RESUMO
BACKGROUND: This study evaluated the expression of ACE and ACE2 in the placenta and white adipose tissue in lean and obese women, and correlated their levels with anthropometric, clinical, and laboratory parameters, and tissue count of inflammatory cells. METHODS: A cross-sectional analytical study was performed with 49 pregnant women and their respective newborns. Samples of placenta and adipose tissue were used for measuring mRNA expression for ACE and ACE2 through qRT-PCR. Inflammatory cell counting was performed through conventional microscopy. RESULTS: An increase in ACE expression and a decrease in ACE2 were observed in the placenta and adipose tissue of women with obesity. ACE2 levels showed a negative correlation with pre-pregnancy BMI and total cholesterol. CONCLUSION: Maternal obesity can modulate the expression of RAS components in the placenta and white adipose tissue, with ACE2 correlated with pre-pregnancy BMI and total cholesterol.
RESUMO
The emergence of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to the global COVID-19 pandemic, significantly impacting the health of pregnant women. Obstetric populations, already vulnerable, face increased morbidity and mortality related to COVID-19, aggravated by preexisting comorbidities. Recent studies have shed light on the potential correlation between COVID-19 and preeclampsia (PE), a leading cause of maternal and perinatal morbidity worldwide, emphasizing the significance of exploring the relationship between these two conditions. Here, we review the pathophysiological similarities that PE shares with COVID-19, with a particular focus on severe COVID-19 cases and in PE-like syndrome cases related with SARS-CoV-2 infection. We highlight cellular and molecular mechanistic inter-connectivity between these two conditions, for example, regulation of renin-angiotensin system, tight junction and barrier integrity, and the complement system. Finally, we discuss how COVID-19 pandemic dynamics, including the emergence of variants and vaccination efforts, has shaped the clinical scenario and influenced the severity and management of both COVID-19 and PE. Continued research on the mechanisms of SARS-CoV-2 infection during pregnancy and the potential risk of developing PE from previous infections is warranted to delineate the complexities of COVID-19 and PE interactions and to improve clinical management of both conditions.
Assuntos
COVID-19 , Pré-Eclâmpsia , Complicações Infecciosas na Gravidez , SARS-CoV-2 , Humanos , COVID-19/fisiopatologia , COVID-19/imunologia , Gravidez , Feminino , Pré-Eclâmpsia/fisiopatologia , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/imunologia , SARS-CoV-2/fisiologia , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/virologia , Sistema Renina-AngiotensinaRESUMO
It is well-established that dysfunction of megalin-mediated albumin endocytosis by proximal tubule epithelial cells (PTECs) and the activation of the Renin-Angiotensin System (RAS) play significant roles in the development of Diabetic Kidney Disease (DKD). However, the precise correlation between these factors still requires further investigation. In this study, we aimed to elucidate the potential role of angiotensin II (Ang II), a known effector of RAS, as the mediator of albumin endocytosis dysfunction induced by high glucose (HG) in PTECs. To achieve this, we utilized LLC-PK1 and HK-2 cells, which are well-established in vitro models of PTECs. Using albumin-FITC or DQ-albumin as tracers, we observed that incubation of LLC-PK1 and HK-2 cells with HG (25 mM for 48 h) significantly reduced canonical receptor-mediated albumin endocytosis, primarily due to the decrease in megalin expression. HG increased the concentration of Ang II in the LLC-PK1 cell supernatant, a phenomenon associated with an increase in angiotensin-converting enzyme (ACE) expression and a decrease in prolyl carboxypeptidase (PRCP) expression. ACE type 2 (ACE2) expression remained unchanged. To investigate the potential impact of Ang II on HG effects, the cells were co-incubated with angiotensin receptor inhibitors. Only co-incubation with 10-7 M losartan (an antagonist for type 1 angiotensin receptor, AT1R) attenuated the inhibitory effect of HG on albumin endocytosis, as well as megalin expression. Our findings contribute to understanding the genesis of tubular albuminuria observed in the early stages of DKD, which involves the activation of the Ang II/AT1R axis by HG.
