Local renin angiotensin system and sperm DNA fragmentation / 亚洲男科学杂志(英文版)

The renin angiotensin system (RAS) appears to influence male fertility at multiple levels. In this work, we analyzed the relationship between the RAS and DNA integrity. Fifty male volunteers were divided into two groups (25 each): control (DNA fragmentation ≤20%) and pathological (DNA fragmentation >20%) cases. Activities of five peptidases controlling RAS were measured fluorometrically: prolyl endopeptidase (which converts angiotensin [A] I and A II to A 1-7), neutral endopeptidase (NEP/CD10: A I to A 1-7), aminopeptidase N (APN/CD13: A III to A IV), aminopeptidase A (A II to A III) and aminopeptidase B (A III to A IV). Angiotensin-converting enzyme (A I to A II), APN/CD13 and NEP/CD10 were also assessed by semiquantitative cytometry and quantitative flow cytometry assays, as were the receptors of all RAS components: A II receptor type 1 (AT1R), A II receptor type 2 (AT2R), A IV receptor (AT4R or insulin-regulated aminopeptidase [IRAP]), (pro)renin receptor (PRR) and A 1-7 receptor or Mas receptor (MasR) None of the enzymes that regulate levels of RAS components, except for APN/CD13 (decrease in fragmented cells), showed significant differences between both groups. Micrographs of RAS receptors revealed no significant differences in immunolabeling patterns between normozoospermic and fragmented cells. Labeling of AT1R (94.3% normozoospermic vs 84.1% fragmented), AT4R (96.2% vs 95.3%) and MasR (97.4% vs 87.2%) was similar between the groups. AT2R (87.4% normozoospermic vs 63.1% fragmented) and PRR (96.4% vs 48.2%) were higher in non-fragmented spermatozoa. These findings suggest that fragmented DNA spermatozoa have a lower capacity to respond to bioactive RAS peptides.

Eje Renina Angiotensina, Enzima Convertidora de Angiotensina 2 y Coronavirus / Renin Angiotensin Axis, Angiotensin Converting Enzyme 2 and Coronavirus

Resumen: El sistema renina angiotensina aldosterona (SRAA) es el principal regulador del volumen plasmático, manteniendo la homeostasis cardiovascular e hidrosalina. En la vía clásica, la enzima convertidora de angiotensina (ECA) genera Angiotensina II (AngII), de potente efecto inflamatorio y vasoconstrictor. Esta vía clásica es a su vez regulada por la ECA2, que convierte AngII a Ang 1-7, cuyas acciones vaso dilatadoras y antiinflamatorias dan balance a los efectos de AngII. La ECA2 se ha relacionado con la patogenia de infecciones respiratorias como el virus respiratorio sincicial y el síndrome respiratorio agudo grave por coronavirus (SARS-CoV y SARS-CoV-2). Estudios recientes han demostrado que la ECA2 corresponde al principal receptor del SARS-CoV-2, que en conjunto con otros receptores como la serin proteasa TMPRSS2, permiten la fijación, fusión y entrada del virus a la célula huésped. En animales infectados por SARS-CoV se produce una caída de la concentración tisular de ECA2 y Ang 1-7, con la consiguiente sobreexpresión de AngII, y sus efectos vasoconstrictores e inflamatorios. Experimentos con ECA2 recombinante han mostrado un efecto protector frente a la sobreexpresión del SRAA en animales infectados por SARS-CoV, efecto similar al demostrado con el uso de bloquea- dores del receptor de AngII, AT1. La evidencia sobre el rol protector de ECA2 parece respaldar las recomendaciones respecto a no suspender estos medicamentos en la infección SARS-CoV-2. En este artículo presentamos el conocimiento actual sobre el rol del SRAA en la infección por SARS-CoV, a partir de conceptos fisiopatológicos, bases moleculares, y evidencia experimental y clínica.

Abstract: The renin-angiotensin-aldosterone system (RAAS) is the main plasma volume regulator, which maintains cardiovascular and hydrosaline homeostasis. In the classical pathway, the angiotensin converting enzyme (ACE) generates Angiotensin II (AngII), which is powerfully inflammatory and vasoconstrictive. This classical pathway is also regulated by ACE2, which converts AngI to Ang 1-9, and degrades AngII to Ang 1-7, whose vasodilatory and anti-inflammatory functions balance out the effects of AngII. ACE2 has been associated with the pathogenesis of respiratory infections such as RSV and severe acute respiratory syndrome coronavirus (SARS-CoV and SARS-CoV-2). Recent studies have shown that ACE2 corresponds to the main SARS-CoV-2 receptor, which together with other receptors such as the TMPRSS2, allows the virus to attach, fuse, and enter the host cell. These studies have shown that in animals infected with coronavirus there is a drop in tissue concentration of ACE2 and Ang 1-7, leading to overexpression of AngII and its vasoconstrictive and inflammatory effects. Experiments with recombinant ACE2 have shown a protective effect against overexpression of RAAS in coronavirus-infected animals, which is similar to that demonstrated with the use of AnglI receptor blockers (AT1). Evidence on the protective role of ACE2 seems to support the recommendations re garding not discontinuing these drugs in COVID-19 infection. In this article, we present the current knowledge about the role of RAAS in coronavirus infection, based on physiopathological concepts, molecular bases, and experimental and clinical evidence.

