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1.
Medicine (Baltimore) ; 100(35): e26544, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34477114

RESUMO

BACKGROUND: To lower albuminuria and to achieve blood pressure (BP) goals, dual renin-angiotensin-aldosterone system (RAAS) inhibitors are sometimes used in clinical practice for the treatment of CKD. However, the efficacy and safety of dual RAAS blockade therapy remains controversial. METHODS: PubMed, EMBASE, and Cochrane Library were searched, and random effects model was used to calculate the effect sizes of eligible studies. Potential sources of heterogeneity were detected by meta-regression and subgroup analysis. RESULTS: The present meta-analysis of 72 randomized controlled trials with 10,296 patients demonstrated that dual RAAS blockade therapy was superior to monotherapy in reducing the urine albumin excretion, urine protein excretion, and BP. These beneficial effects were related to the decrease of glomerular filtration rate, the increase of serum potassium level, and higher rates of hyperkalemia and hypotension. Meanwhile, these effects did not lead to improvements in short-term or long-term outcomes, including doubling of serum creatinine, acute kidney injury, end-stage renal disease, mortality, and hospitalization. Compared with the single therapy, angiotensin-converting enzyme inhibitor (ACEI) in combination with angiotensin-receptor blocker (ARB) was a better dual therapy than ACEI or ARB in combination with renin inhibitor or aldosterone receptor antagonist in decreasing urine albumin excretion, urine protein excretion and BP, and the combination was not associated with a lower glomerular filtration rate. CONCLUSION: Compared with the single therapy, ACEI in combination with ARB was a better dual therapy than ACEI or ARB in combination with renin inhibitor or aldosterone receptor antagonist. Although ACEI in combination with ARB was associated with higher incidences of hyperkalemia and hypotension, careful individualized management and potassium binders may further expand its application (PROSPERO number CRD42020179398).


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Insuficiência Renal Crônica/fisiopatologia
2.
PLoS One ; 16(9): e0257016, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34478478

RESUMO

BACKGROUND: Activation of the immune system is implicated in the Post-Acute Sequelae after SARS-CoV-2 infection (PASC) but the mechanisms remain unknown. Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin II (Ang II) resulting in decreased activation of the AT1 receptor and decreased immune system activation. We hypothesized that autoantibodies against ACE2 may develop after SARS-CoV-2 infection, as anti-idiotypic antibodies to anti-spike protein antibodies. METHODS AND FINDINGS: We tested plasma or serum for ACE2 antibodies in 67 patients with known SARS-CoV-2 infection and 13 with no history of infection. None of the 13 patients without history of SARS-CoV-2 infection and 1 of the 20 outpatients that had a positive PCR test for SARS-CoV-2 had levels of ACE2 antibodies above the cutoff threshold. In contrast, 26/32 (81%) in the convalescent group and 14/15 (93%) of patients acutely hospitalized had detectable ACE2 antibodies. Plasma from patients with antibodies against ACE2 had less soluble ACE2 activity in plasma but similar amounts of ACE2 protein compared to patients without ACE2 antibodies. We measured the capacity of the samples to inhibit ACE2 enzyme activity. Addition of plasma from patients with ACE2 antibodies led to decreased activity of an exogenous preparation of ACE2 compared to patients that did not have antibodies. CONCLUSIONS: Many patients with a history of SARS-CoV-2 infection have antibodies specific for ACE2. Patients with ACE2 antibodies have lower activity of soluble ACE2 in plasma. Plasma from these patients also inhibits exogenous ACE2 activity. These findings are consistent with the hypothesis that ACE2 antibodies develop after SARS-CoV-2 infection and decrease ACE2 activity. This could lead to an increase in the abundance of Ang II, which causes a proinflammatory state that triggers symptoms of PASC.