Assuntos
Albuminas , Angiotensina II , Endocitose , Células Epiteliais , Glucose , Túbulos Renais Proximais , Receptor Tipo 1 de Angiotensina , Endocitose/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Túbulos Renais Proximais/efeitos dos fármacos , Angiotensina II/farmacologia , Glucose/metabolismo , Glucose/farmacologia , Receptor Tipo 1 de Angiotensina/metabolismo , Animais , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Humanos , Albuminas/metabolismo , Suínos , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular , Losartan/farmacologiaRESUMO
OBJECTVE: The purpose of the research was to investigate the effects of aerobic training on renal function, oxidative stress, intrarenal renin-angiotensin system, and mortality of hypertensive and diabetic (SHR-STZ) rats. MATERIALS AND METHODS: Blood pressure, creatinine, urea levels, urinary glucose, urine volume, and protein excretion were reduced in trained SHR-STZ rats. RESULTS: Aerobic training not only attenuated oxidative stress but also elevated the activity of antioxidant enzymes in the kid'ney of SHR-STZ rats. Training increased intrarenal levels of angiotensin-converting enzymes (ACE and ACE2) as well as the neprilysin (NEP) activity, along with decreased intrarenal angiotensin II (Ang II) levels. Aerobic training significantly improved the survival of STZ-SHR rats. CONCLUSION: The protective role of aerobic training was associated with improvements in the renal antioxidative capacity, reduced urinary protein excretion along with reduced intrarenal Ang II and increased NEP activity. These findings might reflect a better survival under the combined pathological conditions, hypertension, and diabetes.
RESUMO
To compare the acute effects of aquatic walking/running versus dry-land walking/running on blood glucose and plasma renin activity (PRA) in individuals with type 2 diabetes, participants with type 2 diabetes performed deep-water or dry-land walking and/or running sessions in a swimming pool or on an athletics track, respectively. Both sessions comprised seven blocks of 3 min at 85-90% of the heart rate deflection point (HRDP), interspersed with 2 min at <85% HRDP, totaling 35 min, with a 48 h interval between sessions. PRA and blood glucose were assessed before and immediately after the sessions. Generalized estimation equations were used to verify the session effects, with the Bonferroni post hoc test, considering the significance level as 0.05. Twelve individuals (53.2 ± 8.9 years) diagnosed with type 2 diabetes for 6.3 ± 6.34 years participated in the study. A reduction in PRA was found only after the aquatic session (-7.75 ng/mL/h; -69%; p: 0.034), while both aquatic and dry-land sessions similarly reduced the blood glucose levels (aquatic: -38 mg/dL, -21%; dry-land: -26 mg/dL, -14%; time effect, p = 0.007). Despite yielding similar glycemic reductions as dry-land walking/running, aquatic walking/running led to an expressive decrease in PRA among individuals with type 2 diabetes.
Assuntos
Glicemia , Diabetes Mellitus Tipo 2 , Renina , Caminhada , Humanos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/terapia , Pessoa de Meia-Idade , Masculino , Renina/sangue , Feminino , Glicemia/análise , Exercício Físico/fisiologia , Corrida/fisiologia , AdultoRESUMO
Edible insects are recognized as promising food sources due to their nutritional composition. Some species, such as Gryllus assimilis, contain proteins, lipids, and carbohydrates of high biological value, which regulate several metabolic functions, including the Renin-Angiotensin System (RAS). In this context, the present study aimed to assess the effects of dietary supplementation with whole Gryllus assimilis powder on the metabolism of malnourished mice. Thirty-two male Swiss mice were used and divided into four treatment groups. The groups were identified as (AIN93-M); AIN93-M + Gryllus assimilis diet (AIN93-M + GA); AIN93-M + Renutrition diet (AIN93-M + REN) and AIN93-M + Renutrition diet + Gryllus assimilis (AIN93-M + REN + GA). The results showed that whole Gryllus assimilis powder inclusion promotes recovery from protein-energy malnutrition, reduces adiposity, and improves glucose tolerance and insulin sensitivity. It also reduces total cholesterol, triglycerides, VLDL, and adipocyte area. We also observed a significant increase in the expression of RAS-related genes, such as ACE2 and MasR, followed by a reduction in Angiotensinogen and ACE. The main findings of the present study suggest the use of black cricket as a viable strategy for the prevention and treatment of protein-energy malnutrition, as well as the reduction of adiposity, and improvement of lipid and glycemic parameters, with antihypertensive potential.