Implicaciones cardiovasculares de la infección por SARS-CoV-2: revisión de literatura / Cardiovascular implications of SARS-CoV-2 infection: a literature review

En diciembre de 2019 se reportó en Wuhan, China, la aparición de una nueva cepa de coronavirus SARS-CoV-2 que producía un compromiso pulmonar severo y progresaba a estrés respiratorio agudo. A la fecha, son más de diecisiete millones los casos confirmados y más de medio millón los fallecidos en todo el mundo a causa de COVID-19. Los estudios reportan que los pacientes con enfermedad cardiovascular son más susceptibles a contraer esta enfermedad y a presentar más complicaciones. El propósito de esta revisión es proporcionar información actualizada para los profesionales de la salud que atienden a pacientes con COVID-19 y que tienen además enfermedad cardiovascular y por ende un riesgo elevado de complicaciones y mortalidad. Realizamos una búsqueda de bibliografía científica acerca de la asociación de enfermedad cardiovascular y COVID-19 en diferentes bases de datos como Scopus, MEDLINE vía PubMed y Cochrane Library. El tratamiento con inhibidores de la enzima convertidora de angiotensina y bloqueadores del receptor de angiotensina ha sido motivo de discusión y no hay evidencia sólida para contraindicarlo en pacientes con COVID-19. Respecto al tratamiento con hidroxicloroquina asociado o no con azitromicina, hay evidencia que demuestra un mayor riesgo con su utilización, que beneficio clínico y/o disminución de mortalidad. En este contexto, los pacientes con insuficiencia cardíaca representan un grupo importante de riesgo por su condición per se y por el dilema diagnóstico generado al evaluar un paciente con COVID-19, en el que los signos de insuficiencia cardíaca aguda podrían enmascararse. Por otro lado, en los pacientes con síndrome coronario agudo, el enfoque terapéutico inicial podría cambiar en el contexto de la pandemia, aunque sólo sobre la base de opiniones de expertos. Quedan, sin embargo, muchos temas en controversia que serán motivo de investigaciones futuras.

In December 2019, a new strain of the SARS-CoV-2 coronavirus was reported in Wuhan, China, which produced severe lung involvement and progressed to respiratory distress. To date, more than seventeen million confirmed cases and more than half a million died worldwide from COVID-19. Patients with cardiovascular disease are more susceptible to contracting this disease and presenting more complications. We did a literature search on the association of cardiovascular disease and COVID-19 in databases such as Scopus, PubMed/MEDLINE, and the Cochrane Library. The purpose of this review is to provide updated information for health professionals who care for patients with COVID-19 and cardiovascular disease, given that they have a high risk of complications and mortality. Treatment with angiotensin-converting enzyme inhibitors and receptor blockers is controversial, and there is no evidence not to use these medications in patients with COVID-19. Regarding treatment with hydroxychloroquine associated or not with azithromycin, there is evidence of a higher risk with its use than clinical benefit and decreased mortality. Likewise, patients with heart failure are an important risk group due to their condition per se. Patients with heart failure and COVID-19 are a diagnostic dilemma because the signs of acute heart failure could be masked. On the other hand, in patients with acute coronary syndrome, the initial therapeutic approach could change in the context of the pandemic, although only based on expert opinions. Nonetheless, many controversial issues will be the subject of future research.

Fisiopatología de COVID-19: función del receptor ACE2 y su vínculo con el ejercicio físico de moderada intensidad / COVID-19 pathophysiology: ACE2 receptor function and its link to moderate-intensity physical exercise

OBJETIVO: Se realizó una revisión que asoció de modo indirecto los efectos del ejercicio físico y los mecanismos fisiopatológicos de Covid-19 con el objetivo de aportar más antecedentes a una posible relación descrita previamente. FUENTES: Se obtuvo la información desde las bases de datos de PubMed y Sciencedirect. MÉTODOS: Fueron incluidos artículos descriptivos y experimentales considerando que la evidencia estuviese respaldada por datos estadísticamente significativos. La información se organizó relacionando los mecanismos compartidos por el ejercicio y la fisiopatología de Covid-19. RESULTADOS: Se logró establecer una asociación bastante concluyente, considerando que la información recopilada guarda una relación indirecta. Conclusiones: El ejercicio físico es un potencial factor protector que podría impedir el avance del virus y sus consecuencias en el organismo posterior a un eventual contagio. Para confirmar definitivamente esta hipótesis es necesario estudiar los efectos del ejercicio físico en condiciones que contemplen una relación más directa con la enfermedad.

OBJECTIVE: The aim of this review is to create a background from the relationship between the pathophysiological mechanisms of Covid-19, the activity of the ACE2 receptor and the effects of physical exercise. SOURCES: Studies were obtained from PubMed and Science direct databases. METHODS: Descriptive and experimental articles were selected, considering that the evidence was supported by statistically significant data. Subsequently, the information was organized by establishing relationships between the pathophysiology of Covid-19 and the physiological mechanisms of exercise. RESULTS: A logical and coherent association was formulated between ACE2 receptor activity, the effects of physical exercise, and the pathophysiological mechanisms of Covid-19. CONCLUSIONS: There is common relationship between Physiological mechanisms and physical exercise with Covid-19. We could establish as incipient evidence an eventual protective role of physical exercise within this disease. Future research could support prevention measures that include the practice of physical exercise.

COVID-19 y el sistema renina, angiotensina, aldosterona. Una relación compleja / COVID-19 and the renin, angiotensin, aldosterone system. A complex relationship

Resumen La pandemia por COVID-19 ha tenido muy importantes repercusiones negativas, sanitarias, psicológicas, sociales y económicas para las personas, las familias, las comunidades, los países y para las para la humanidad en general. La interrelación con la edad y la presencia de enfermedades crónicas no trasmisibles (hipertensión, diabetes, obesidad, tabaquismo) parece ir mas lejos que lo que explicaría la prevalencia y distribución de ambas. Los medicamentos que actúan sobre el sistema renina-angiotensina-aldosterona, son pilares básicos en el manejo de estas enfermedades. Se sabe de tiempo atrás que estos fármacos aumentan en forma significativa la expresión en el tejido pulmonar de receptores para la enzima de conversión de angiotensina de tipo 2. Este hecho junto con el conocimiento de que la vía de entrada del virus a la célula es precisamente el receptor de ECA-2, inició una hipótesis, basada en evidencia de muy baja calidad, que rápidamente se generalizó en los medios de comunicación, de que el empleo de estos medicamentos podría ser negativo y que deberían suspenderse. La respuesta de prácticamente todas las sociedades científicas fue casi inmediata, con la indicación precisa de que no debería suspenderse el tratamiento con estos fármacos, puesto que la evidencia de su utilidad está basada en una evidencia muy sólida y de gran calidad. Casi simultáneamente también apareció la hipótesis, también basada en evidencia muy preliminar, de que estos medicamentos no solo resultan dañinos sino que son benéficos, tampoco se aceptan todavía como agentes para la prevención o tratamiento de esta enfermedad o sus complicaciones. La presente revisión relata los conocimientos actuales sobre la relación entre COVID-19 y SRAA.

