pancreatic islets and the factors contributing to pancreatic islet damage such as RAS, transforming growth factor (TGF)-beta and alpha-smooth muscle actin (SMA). (4) To examine changes of systemic and renal adipose tissue and the factors contributing to adipopathy such as RAS, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and hydroxy-3-methylglutary coenzyme A reductase (HMGCR). (5) To investigate preventive effect of RAS blockades by the ACEI-lisinopril (4 mg/kg body weight) and ARB-olmesartan (4 mg/kg body weight) on the rat model of progressive renal deficiency. / Results. (1) UNX rats developed time-dependent progressive renal functional impairment and marked glomerulosclerosis and tubulointerstitial lesions. (2) UNX rats showed fasting hyperglycemia, progressive glucose intolerance, hyperlipidemia and insulin resistance. (3) UNX rats demonstrated insulin secretory deficiency in parallel to pancreatic islet fibrosis, beta-cell deficit, and overexpression of RAS components, TGF-beta, and alpha-SMA. (4) UNX rats displayed adipopathy evidenced by shifts the subcutaneous and visceral fats to the ectopic fat with lipid accumulation, lipofuscin pigmentation and adipocytes transformation. The adipopathy associated with down-regulation of AT1R and over-expression of angiotensin, AT2R, PPAR-gamma and HMGCR in the remnant kidney. (5) Treatment with lisinopril and olmesartan significantly attenuated the development of chronic renal impairment, RAS dysregulation and aberrant proteins expression, islet damage, adipose redistribution, and glucose and lipid dysmetabolism. / Sui, Yi. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3422. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 195-220). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

La stimulation du récepteur de la rénine/prorénine [(P) RR], un membre récemment découvert du système rénine-angiotensine (SRA), augmente l'activité du SRA et des voies de signalisation angiotensine II-indépendante. Pour étudier l'impact potentiel du (P)RR dans le développement de l`obésité, nous avons émis l'hypothèse que les souris déficientes en (P)RR uniquement dans le tissus adipeux (KO) auront une diminution du poids corporel en ciblant le métabolisme du tissu adipeux, l'activité locomoteur et/ou la prise alimentaire. Ainsi, des souris KO ont été générées en utilisant la technologie Cre/Lox. Le gain de poids et la prise alimentaire ont été évalués hebdomadairement dans les mâles et femelles KO et de type sauvage (WT) pendant 4 semaines alors qu’ils étaient maintenu sur une diète normal. De plus, un groupe de femelles a été placé pour 6 semaines sur une diète riche en gras et en glucides (HF/HC). La composition corporelle et l'activité ambulatoire ont été évaluées par l’EchoMRI et à l’aide de cages Physioscan, respectivement. Les tissus adipeux ont été prélevés et pesés. De plus, les gras péri-gonadaux ont été utilisés pour le microarray. Finalement, le niveaux d'expression d'ARNm du (P)RR ont été évalués. Comme le gène du (P)RR est situé sur le chromosome X, les mâles étaient des KOs complets et les femelles étaient des KOs partielles. Les souris KO avaient un poids corporel significativement plus petit par rapport à WT, les différences étant plus prononcées chez les mâles. De plus, les femelles KOs étaient résistantes à l'obésité lorsqu'elles ont été placées sur la diète HF/HC et donc elles avaient significativement moins de masse grasse par rapport aux WTs. L’analyse histologique des gras péri-gonadaux des KOs nous ont dévoilés qu’il avait une réduction du nombre d'adipocytes mais de plus grande taille. Bien qu'il n'y ait eu aucun changement dans la consommation alimentaire, une augmentation de près de 3 fois de l'activité ambulatoire a été détectée chez les mâles. De plus, nous avons observé que leurs tibias étaient de longueur réduite ce qui suggère fortement l'affection de leur développement. Les gras péri-gonadaux des souris KO avaient une expression réduite de l`ABLIM2 (Actin binding LIM protein family, member 2) qui est associé avec le diabète de type II chez l'humain. Ainsi, les données recueillies suggèrent fortement que le (P)RR est impliquée dans la régulation du poids corporelle. / Stimulation of the (pro)renin receptor [(P)RR], a recently discovered member of the renin-angiotensin system (RAS), increases the activity of the RAS and stimulates angiotensin II-independent signaling pathways. To investigate the possible impact of the (P)RR on obesity development, we hypothesized that mice deficient in the (P)RR specifically in their adipose tissue (KO) would have a decrease in body weight by targeting adipose tissue metabolism, locomotor activity and/or food intake. As such, KO mice were generated using the Cre/Lox technology. Weekly weight gain and food intake were assessed in both male and female KO and wild-type (WT) littermates for 4 weeks on a normal diet. A group of females were also placed for an additional 6 weeks on a high-fat/high-carbohydrate diet (HF/HC). Body composition and physical activity were evaluated using EchoMRI and Physioscan cages, respectively. Adipose tissues were collected and weighed at sacrifice. Moreover, perigonadal fat was used for Gene assay and histological analysis. (P)RR mRNA expression levels were evaluated using real-time PCR. Different circulating metabolites and proteinuria were measured by ELISA kits. As the (P)RR gene is located on the X chromosome, males were complete KOs and females were partial KOs. KO body weights were significantly lower compared to WTs, the differences being more pronounced in males. Female KOs were resistant to obesity development when placed on a HF/HC diet and as such, had significantly smaller fat mass as well as lower circulating leptin levels compared to WTs. All KO perigonadal fat had a reduced number of adipocytes but of bigger size. Although there were no changes in food intake, an almost 3-fold increase in activity was detected in males. Moreover, they presented with shorter tibial length which strongly suggests that they may have developmental issues. Gonadal fat of KO mice showed a reduced expression of ABLIM2 gene (Actin binding LIM protein family, member 2) which is associated with type II diabetes in humans. Conversely, no obvious changes in glycemia were detected while tendencies for lower proteinuria could be observed. The data collected thus strongly suggests that the (P)RR is implicated in body weight regulation.

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...