Assuntos
Autoanticorpos/sangue , COVID-19/imunologia , SARS-CoV-2/isolamento & purificação , Glicoproteína da Espícula de Coronavírus/sangue , Angiotensina II/sangue , Angiotensina II/imunologia , Enzima de Conversão de Angiotensina 2/genética , Autoanticorpos/imunologia , Autoanticorpos/isolamento & purificação , COVID-19/sangue , COVID-19/virologia , Feminino , Humanos , Masculino , Peptidil Dipeptidase A/sangue , Receptor Tipo 1 de Angiotensina/sangue , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/imunologia , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/imunologia , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/isolamento & purificação
3.
J Int Med Res ; 49(9): 3000605211041439, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34521238

RESUMO

OBJECTIVE: The effect of renin-angiotensin system inhibitors (RASIs) in patients with heart failure (HF) and atrial fibrillation (AF) remains unclear. This study aimed to investigate associations between RASI use and all-cause mortality and cardiovascular outcomes in patients with AF and HF. METHODS: Using data from the China Atrial Fibrillation Registry study, we included 938 patients with AF and HF with a left ventricular ejection fraction <50%. Cox regression models for RASIs vs. non-RASIs with all-cause mortality as the primary outcome were fitted in a 1:1 propensity score-matched cohort. A sensitivity analysis was performed by using a multivariable time-dependent Cox regression model. As an internal control, we assessed the relation between ß-blocker use and all-cause mortality. RESULTS: During a mean follow-up of 35 months, the risk of all-cause mortality was similar in RASI users compared with non-users (hazard ratio: 0.92; 95% confidence interval: 0.67-1.26). Similar results were obtained in the sensitivity analysis. In contrast, ß-blocker use was associated with significantly lower all-cause mortality in the same population. CONCLUSIONS: RASI use was not associated with better outcomes in patients with AF and HF in this prospective cohort, which raises questions about their value in this specific subset.Trail Registration: ChiCTR-OCH-13003729.


Assuntos
Fibrilação Atrial , Insuficiência Cardíaca , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , China , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Pontuação de Propensão , Estudos Prospectivos , Sistema de Registros , Sistema Renina-Angiotensina , Volume Sistólico , Função Ventricular Esquerda
4.
Rev Assoc Med Bras (1992) ; 67Suppl 1(Suppl 1): 121-126, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34406302

RESUMO

Severe Acute Respiratory Syndrome Coronavirus 2 is part of the Cononaviridae family and is the causative agent of the 2019 (Covid-19) Coronavirus pandemic declared by the World Health Organization in March, 2020. This virus has a high rate of transmission, affecting several individuals, and has caused thousands of deaths. The clinical manifestations of Severe Acute Respiratory Syndrome Coronavirus 2 infection are not restricted only to the respiratory tract, and there is an express involvement of the cardiovascular system with a higher risk of death in this group. In such patients there is an overactivation of renin-angiotensin-aldosterone system, which promotes an increase in the expression of angiotensin-converting enzyme - 2 that acts as a receptor for the SPIKE protein expressed by the virus and enables the interaction between the host cell and Severe Acute Respiratory Syndrome Coronavirus 2. This process of infection causes a hyperinflammatory state that increases the inflammatory markers of cardiac injury. Hence, an adequate understanding and clinical guidance regarding the monitoring, and controlling the damage in these patients is essential to avoid worsening of their clinical condition and to prevent death.


Assuntos
COVID-19 , Sistema Cardiovascular , Humanos , Pandemias , Sistema Renina-Angiotensina , SARS-CoV-2
5.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445329

RESUMO

Melatonin is registered to treat circadian rhythm sleep-wake disorders and insomnia in patients aged 55 years and over. The essential role of the circadian sleep rhythm in the deterioration of sleep quality during COVID-19 confinement and the lack of an adverse effect of melatonin on respiratory drive indicate that melatonin has the potential to be a recommended treatment for sleep disturbances related to COVID-19. This review article describes the effects of melatonin additional to its sleep-related effects, which make this drug an attractive therapeutic option for treating patients with COVID-19. The preclinical data suggest that melatonin may inhibit COVID-19 progression. It may lower the risk of the entrance of the SARS-CoV-2 virus into cells, reduce uncontrolled hyper-inflammation and the activation of immune cells, limit the damage of tissues and multiorgan failure due to the action of free radicals, and reduce ventilator-induced lung injury and the risk of disability resulting from fibrotic changes within the lungs. Melatonin may also increase the efficacy of COVID-19 vaccination. The high safety profile of melatonin and its potential anti-SARS-CoV-2 effects make this molecule a preferable drug for treating sleep disturbances in COVID-19 patients. However, randomized clinical trials are needed to verify the clinical usefulness of melatonin in the treatment of COVID-19.