Abstract The COVID-19 pandemic has had major negative health, psychological, social and economic repercussions for individuals, families, communities, countries and for humanity in general. The interrelation with age and the presence of chronic non-communicable diseases (hypertension, diabetes, obesity, smoking) seems to go further than what would be explained by the prevalence and distribution of both. The drugs that act on the renin-angiotensin-aldosterone system are in many cases the backbone for the management of these diseases, it has been known for a long time that these drugs significantly increase the expression of receptors for angiotensin conversion enzyme type 2 in the lung tissue. This fact, together with the knowledge that the route of entry of the virus into the cell is precisely the ACE-2 receptor, initiated a hypothesis, based on very low-quality evidence, which quickly became generalized in the media, that the use of these drugs could be negative and that they should be interrupted immediately. The response of practically all Scientific Societies was almost immediate, with the precise indication that treatment with these drugs should not be discontinued, since the evidence of their usefulness is based on very solid and high-quality evidence. Simultaneously, a different hypothesis also appeared, also based on very preliminary evidence, that these drugs are not only harmful but also beneficial, however these medicaments are not yet accepted as agents for the prevention or treatment of this disease or its complications. This review reports current knowledge on the relationship between COVID-19 and SRAA.

The status and research progress on vitamin d deficiency and atrial fibrillation

Abstract Atrial fibrillation is a common type of arrhythmia and is an important cause of stroke and heart failure. vitamin D is an emerging risk factor of AF, and is implicated in the pathophysiology of atrial fibrillation. It has been established that this vitamin is extensively involved in the regulation of both the renin angiotensin aldosterone system and the immune system. Epidemiological studies have not yet reached a consensus on the possible association between vitamin D deficiency and atrial fibrillation. Better research designs and methods can further clarify the relationship between the two.

Actualización en el manejo clínico de la hipertensión hiporreninémica / Update in the clinical management of low renin hypertension

The renin-angiotensin-aldosterone system modulates volume, sodium and potassium homeostasis. In the setting of a high sodium diet, up to 30% of patients with hypertension have a low or suppressed renin and increased volume. This phenotype of low renin hypertension (LRH) is multifactorial and includes infrequent inherited genetic syndromes, milder phenotypes of classic diseases and environmental exposures. All these conditions have in common a higher cardiovascular risk mediated by the over activation of the mineralocorticoid receptor (MR), present not only in the kidney, but also in vasculature, myocardium and adipocytes. Consequently, the aim of LRH treatment goes beyond the control of blood pressure and requires antagonizing MR with specific pharmacologic agents, pursuing normalization of renin as a clinical objective. Due to the unusual evaluation of renin status by non-endocrinologists and lack of disease awareness, only a minority of hypertensive patients receive this pathophysiologically-driven treatment that should reduce cardiovascular outcomes.

Superimposing a high-fat diet on schistosoma mansoni infection affects renin-angiotensin system components in the mouse kidney

Abstract INTRODUCTION: The levels of the full-length form of the (pro)renin receptor (PRR), a component of the renin-angiotensin system (RAS), may be reduced in the membranes of kidneys in renal diseases. This study aimed to investigate the RAS components in the kidneys of mice submitted to a combination of a high-fat diet and Schistosoma mansoni infection. METHODS: Female BALB/c mice were maintained on a control or high-fat diet from 3 weeks of age. After 10 weeks on the designated diets, half the mice in each group were infected with S. mansoni cercariae. The blood and kidneys were harvested 8 weeks after infection. RESULTS: The high-fat diet increased the number of eggs in the feces and the number of adult worms in the mesenteric bed. Schistosoma mansoni infection reduced the plasma levels of glucose, triglycerides, and HDL cholesterol in the control and high-fat diet groups. In mice on the control diet, S. mansoni infection resulted in increased expression of IL-6 in the kidneys; however, in mice on the high-fat diet, the levels of IL-6 were reduced and those of superoxide anions were increased. The RAS components evaluated were ACE2, renin, PRR, AT1R, and AT2R, and the levels of PRR were found to be reduced in the kidneys of infected mice on the high-fat diet. CONCLUSIONS: The finding regarding PRR is not yet clear. However, combining a high-fat diet and S. mansoni infection resulted in increased oxidative stress in the kidney that can aggravate hypertension as well as its associated complications.

Avaliação dos eixos ECA / ANG II / AT1 e ECA-2 / ANG (1-7) / MAS em fibroblastos de gengiva e ligamento periodontal humanos estimulados por IL-1ß e sua contribuição na produção e regulação de citocinas e quimiocinas / Evaluation ACE /ANG II /AT1 and ACE-2 /ANG (1-7) /MAS axis in gingival and periodontal ligament human fibroblasts stimulated with IL-1ß and its contribution in the production of cytokines and chemokines