Assuntos
Tecido Adiposo , Suplementos Nutricionais , Gryllidae , Desnutrição Proteico-Calórica , Sistema Renina-Angiotensina , Animais , Sistema Renina-Angiotensina/efeitos dos fármacos , Masculino , Camundongos , Desnutrição Proteico-Calórica/metabolismo , Desnutrição Proteico-Calórica/dietoterapia , Tecido Adiposo/metabolismo , Adiposidade , Resistência à InsulinaRESUMO
Acute leukemias (ALs) are the most common cancers in pediatric population. There are two types of ALs: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Some studies suggest that the Renin Angiotensin System (RAS) has a role in ALs. RAS signaling modulates, directly and indirectly, cellular activity in different cancers, affecting tumor cells and angiogenesis. Our review aimed to summarize the role of RAS in ALs and to explore future perspectives for the treatment of these hematological malignancies by modulating RAS molecules. The database including Pubmed, Scopus, Cochrane Library, and Scielo were searched to find articles about RAS molecules in ALL and in pediatric patients. The search terms were "RAS", "Acute Leukemia", "ALL", "Angiotensin-(1-7)", "Pediatric", "Cancer", "Angiotensin II", "AML". In the bone marrow, RAS has been found to play a key role in blood cell formation, affecting several processes including apoptosis, cell proliferation, mobilization, intracellular signaling, angiogenesis, fibrosis, and inflammation. Local tissue RAS modulates tumor growth and metastasis through autocrine and paracrine actions. RAS mainly acts via two molecules, Angiotensin II (Ang II) and Angiotensin (1-7) [Ang-(1-7)]. While Ang II promotes tumor cell growth and stimulates angiogenesis, Ang-(1-7) inhibits the proliferation of neoplastic cells and the angiogenesis, suggesting a potential therapeutic role of this molecule in ALL. The interaction between ALs and RAS reveals a complex network of molecules that can affect the hematopoiesis and the development of hematological cancers. Understanding these interactions could pave the way for innovative therapeutic approaches targeting RAS components.
Assuntos
Angiotensina II , Leucemia-Linfoma Linfoblástico de Células Precursoras , Sistema Renina-Angiotensina , Humanos , Sistema Renina-Angiotensina/fisiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Angiotensina II/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Transdução de Sinais , Angiotensina I/metabolismo , Neovascularização Patológica/metabolismo , Animais , Fragmentos de Peptídeos/metabolismoRESUMO
Midlife cerebrovascular risk factors increase risk of late life cognitive impairment and dementia, while their presence in patients with dementia may lead to cognitive improvement or stabilization in late life. Defining the best measure of blood pressure (BP) to be associated with cognitive decline remains debatable, also due to possible bidirectionality. BP variability, pulse pressure, systolic and diastolic BP have been associated with cognitive status, dementia risk and Alzheimer's disease biomarkers. Proper BP control notwithstanding, BP variability increases risk for pathophysiological change in the Alzheimer's disease continuum, implying the need for selection of anti-hypertensive drugs with neurobiological evidence of benefits.