O Sistema renina-angiotensina (SRA) tem sido relatado como um importante modulador de processos inflamatórios e imunológicos, incluindo a doença periodontal (DP). Estudos sugerem neste sistema um eixo alternativo (ECA-2 /ANG(1-7) /MAS) que atuaria como um contra-regulador de efeitos mediados pelo clássico eixo (ECA /ANGII /AT1). Sabe-se que bactérias periodontopatogênicas, como a Porphyromonas gingivalis (Pg), possuem componentes bioativos de membrana (ex. lipopolissacarídeos-LPS) capazes de induzir uma forte resposta imune no hospedeiro devido à liberação de citocinas nas células, entre elas Interleucina (IL)- 1ß. Neste contexto, fibroblastos são as células mais abundantes nos tecidos periodontais e possuem em sua superfície celular receptores necessários para o reconhecimento da invasão bacteriana, ativando cascatas intracelulares, que levam à produção de citocinas. O objetivo deste estudo foi verificar se os eixos ECA/ ANGII/ AT1 e ECA-2/ ANG(1-7)/ MAS contribuem para a produção e/ ou regulação de citocinas inflamatórias (CI) por fibroblastos de gengiva humana (HGF) e ligamento periodontal humano (HPLF) estimulados por IL-1ß. Após o pré-tratamento com Losartan e Ang (1-7) ou silenciamento mediado por RNA de interferência (RNAi) de AT1, HGF e HPLF foram estimulados por IL-1ß por 3 horas (RNAm) ou 24 horas (proteína). Expressão de RNAm para AT1, MAS, ECA, ECA-2, IL-1ß, TNF-α, IL-6, IL-8, IL-10, TGF-ß, CXCL12, RANK-L e OPG foram avaliados por RT-qPCR e das proteínas IL-6, IL-8, ECA e ECA-2 por ELISA. Foi realizado também Western Blot para detecção de AT1 e ECA nos extratos celulares e dosagem de nitrito no sobrenadante das culturas. Ambos os subtipos de fibroblastos mostraram aumento da expressão de RNAm para AT1, IL-1ß, IL-6, IL-8, TNF-α e OPG, quando estimulados por IL-1ß. No entanto, apenas em HPLF foi observado aumento para MAS, ECA e TGF-ß. Losartan e Ang (1-7) não modularam o transcrito, a secreção de CI e nem a produção de nitrito no sobrenadante das culturas, tanto em HGF como em HPLF. O silenciamento do receptor AT1 reduziu a secreção de IL-6 e IL-8 induzida por IL-1ß em cultura de HGF e HPLF e aumentou a expressão gênica de OPG somente em HGF. Estes resultados sugerem que o silenciamento de AT1, mas não o bloqueio farmacológico deste receptor pelo antagonista Losartan, em HGF e HPLF, pode controlar a produção de IL-6 e IL-8, que por sua vez contribuem para a patogênese periodontal.(AU)

The renin-angiotensin system (RAS) has been reported as an important modulator of inflammatory and immune responses, including periodontal disease (PD). Studies suggest an alternative axis as part of this system (ACE-2 / ANG (1-7) / MAS) that would act as counter-regulatory to the classical axis (ECA / ANGII / AT1). It is known that periodontal bacteria such as Porphyromonas gingivalis (Pg) have bioactive components in their membrane (such as lipopolysaccharide-LPS) capable of inducing a strong immune response in the host due to the release of cytokines in cells, including interleukin (IL) - 1ß. In this regard, fibroblasts are the most abundant cells in periodontal tissues and receptors needed for the recognition of bacterial invasion by activating intracellular cascades that lead to cytokine production. The aim of this study was to determine whether the axes ACE / ANGII / AT1 and ACE-2 / ANG (1-7) / MAS contribute to the production and / or regulation of inflammatory cytokines (IC) by fibroblasts of human gingiva (HGF) and human periodontal ligament (HPLF) stimulated IL-1ß. After pre-treatment with Losartan, Ang (1-7) or silencing mediated by RNA interference (RNAi) of AT1, HGF and HPLF were stimulated by IL-1ß for 3 hours (RNAm) or 24 hours (protein). Expression mRNA for AT1, MAS, ACE, ACE-2, IL-1ß, TNF-α, IL-6, IL-8, IL-10, TGF-ß, CXCL12, RANK-L and OPG was assessed by RT- qPCR and proteins IL-6, IL-8, ACE and ACE-2 by ELISA. Western Blot for the detection of AT1 and ECA and dosage of nitrite was also performed. Experiments stimulated by IL-1ß showed a positive control for gene expression AT1, IL-1ß, IL-6, IL-8, TNF-α and OPG in HGF and HPLF and MAS, ACE and TGF-ß only HPLF. Losartan and Ang (1-7) did not modulate the transcription and secretion of IC and no nitrite production in the culture supernatant of HGF and HPLF. The silencing AT1 reduced IL-6 secretion and IL-8 induced by IL- ß in cultured HGF and HPLF and increased OPG gene expression only HGF. These results suggest that silencing AT1, but not pharmacological blockade of this receptor by Losartan in HPLF and HGF, can control the production of IL-6 and IL-8, which in turn contribute to the pathogenesis of periodontal disease.(AU)

Sistema renina angiotensina, novas evidências na fisiopatologia da hipertensão: importância para a prática clínica / Renin-angiotensin system, new evidence in the pathophysiology of hypertension: critical role for the clinical practice

O Sistema Renina Angiotensina é reconhecidamente um poderoso determinante da homeostase e da hemodinâmica renal e cardiovascular. Nos últimos anos, os estudos têm focado o eixo angiotensina II (Ang II)/receptor AT1 e o eixo angiotensina 1-7 (Ang 1-7)/receptor Mas, evidenciando que a atividade dos peptídeos é modulada com a Ang1-7antagonizando as ações da Ang II. As ações da Ang II, via receptor AT1, relacionadas à vasoconstrição, estresse oxidativo, inflamação, proliferação e fibrose são equilibradas pelas ações da Ang 1-7, mediadas pelo receptor Mas, que levam à vasodilatação, inibem o estresse oxidativo, a proliferação e a fibrose tecidual. O balanço obtido entre os eixos parece conduzir as ações do sistema para condições fisiológicas ou para o desenvolvimento de patologias, e sobretudo, tem dissociado o sistema circulante do tecidual. O conhecimento de marcadores biológicos que possam ser utilizados no diagnóstico e prognóstico de doenças cardiovasculares é de extrema importância para o desenvolvimento aprimoramento de métodos terapêuticos e profiláticos incluindo novas drogas.

The Renin Angiotensin System has a critical role in renal and cardiovascular homeostasis and hemodynamics. In recent years, studies have focused in the two main axes of RAS: angiotensin II (Ang II)/AT1 receptor and angiotensin 1-7 axis (Ang 1-7)/Mas receptor, evidencing that the peptide activity is modulated with Ang1-7 antagonizing the actions of Ang II. The actions of Ang II, via the AT1 receptor, related to vasoconstriction, oxidative stress,inflammation, proliferation and fibrosis, are balanced by the actions of Ang 1-7. These, in turn, are mediated by the Mas receptor, but lead to vasodilation and inhibit oxidative stress, proliferation and tissue fibrosis. The balance obtained between the axes of the system appearsto lead to physiological conditions or pathologies, and above all, has disassociated the circulatory system from the tissue system. The discovery of biomarkers that may be useful inthe diagnosis and prognosis of cardiovascular diseases is critical for the development and improvement of therapeutic and prophylactic approaches, including new drugs.

Urinary Sodium Excretion Has Positive Correlation with Activation of Urinary Renin Angiotensin System and Reactive Oxygen Species in Hypertensive Chronic Kidney Disease

It is not well described the pathophysiology of renal injuries caused by a high salt intake in humans. The authors analyzed the relationship between the 24-hr urine sodium-to-creatinine ratio (24HUna/cr) and renal injury parameters such as urine angiotensinogen (uAGT/cr), monocyte chemoattractant peptide-1 (uMCP1/cr), and malondialdehyde-to-creatinine ratio (uMDA/cr) by using the data derived from 226 hypertensive chronic kidney disease patients. At baseline, the 24HUna/cr group or levels had a positive correlation with uAGT/cr and uMDA/cr adjusted for related factors (P or =200 mEq/g cr was higher than in patients with or =200 mEq/g cr (P=0.016). During the 16-week follow-up period, an increase in urinary sodium excretion predicted an increase in urinary angiotensinogen excretion. In conclusion, high salt intake increases renal renin-angiotensin-system (RAS) activation, primarily, and directly or indirectly affects the production of reactive oxygen species through renal RAS activation.

Sistema renina-angiotensina, deterioro cognitivo y demencia. Implicancias terapéuticas de su inhibición / Renin-angiotensin system, cognitive deterioration and dementia. therapeutic implications of their Inhibition

La acumulación de amiloide, la edad y la enfermedad vascular son los principales factores de riesgo para desarrollar una demencia. Existe un interjuego entre los factores genéticos y vasculares para desarrollar la enfermedad de Alzheimer de inicio tardío. La activación sostenida del sistema renina Angiotensina parece ocupar un papel destacado en la fisiopatología de las demencias incluyendo la enfermedad de Alzheimer. El tratamiento antihipertensivo con inhibidores de la enzima de conversión de Angiotensina tanto como el bloqueo de los receptores de la Angiotensina II, parecen superiores sobre otros fármacos en la prevención de las demencias

The age, aggregation of amyloid, and vascular disease are major risk factors for developing dementia. There is interplay between genetic and vascular factors to develop late-onset Alzheimer's disease. Sustained the renin angiotensin system activation seems to occupy an important role in the pathophysiology of dementia including Alzheimer's disease. Antihypertensive treatment with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockade, seem superior over other drugs in the prevention of dementia

Involvement of Src tyrosine kinase and protein kinase C in the expression of macrophage migration inhibitory factor induced by H2O2 in HL-1 mouse cardiac muscle cells

Macrophage migration inhibitory factor (MIF), a pleiotropic cytokine, plays an important role in the pathogenesis of atrial fibrillation; however, the upstream regulation of MIF in atrial myocytes remains unclear. In the present study, we investigated whether and how MIF is regulated in response to the renin-angiotensin system and oxidative stress in atrium myocytes (HL-1 cells). MIF protein and mRNA levels in HL-1 cells were assayed using immunofluorescence, real-time PCR, and Western blot. The result indicated that MIF was expressed in the cytoplasm of HL-1 cells. Hydrogen peroxide (H2O2), but not angiotensin II, stimulated MIF expression in HL-1 cells. H2O2-induced MIF protein and gene levels increased in a dose-dependent manner and were completely abolished in the presence of catalase. H2O2-induced MIF production was completely inhibited by tyrosine kinase inhibitors genistein and PP1, as well as by protein kinase C (PKC) inhibitor GF109203X, suggesting that redox-sensitive MIF production is mediated through tyrosine kinase and PKC-dependent mechanisms in HL-1 cells. These results suggest that MIF is upregulated by HL-1 cells in response to redox stress, probably by the activation of Src and PKC.

Hipertensão arterial no paciente diabético / Arterial hypertension in diabetic patients

A frequente associação entre hipertensão arterial e diabetes tem como consequência um grande aumento no risco cardiovascular e reanl. O tratamento da hipertensão arterial é particularmente importante nos pacientes diabéticos, tanto para a prevenção da doença cardiovascular quanto para minimizar a progressão da doença renal e da retinopatia diabética. A terapêutica inicial inclui métodos não medicamentoso, tais como redução de peso, prática de exercícios físicos, moderação no consumo de sal e álcool e abandono do fumo. A maioria das diretrizes recomenda que os pacientes diabéticos devam manter a pressão arterial abaixo de 130/80 mmHg, embora alguns estudos recentes sugiram que esta concha não é mais vantajosa do que reduzir a pressão apenas a valores inferiores a 140/90 mmHg, a não ser para pacientes com nefropatia. Vários agentes anti-hipertensivos podem se utilizados, sendo que, na maioria das vezes, dois ou três deles precisam ser associados para atingir níveis de controle. Existem vantagens na inclusão de bloqueadores do sistema renina angiotensina (SRA) no esquema terapêutico antihipertensivo, tanto para proteção renal quanto cardiovascular. Na vigência de microalbuminúria ou proteinúria, o bloqueio do SRA é, comprovadamente, a medida mais eficiente para deter a progressão da doença renal.