Assuntos
Pressão Sanguínea , Demência , Humanos , Pressão Sanguínea/fisiologia , Demência/epidemiologia , Fatores de Risco , Transtornos Cognitivos/etiologia , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/etiologia , Hipertensão/complicações , Hipertensão/fisiopatologiaRESUMO
Obesity over-activates the classical arm of the renin-angiotensin system (RAS), impairing skeletal muscle remodeling. We aimed to compare the effect of exercise training and enalapril, an angiotensin-converting enzyme inhibitor, on RAS modulation in the skeletal muscle of obese animals. Thus, we divided C57BL/6 mice into two groups: standard chow (SC) and high-fat (HF) diet for 16 weeks. At the eighth week, the HF-fed animals were divided into four subgroups-sedentary (HF), treated with enalapril (HF-E), exercise training protocol (HF-T), and combined interventions (HF-ET). After 8 weeks of treatment, we evaluated body mass and index (BMI), body composition, exercise capacity, muscle morphology, and skeletal muscle molecular markers. All interventions resulted in lower BMI and attenuation of overactivation in the classical arm, while favoring the B2R in the bradykinin receptors profile. This was associated with reduced apoptosis markers in obese skeletal muscles. The HF-T group showed an increase in muscle mass and expression of biosynthesis markers and a reduction in expression of degradation markers and muscle fiber atrophy due to obesity. These findings suggest that the combination intervention did not have a synergistic effect against obesity-induced muscle remodeling. Additionally, the use of enalapril impaired muscle's physiological adaptations to exercise training.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Enalapril , Camundongos Endogâmicos C57BL , Músculo Esquelético , Obesidade , Condicionamento Físico Animal , Animais , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Obesidade/metabolismo , Obesidade/fisiopatologia , Condicionamento Físico Animal/fisiologia , Camundongos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Enalapril/farmacologia , Dieta Hiperlipídica/efeitos adversos , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologiaRESUMO
This review examines the impact of obesity on the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and focuses on novel mechanisms for HFpEF prevention using a glucagon-like peptide-1 receptor agonism (GLP-1 RA). Obesity can lead to HFpEF through various mechanisms, including low-grade systemic inflammation, adipocyte dysfunction, accumulation of visceral adipose tissue, and increased pericardial/epicardial adipose tissue (contributing to an increase in myocardial fat content and interstitial fibrosis). Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the enteroendocrine L-cells in the gut. GLP-1 reduces blood glucose levels by stimulating insulin synthesis, suppressing islet α-cell function, and promoting the proliferation and differentiation of ß-cells. GLP-1 regulates gastric emptying and appetite, and GLP-1 RA is currently indicated for treating type 2 diabetes (T2D), obesity, and metabolic syndrome (MS). Recent evidence indicates that GLP-1 RA may play a significant role in preventing HFpEF in patients with obesity, MS, or obese T2D. This effect may be due to activating cardioprotective mechanisms (the endogenous counter-regulatory renin angiotensin system and the AMPK/mTOR pathway) and by inhibiting deleterious remodeling mechanisms (the PKA/RhoA/ROCK pathway, aldosterone levels, and microinflammation). However, there is still a need for further research to validate the impact of these mechanisms on humans.
Assuntos
Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Insuficiência Cardíaca , Síndrome Metabólica , Volume Sistólico , Humanos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Síndrome Metabólica/metabolismo , Síndrome Metabólica/tratamento farmacológico , Volume Sistólico/efeitos dos fármacos , Animais , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Obesidade/metabolismo , Obesidade/complicações , Obesidade/tratamento farmacológicoRESUMO
The renin-angiotensin system (RAS) is an endocrine system composed of two main axes: the classical and the counterregulatory, very often displaying opposing effects. The classical axis, primarily mediated by angiotensin receptors type 1 (AT1R), is linked to obesity-associated metabolic effects. On the other hand, the counterregulatory axis appears to exert antiobesity effects through the activation of two receptors, the G protein-coupled receptor (MasR) and Mas-related receptor type D (MrgD). The local RAS in adipose organ has prompted extensive research into white adipose tissue and brown adipose tissue (BAT), with a key role in regulating the cellular and metabolic plasticity of these tissues. The MasR activation favors the brown plasticity signature in the adipose organ by improve the thermogenesis, adipogenesis, and lipolysis, decrease the inflammatory state, and overall energy homeostasis. The MrgD metabolic effects are related to the maintenance of BAT functionality, but the signaling remains unexplored. This review provides a summary of RAS counterregulatory actions triggered by Mas and MrgD receptors on adipose tissue plasticity. Focus on the effects related to the morphology and function of adipose tissue, especially from animal studies, will be given targeting new avenues for treatment of obesity-associated metabolic effects.