The frequent association between hypertension and diabetes has resulted in a increase in cardiovascular and renal risk. The treatment of hypertension in particularly important in diabetic patients, both for the prevention of cardiovascular disease as well as to reduce the progression of renal disease and retinopathy. Initial therapy includes non-pharmacological methods such as weight reduction, physical exercise, moderation in salt and alcohol consuption and smoking cessation. Most guidelines recommend that patients with diabetes should keep blood pressure below 130/80 mmHg although some recent studies suggest that this conduct is not more advantageous than just reduce the blood pressure values below 140/90 mmHg, except for patients with nephropathy. All antihypertensive agents can be used and in most cases two or three of them must be associated for blood pressure control. there are advantages in adding renin - angiotensin system (RAS) blocking agents to antihypertensive therapy, both for cardiovascular and renal protection. In the presence of microalbuminuria or proteinuria, RAS blockade is arguably the most effective measure to stop the progression of renal disease.

Hipertensão arterial nos pacientes com doença renal crônica / Hypertension in patients with chronic kidney disease

A hipertensão arterial é o maior fator de risco para doença cardiovascular e renal. Inversamente, a doença renal crônica é a forma mais comum de hipertensão secundária e várias evidências sugerem que é um fator de risco independente para mortalidade e morbidade cardiovascular. Balanço de sal positivo é o fator dominante, mas não único na gênese da hipertensão na doença renal crônica. As evidências experimentais demonstraram , claramente que a hipertensão devido à retenção de sal e água é mantida pelos aumento da resistência periférica.O diagnóstico da hipertensão é criticamente dependente das medidas adequadas da pressão arterial, principalmente em pacientes com doença renal crônica, cujo tratamento anti-hipertensivo precoce é mandatório para a prevenção de eventos cardiovasculares. A monitorização ambulatorial da pressão arterial permitiu identificar pacientes hipertensos de risco elevado. O tratamento da hipertensão em pacientes com doença renal crônica deve levar em consideração a natureza da doença renal subjacente. Pacientes com nefropatia diabética ou doença renal não diabética proteinúrica se beneficiam do tratamento com inibidores da enzima de conversãoda angiotensina ou bloqueadores do receptor de angiotensina II para a meta de pressão arterial < 130/80 mmHG, se tolerado. A meta abaixo de 140/90 mmHg é aceitável para muitos pacientes com outras formas de doença renal. Bloqueio duplo ou triplo do sistema renina angiotensina deve ser evitado.

Hypertension is a major risk factor for cardiovascular and renal disease. Conversely, chronic kidney disease is the most common form of secondary hypertension and mounting evidence suggest it is independent risk factor for cardiovascular morbidity and mortality. positive salt balance is the dominant but not the sole factor in the genesis of hypertension in chronic kidney disease. The experimental evidences have clearly demonstrated that hypertension due to retention of salt and water is maintained by increased peripheral resistance. The diagnosis of hypertension is critically dependent on accurate blood pressure measurement, especially in patients with chronic kidney disease, in whom early antihypertensive treatment is imperative to prevent cardiovascular events. Ambulatory blood pressure monitoring has successfully identified hypertensive patients at increased risk. The treatment of hypertension in chronic kidney disease patients should take into consideration the nature of the underlying kidney disease. Patients with diabetic nephropathy or proteinuric nondiabetic kidney disease benefit from treatment with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers to a goal blood pressure of < 140/90 mmHg is acceptable for most patients with other forms of chronic kidney disease. Dual or triple blockade of the renin-angiotensin system should generally be avoided.

Inibidor direto da renina e hipertensao arterial: uma revisão / Direct renin inhibitor and hypertension: a review

A hipertensão arterial é considerada um problema de saúde pública e também um dos fatores de risco para o desenvolvimento de doenças cardiovasculares. Assim, medidas de tratamento devem ser tomadas afim de melhorar esse quadro. O inibidor direto da renina (IDR) é uma nova alternativa de tratamento anti-hipertensivo, comercializado pelo princípio ativo alisquireno. O objetivo deste estudo foi revisar a literatura quanto aos efeitos do tratamento com o IDR, na monoterapia ou terapia combinada a outras classesde anti-hipertensivos, tanto em animais quanto em seres humanos. Após o filtro de buscas na base de dados Medline, foram selecionados 11 artigosenvolvendo animais e 28 artigos envolvendo seres humanos. O IDR foi eficiente em reduzir a pressão arterial, seja administrado isoladamente seja emterapia combinada. No entanto, doses maiores parecem ser mais eficientes comparadas a doses mais baixas. Além disso, parece apresentar algumasvantagens adicionais quando comparado a outros bloqueadores do sistema renina-angiotensina, como a redução de efeitos adversos. Os mecanismosfisiológicos envolvidos nas respostas ao alisquireno ainda estão em fase de estudos, mas existem evidênciasde que há redução na atividade da renina plasmática.

Mechanisms of endothelial dysfunction in obesity-associated hypertension

Obesity is strongly associated with high blood pressure, dyslipidemia, and type 2 diabetes. These conditions synergistically increase the risk of cardiovascular events. A number of central and peripheral abnormalities can explain the development or maintenance of high blood pressure in obesity. Of great interest is endothelial dysfunction, considered to be a primary risk factor in the development of hypertension. Additional mechanisms also related to endothelial dysfunction have been proposed to mediate the development of hypertension in obese individuals. These include: increase in both peripheral vasoconstriction and renal tubular sodium reabsorption, increased sympathetic activity and overactivation of both the renin-angiotensin system and the endocannabinoid system and insulin resistance. The discovery of new mechanisms regulating metabolic and vascular function and a better understanding of how vascular function can be influenced by these systems would facilitate the development of new therapies for treatment of obesity-associated hypertension.