Assuntos
Tecido Adiposo , Proto-Oncogene Mas , Receptores Acoplados a Proteínas G , Sistema Renina-Angiotensina , Animais , Humanos , Tecido Adiposo/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Metabolismo Energético , Obesidade/metabolismo , Obesidade/patologia , Receptores Acoplados a Proteínas G/metabolismo , Sistema Renina-Angiotensina/fisiologia , Transdução de SinaisRESUMO
The renin-angiotensin system (RAS) plays a key role in blood pressure regulation. The RAS is a complex interconnected system composed of two axes with opposite effects. The pressor arm, represented by angiotensin (Ang) II and the AT1 receptor (AT1R), mediates the vasoconstrictor, proliferative, hypertensive, oxidative, and pro-inflammatory effects of the RAS, while the depressor/protective arm, represented by Ang-(1-7), its Mas receptor (MasR) and the AT2 receptor (AT2R), opposes the actions elicited by the pressor arm. The AT1R, AT2R, and MasR belong to the G-protein-coupled receptor (GPCR) family. GPCRs operate not only as monomers, but they can also function in dimeric (homo and hetero) or higher-order oligomeric states. Due to the interaction with other receptors, GPCR properties may change: receptor affinity, trafficking, signaling, and its biological function may be altered. Thus, heteromerization provides a newly recognized means of modulation of receptor function, as well as crosstalk between GPCRs. This review is focused on angiotensin receptors, and how their properties are influenced by crosstalk with other receptors, adding more complexity to an already complex system and potentially opening up new therapeutic approaches.
Assuntos
Receptores Acoplados a Proteínas G , Sistema Renina-Angiotensina , Humanos , Sistema Renina-Angiotensina/fisiologia , Animais , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/fisiologia , Receptor Cross-Talk/fisiologia , Receptores de Angiotensina/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Pressão Sanguínea/fisiologia , Receptor Tipo 2 de Angiotensina/metabolismoRESUMO
Background: SARS-CoV-2 binding to ACE2 is potentially associated with severe pneumonia due to COVID-19. The aim of the study was to test whether Mas-receptor activation by 20-hydroxyecdysone (BIO101) could restore the Renin-Angiotensin System equilibrium and limit the frequency of respiratory failure and mortality in adults hospitalized with severe COVID-19. Methods: Double-blind, randomized, placebo-controlled phase 2/3 trial. Randomization: 1:1 oral BIO101 (350 mg BID) or placebo, up to 28 days or until an endpoint was reached. Primary endpoint: mortality or respiratory failure requiring high-flow oxygen, mechanical ventilation, or extra-corporeal membrane oxygenation. Key secondary endpoint: hospital discharge following recovery (ClinicalTrials.gov Number, NCT04472728). Findings: Due to low recruitment the planned sample size of 310 was not reached and 238 patients were randomized between August 26, 2020 and March 8, 2022. In the modified ITT population (233 patients; 126 BIO101 and 107 placebo), respiratory failure or early death by day 28 was 11.4% lower in the BIO101 (13.5%) than in the placebo (24.3%) group, (p = 0.0426). At day 28, proportions of patients discharged following recovery were 80.1%, and 70.9% in the BIO101 and placebo group respectively, (adjusted difference 11.0%, 95% CI [-0.4%, 22.4%], p = 0.0586). Hazard Ratio for time to death over 90 days: 0.554 (95% CI [0.285, 1.077]), a 44.6% mortality reduction in the BIO101 group (not statistically significant). Treatment emergent adverse events of respiratory failure were more frequent in the placebo group. Interpretation: BIO101 significantly reduced the risk of death or respiratory failure supporting its use in adults hospitalized with severe respiratory symptoms due to COVID-19. Funding: Biophytis.
RESUMO
Currently, cardiovascular diseases are a major contributor to morbidity and mortality worldwide, having a significant negative impact on both the economy and public health. The renin-angiotensin system contributes to a high spectrum of cardiovascular disorders and is essential for maintaining normal cardiovascular homeostasis. Overactivation of the classical renin-angiotensin system is one of the most important pathophysiological mechanisms in the progression of cardiovascular diseases. The counter-regulatory renin-angiotensin system is an alternate pathway which favors the synthesis of different peptides, including Angiotensin-(1-7), Angiotensin-(1-9), and Alamandine. These peptides, via the angiotensin type 2 receptor (AT2R), MasR, and MrgD, initiate multiple downstream signaling pathways that culminate in the activation of various cardioprotective mechanisms, such as decreased cardiac fibrosis, decreased myocardial hypertrophy, vasodilation, decreased blood pressure, natriuresis, and nitric oxide synthesis. These cardioprotective effects position them as therapeutic alternatives for reducing the progression of cardiovascular diseases. This review aims to show the latest findings on the cardioprotective effects of the main peptides of the counter-regulatory renin-angiotensin system.
RESUMO
Overactivation of the classic arm of the renin-angiotensin system (RAS) is one of the main mechanisms involved in obesity-related cardiac remodeling, and a possible relationship between RAS and ER stress in the cardiovascular system have been described. Thus, the aim of this study is to evaluate if activating the protective arm of the RAS by ACE inhibition or aerobic exercise training could overturn diet-induced pathological cardiac hypertrophy by attenuating ER stress. Male C57BL/6 mice were fed a control (SC) or a high-fat diet (HF) for 16 weeks. In the 8th week, HF-fed animals were randomly divided into HF, enalapril treatment (HF-En), and aerobic exercise training (HF-Ex) groups. Body mass (BM), food and energy intake, plasma analyzes, systolic blood pressure (SBP), physical conditioning, and plasma ACE and ACE2 activity were evaluated. Cardiac morphology, and protein expression of hypertrophy, cardiac metabolism, RAS, and ER stress markers were assessed. Data presented as mean ± standard deviation and analyzed by one-way ANOVA with Holm-Sidak post-hoc. HF group had increased BM and SBP, and developed pathological concentric cardiac hypertrophy, with overactivation of the classic arm of the RAS, and higher ER stress. Both interventions reverted the increase in BM, and SBP, and favored the protective arm of the RAS. Enalapril treatment improved pathological cardiac hypertrophy with partial reversal of the concentric pattern, and slightly attenuated cardiac ER stress. In contrast, aerobic exercise training induced physiological eccentric cardiac hypertrophy, and fully diminished ER stress.