Estudo da expressão e produção de componentes do sistema renina-angiotensina por fibroblastos de gengiva e ligamento periodontal humanos / Study of expression and production of the renin-angiotensin system components by gingival and periodontal ligament human fibroblasts

O Sistema Renina-angiotensina (SRA), e um sistema capaz de gerar hormonios peptideos com grande impacto na regulacao cardiovascular e na patogenese das doencas cardiovasculares. Este sistema opera, por meio das acoes da Angiotensina II, tanto em nivel sistemico (endocrino) quanto tecidual (local, paracrino/autocrino) controlando importantes funcoes, varias delas relacionadas a facilitacao da instalacao e progressao do processo inflamatorio. Por este motivo, a producao desta proteina nos tecidos pode estar relacionada a patogenese de muitas doencas, dentre elas a doenca periodontal (DP), tendo em vista seu carater infeccioso-inflamatorio e os achados da literatura que mostram que a inibicao da formacao de Ang II, diminui a perda óssea da DP em animais. Desta forma, o presente trabalho teve como objetivos: Avaliar in vitro, a) A expressao de componentes do SRA (ANGT, RENINA, ECA, ECA-2, AT1, AT2 e Mas) por fibroblastos de gengiva e ligamento periodontal humanos, por RT-qPCR; b) A producao de componentes do SRA (RENINA, ECA, ECA-2) no sobrenadante de culturas de fibroblastos de gengiva e ligamento periodontal humanos, por ELISA; c) A producao dos receptores do SRA (AT1, AT2 e Mas), nestes fibroblastos, por Imunofluorescencia e d) Se a expressao e a producao dos componentes do SRA por fibroblastos de gengiva e ligamento periodontal humanos, se alteram com a estimulacao por LPS de P. gingivalis e E. coli. Apos a coleta, os dados foram analisados com o auxilio do programa GraphPad Prism 5.0. por meio da analise de variancia a 2 criterios (ANOVA-two way) seguida do pos teste de Bonferroni, com nivel de significancia de 5% para a verificacao das possíveis diferencas. Foi detectada a expressao genica para alguns dos componentes do SRA (ANGT, RENINA, ECA, AT1) por fibroblastos tanto de gengiva quanto de ligamento periodontal. Foi detectada ainda uma expressao genica diferenciada entre fibroblastos de gengiva e ligamento periodontal para...

The Renin-angiotensin system (RAS) can generate hormones that have a high-impact on cardiovascular regulation as well as in the pathogenesis of cardiovascular disease. This system acts through both systemic (endocrine) and local (paracrine/autocrine) effects of Angiotensin II, controlling important functions related to the facilitation of installation and progression of the inflammatory process. For this reason, this proteins production in tissues can be associated to the pathogenesis of many diseases, including periodontal disease (PD). In the PD setting, a infectious-inflammatory characterized disease, the literature findings shows that inhibition of the Ang II formation can decrease the bone loss in animals. In this context, the aims of the present study were: to investigate in vitro: a) the expression of RAS components (ANGT, RENIN, ECA, ECA- 2, AT1, AT2 and Mas) by human gingival and periodontal ligament fibroblasts by RT-qPCR; b) the production of RAS receptors (AT1, AT2 and Mas) by human cultured gingival and periodontal ligament fibroblasts by Immunofluorescence and d) the production of RAS components (RENIN, ECA, ECA-2) if the expression and production of RAS components by gingival and periodontal ligament fibroblasts modify under P. gingivalis and E. coli LPS stimulation. After collected, the data were analysed using GraphPad Prism 5.0, by the two way ANOVA followed by Bonferroni post test with a significance level of 5%. Gene expression was detected for some of the RAS components (ANGT, RENIN, ECA, AT1) by both gingival and periodontal ligament fibroblasts. It was detected a differential gene expression between gingival and periodontal ligament fibroblasts for ECA, being significantly higher in gingival fibroblasts. There was a stain in Immunofluorescence compatible with the production of RAS receptors (AT1 and Mas). It must be noted that the...

Estudo da expressão e produção de componentes do sistema renina-angiotensina por fibroblastos de gengiva e ligamento periodontal humanos / Study of expression and production of the renin-angiotensin system components by gingival and periodontal ligament human fibroblasts

O Sistema Renina-angiotensina (SRA), e um sistema capaz de gerar hormonios peptideos com grande impacto na regulacao cardiovascular e na patogenese das doencas cardiovasculares. Este sistema opera, por meio das acoes da Angiotensina II, tanto em nivel sistemico (endocrino) quanto tecidual (local, paracrino/autocrino) controlando importantes funcoes, varias delas relacionadas a facilitacao da instalacao e progressao do processo inflamatorio. Por este motivo, a producao desta proteina nos tecidos pode estar relacionada a patogenese de muitas doencas, dentre elas a doenca periodontal (DP), tendo em vista seu carater infeccioso-inflamatorio e os achados da literatura que mostram que a inibicao da formacao de Ang II, diminui a perda óssea da DP em animais. Desta forma, o presente trabalho teve como objetivos: Avaliar in vitro, a) A expressao de componentes do SRA (ANGT, RENINA, ECA, ECA-2, AT1, AT2 e Mas) por fibroblastos de gengiva e ligamento periodontal humanos, por RT-qPCR; b) A producao de componentes do SRA (RENINA, ECA, ECA-2) no sobrenadante de culturas de fibroblastos de gengiva e ligamento periodontal humanos, por ELISA; c) A producao dos receptores do SRA (AT1, AT2 e Mas), nestes fibroblastos, por Imunofluorescencia e d) Se a expressao e a producao dos componentes do SRA por fibroblastos de gengiva e ligamento periodontal humanos, se alteram com a estimulacao por LPS de P. gingivalis e E. coli. Apos a coleta, os dados foram analisados com o auxilio do programa GraphPad Prism 5.0. por meio da analise de variancia a 2 criterios (ANOVA-two way) seguida do pos teste de Bonferroni, com nivel de significancia de 5% para a verificacao das possíveis diferencas. Foi detectada a expressao genica para alguns dos componentes do SRA (ANGT, RENINA, ECA, AT1) por fibroblastos tanto de gengiva quanto de ligamento periodontal. Foi detectada ainda uma expressao genica diferenciada entre fibroblastos de gengiva e ligamento periodontal para...