Assuntos
Cardiomegalia , Enalapril , Estresse do Retículo Endoplasmático , Obesidade , Condicionamento Físico Animal , Animais , Masculino , Enzima de Conversão de Angiotensina 2/sangue , Cardiomegalia/etiologia , Cardiomegalia/terapia , Enalapril/farmacologia , Enalapril/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Camundongos Endogâmicos C57BL , Obesidade/complicações , Peptidil Dipeptidase A/sangue , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Transdução de Sinais/fisiologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêuticoRESUMO
During the early stages of the development of the living multiorgan systems, genome modifications other than sequence variation occur that guide cell differentiation and organogenesis. These modifications are known to operate as a fetal programming code during this period, and recent research indicates that there are some tissue-specific codes in organogenesis whose effects may persist after birth until adulthood. Consequently, the events that disrupt the pre-established epigenetic pattern could induce shifts in organ physiology, with implications on health from birth or later in adult life. Chronic kidney disease (CKD) is one of the main causes of mortality worldwide; its etiology is multifactorial, but diabetes, obesity, and hypertension are the main causes of CKD in adults, although there are other risk factors that are mainly associated with an individual's lifestyle. Recent studies suggest that fetal reprogramming in the developing kidney could be implicated in the susceptibility to kidney disease in both childhood and adulthood. Some epigenetic modifications, such as genome methylation status, dysregulation of miRNA, and histone coding alterations in genes related to the regulation of the renin-angiotensin axis, a common denominator in CKD, may have originated during fetal development. This review focuses on epigenetic changes during nephrogenesis and their repercussions on kidney health and disease. In addition, the focus is on the influence of environmental factors during pregnancy, such as maternal metabolic diseases and dietary and metabolic conditions, as well as some sex differences in fetal kidney reprogramming during which dysregulation of the renin-angiotensin system is involved.
Assuntos
Insuficiência Renal Crônica , Sistema Renina-Angiotensina , Gravidez , Feminino , Humanos , Masculino , Criança , Sistema Renina-Angiotensina/genética , Caracteres Sexuais , Rim , ReninaRESUMO
OBJECTIVE: Pressure overload can result in significant changes to the structure of blood vessels, a process known as vascular remodeling. High levels of tension can cause vascular inflammation, fibrosis, and structural alterations to the vascular wall. Prior research from our team has demonstrated that the oral administration of alamandine can promote vasculoprotective effects in mice aorta that have undergone transverse aortic constriction (TAC). Furthermore, changes in local hemodynamics can affect the right and left carotid arteries differently after TAC. Thus, in this study, we aimed to assess the effects of alamandine treatment on right carotid remodeling and the expression of oxidative stress-related substances induced by TAC. METHODS AND RESULTS: Male C57BL/6 mice were categorized into three groups: Sham, TAC, and TAC treated with alamandine (TAC+ALA). Alamandine treatment was administered orally by gavage (30 µg/kg/day), starting three days before the surgery, and continuing for a period of fourteen days. Morphometric analysis of hematoxylin and eosin-stained sections revealed that TAC induced hypertrophic and positive remodeling in the right carotid artery. Picrosirius Red staining also demonstrated an increase in total collagen deposition in the right carotid artery due to TAC-induced vascular changes. Alamandine treatment effectively prevented the increase in reactive oxygen species production and depletion of nitric oxide levels, which were induced by TAC. Finally, alamandine treatment was also shown to prevent the increased expression of nuclear factor erythroid 2-related factor 2 and 3-nitrotyrosine that were induced by TAC. CONCLUSION: Our results suggest that alamandine can effectively attenuate pathophysiological stress in the right carotid artery of animals subjected to TAC.
Assuntos
Artérias Carótidas , Estresse Oxidativo , Masculino , Camundongos , Animais , Constrição , Camundongos Endogâmicos C57BL , Artérias Carótidas/cirurgia , Remodelação Ventricular , Modelos Animais de DoençasRESUMO
OBJECTIVES: COVID-19, caused by SARS-CoV-2, has spread around the world since 2019. In severe cases, COVID-19 can lead to hospitalization and death. Systemic arterial hypertension and other comorbidities are associated with serious COVID-19 infection. Literature is unclear whether antihypertensive therapy with angiotensin receptor blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors affect COVID-19 outcomes. We aim to assess whether ACEI/ARB therapy is a risk factor for worse respiratory outcomes related to COVID-19 in hospitalized patients. METHODS: Retrospective study enrolling admitted COVID-19-diagnosed patients by RT-PCR at the Hospital Geral de Fortaleza, Brazil, during 2021. Patient medical records, sociodemographic, and clinical data were analyzed. Chest CT images were analyzed using CAD4COVID-CT/Thirona™ software. RESULTS: A total of 294 patients took part in the study. A cut-off point of 66% of pulmonary involvement was found by ROC curve, with patients having higher risk of death and intubation and lower 60-day survival. Advanced age (RR 1.025, P=0.001) and intubation (RR 16.747, P<0.001) were significantly associated with a higher risk of death. Advanced age (RR 1.023, P=0.001) and the use of noninvasive ventilation (RR 1.548, P=0.037) were associated with a higher risk of intubation. Lung involvement (>66%) increased the risk of death by almost 2.5-fold (RR 2.439, P<0.001) and by more than 2.3-fold the risk of intubation (RR 2.317, P<0.001). CONCLUSIONS: Altogether, our findings suggest that ACEI or ARB therapy does not affect the risk of death and disease course during hospitalization.
Assuntos
COVID-19 , Hipertensão , Humanos , COVID-19/complicações , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/efeitos adversos , SARS-CoV-2 , Estudos Retrospectivos , Receptores de Angiotensina/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologiaRESUMO
BACKGROUND: Neuropsychiatric disorders, such as mood disorders, schizophrenia, and Alzheimer's disease (AD) and related dementias, are associated to significant morbidity and mortality worldwide. The pathophysiological mechanisms of neuropsychiatric disorders remain to be fully elucidated, which has hampered the development of effective therapies. The Renin Angiotensin System (RAS) is classically viewed as a key regulator of cardiovascular and renal homeostasis. The discovery that RAS components are expressed in the brain pointed out a potential role for this system in central nervous system (CNS) pathologies. The understanding of RAS involvement in the pathogenesis of neuropsychiatric disorders may contribute to identifying novel therapeutic targets. AIMS: We aim to report current experimental and clinical evidence on the role of RAS in physiology and pathophysiology of mood disorders, schizophrenia, AD and related dementias. We also aim to discuss bottlenecks and future perspectives that can foster the development of new related therapeutic strategies. CONCLUSION: The available evidence supports positive therapeutic effects for neuropsychiatric disorders with the inhibition/antagonism of the ACE/Ang II/AT1 receptor axis or the activation of the ACE2/Ang-(1-7)/Mas receptor axis. Most of this evidence comes from pre-clinical studies and clinical studies lag much behind, hampering a potential translation into clinical practice.
Assuntos
Doença de Alzheimer , Sistema Renina-Angiotensina , Humanos , Sistema Renina-Angiotensina/fisiologia , Peptidil Dipeptidase A/metabolismo , Peptidil Dipeptidase A/uso terapêutico , Rim/metabolismo , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Sistema Nervoso Central/metabolismoRESUMO
In addition to being recognised for involvement in cardiovascular control and hydromineral balance, the renin-angiotensin system (RAS) has also been associated with the neuroendocrine control of energy balance. One of the main brain sites for angiotensin II (ANG II)/type 1 receptor (AT1 R) signalling is the subfornical organ (SFO), a circumventricular organ related to the control of autonomic functions, motivated behaviours and energy metabolism. Thus, we hypothesised that circulating ANG II may act on the SFO AT1 R receptors to integrate metabolic and hydromineral balance. We evaluated whether food deprivation can modulate systemic RAS activity and Agrt1a brain expression, and if ANG II/AT1 R signalling influences the hypothalamic expression of mRNAs encoding neuropeptides and food and water ingestion in fed and fasted Wistar rats. We found a significant increase in both ANG I and ANG II plasma levels after 24 and 48 h of fasting. Expression of Agrt1a mRNA in the SFO and paraventricular nucleus (PVN) also increased after food deprivation for 48 h. Treatment of fasted rats with low doses of losartan in drinking water attenuated the decrease in glycemia and meal-associated water intake without changing the expression in PVN or arcuate nucleus of mRNAs encoding selected neuropeptides related to energy homeostasis control. These findings point to a possible role of peripheral ANG II/SFO-AT1 R signalling in the control of refeeding-induced thirst. On the other hand, intracerebroventricular losartan treatment decreased food and water intake over dark time in fed but not in fasted rats.