The Renin-angiotensin system (RAS) can generate hormones that have a high-impact on cardiovascular regulation as well as in the pathogenesis of cardiovascular disease. This system acts through both systemic (endocrine) and local (paracrine/autocrine) effects of Angiotensin II, controlling important functions related to the facilitation of installation and progression of the inflammatory process. For this reason, this proteins production in tissues can be associated to the pathogenesis of many diseases, including periodontal disease (PD). In the PD setting, a infectious-inflammatory characterized disease, the literature findings shows that inhibition of the Ang II formation can decrease the bone loss in animals. In this context, the aims of the present study were: to investigate in vitro: a) the expression of RAS components (ANGT, RENIN, ECA, ECA- 2, AT1, AT2 and Mas) by human gingival and periodontal ligament fibroblasts by RT-qPCR; b) the production of RAS receptors (AT1, AT2 and Mas) by human cultured gingival and periodontal ligament fibroblasts by Immunofluorescence and d) the production of RAS components (RENIN, ECA, ECA-2) if the expression and production of RAS components by gingival and periodontal ligament fibroblasts modify under P. gingivalis and E. coli LPS stimulation. After collected, the data were analysed using GraphPad Prism 5.0, by the two way ANOVA followed by Bonferroni post test with a significance level of 5%. Gene expression was detected for some of the RAS components (ANGT, RENIN, ECA, AT1) by both gingival and periodontal ligament fibroblasts. It was detected a differential gene expression between gingival and periodontal ligament fibroblasts for ECA, being significantly higher in gingival fibroblasts. There was a stain in Immunofluorescence compatible with the production of RAS receptors (AT1 and Mas). It must be noted that the...

Fenofibrato (agonista do receptor ativador da proliferação peroxissomal) modula o sistema renina-angiotensina no coração de camundongos alimentados com dieta hiperlipídica / Fenofibrate (peroxisome proliferator-activated receptor alpha agonist) modulates the renin-angiotensin system in the heart of mice fed with a high-fat diet

O objetivo deste trabalho foi estudar a ação do fenofibrato, um agonista do receptor ativador da proliferação peroxissomal alfa, no remodelamento cardíaco e na expressão de componentes do sistema renina-angiotensina (SRA) em um modelo de obesidade induzida por dieta. Camundongos machos C57B1/6 com três meses de idade foram alimentados durante 11 semanas com dieta controle (grupo C, 3,57 kcal/g de dieta) ou dieta hiperlipídica (grupo HL, 5,40 kcal/g de dieta), em seguida foram separados em quatro grupos e estudados durante cinco semanas: C; HO; C-L (C mais fenofibrato) e HL-F (HL mais fenofibrato). Os animais HL foram mais pesados e apresentaram maior pressão arterial (PA) comparados aos animais C, mas HL-F foram mais leves e tiveram PA menor que HL. A resistência insulínica vista nos camundongos HL foi melhorada com fenofibrato nos camundongos HL-F. Fenofibrato reduziu colesterol total, triglicerídeos e aumentou HDL-c. Os animais HL apresentou um ventrículo esquerdo (VE) mais pesado e com espessura da parede maior, como também cardiomiócitos maiores e uma menor razão cardiomiócito/capilares que os animais C. Fenofibrato foi eficiente em melhorar estas alterações. As expressões cardíacas de Angiotensina II (ANG II) e de seu receptor tipo 1 (AT1R) foram maiores, enquanto que a expressão de seu receptor tipo 2 (AT2R) foi menor nos animais HL que nos animais C, e fenofibrato foi eficiente em atenuar estas diferenças. Como conclusão, a dieta HL lidera para a obesidade, elevação da PA, hipertrofia cardíaca, alterações metabólicas e expressão proteica alterada do SRA em camundongos, sugerindo a participação do SRA nestas alterações. Fenofibrato é eficiente em diminuir a PA e controlar a expressão proteica do SRA, assim como no tratamento da resistência insulínica e do remodelamento cardíaco adverso, diminuindo a hipertrofia dos cardiomiócitos e melhorando a vascularização do miocárdio, desta maneira, diminuindo importantes fatores de risco para doenças ...

The aim was to study the action of fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, in cardiac remodeling and protein expressions of RAS components in a model of obesity induced by diet. 3-mo-old C57B1/6 male were fed for 11 weeks with standard chow (SC group, 3.57 kcal/g of chow) or high-fat chow (HF group, 5.40 kcal/g of chow), then they were separated into four groups and studied for five weeks: SC; HF; SC-F (SC plus fenofibrate) and HF-F (HF plus fenofibrate). HF was heavier and had higher blood pressure (BP) than SC, but HF-F was lighter and had lower BP than HF. The insulin resistance seen in HF mice was corrected by fenofibrate in HF-F mice. Fenofibrate reduced total cholesterol, triglycerides and raised the HDL-c. HF had thicker and heavier left ventricle (LV) with bigger LV cardiomyocyte and smaller cardiomyocyte-to-capillaries ratio than SC, and fenofibrate was efficient in treating these alterations. Cardiac expressions of angiotensin II (ANG II) and ANG II receptor 1 were higher, and ANG II receptor 2 was lower in HF than in SC, and fenofibrate was efficient in attenuating these differences. In conclusion , HF diet leads to obesity, BP elevation, cardiac hypertrophy, metabolic changes and altered RAS protein expression in mice, suggesting that RAS is involved. Fenofibrate is efficient in decreasing BP and in controlling RAS protein expressions, and treats the insulin resistance and the adverse cardiac remodeling decreasing the cardiomyocyte hypertrophy and improving the myocardial vascularization, therefore, decreasing important cardiovascular risk factors