Assuntos
COVID-19/tratamento farmacológico , Melatonina/farmacologia , SARS-CoV-2/efeitos dos fármacos , COVID-19/virologia , Vacinas contra COVID-19/farmacologia , Citocinas/metabolismo , Sequestradores de Radicais Livres/metabolismo , Humanos , Melatonina/uso terapêutico , Sistema Renina-Angiotensina , Transtornos do Sono-Vigília/tratamento farmacológico
6.
Adv Biol Regul ; 81: 100820, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34419773

RESUMO

The article describes the possible pathophysiological origin of COVID-19 and the crucial role of renin-angiotensin system (RAS), providing several "converging" evidence in support of this hypothesis. SARS-CoV-2 has been shown to initially upregulate ACE2 systemic activity (early phase), which can subsequently induce compensatory responses leading to upregulation of both arms of the RAS (late phase) and consequently to critical, advanced and untreatable stages of COVID-19 disease. The main and initial actors of the process are ACE2 and ADAM17 zinc-metalloproteases, which, initially triggered by SARS-CoV-2 spike proteins, work together in increasing circulating Ang 1-7 and Ang 1-9 peptides and downstream (Mas and Angiotensin type 2 receptors) pathways with anti-inflammatory, hypotensive and antithrombotic activities. During the late phase of severe COVID-19, compensatory secretion of renin and ACE enzymes are subsequently upregulated, leading to inflammation, hypertension and thrombosis, which further sustain ACE2 and ADAM17 upregulation. Based on this hypothesis, COVID-19-phase-specific inhibition of different RAS enzymes is proposed as a pharmacological strategy against COVID-19 and vaccine-induced adverse effects. The aim is to prevent the establishment of positive feedback-loops, which can sustain hyperactivity of both arms of the RAS independently of viral trigger and, in some cases, may lead to Long-COVID syndrome.


Assuntos
Proteína ADAM17/biossíntese , Enzima de Conversão de Angiotensina 2/biossíntese , COVID-19/metabolismo , Sistema Renina-Angiotensina , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Proteína ADAM17/antagonistas & inibidores , Angiotensina I/metabolismo , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , COVID-19/tratamento farmacológico , Regulação Enzimológica da Expressão Gênica , Humanos , Fragmentos de Peptídeos/metabolismo , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Regulação para Cima
7.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361021

RESUMO

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the virus responsible for the COVID-19 pandemic. Patients may present as asymptomatic or demonstrate mild to severe and life-threatening symptoms. Although COVID-19 has a respiratory focus, there are major cardiovascular complications (CVCs) associated with infection. The reported CVCs include myocarditis, heart failure, arrhythmias, thromboembolism and blood pressure abnormalities. These occur, in part, because of dysregulation of the Renin-Angiotensin-Aldosterone System (RAAS) and Kinin-Kallikrein System (KKS). A major route by which SARS-CoV-2 gains cellular entry is via the docking of the viral spike (S) protein to the membrane-bound angiotensin converting enzyme 2 (ACE2). The roles of ACE2 within the cardiovascular and immune systems are vital to ensure homeostasis. The key routes for the development of CVCs and the recently described long COVID have been hypothesised as the direct consequences of the viral S protein/ACE2 axis, downregulation of ACE2 and the resulting damage inflicted by the immune response. Here, we review the impact of COVID-19 on the cardiovascular system, the mechanisms by which dysregulation of the RAAS and KKS can occur following virus infection and the future implications for pharmacological therapies.


Assuntos
COVID-19/complicações , Doenças Cardiovasculares/etiologia , Sistema Calicreína-Cinina , Sistema Renina-Angiotensina , Enzima de Conversão de Angiotensina 2/metabolismo , Bradicinina/metabolismo , COVID-19/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/metabolismo , Humanos
8.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360741

RESUMO

The present review is aimed at analysing the current evidence concerning the potential modulation of obesity and/or diet in adipose tissue ACE2. Additionally, the potential implications of these effects on COVID-19 are also addressed. The results published show that diet and obesity are two factors that effectively influence the expression of Ace2 gene in adipose tissue. However, the shifts in this gene do not always occur in the same direction, nor with the same intensity. Additionally, there is no consensus regarding the implications of increased adipose tissue ACE2 expression in health. Thus, while in some studies a protective role is attributed to ACE2 overexpression, other studies suggest otherwise. Similarly, there is much debate regarding the role played by ACE2 in COVID-19 in terms of degree of infection and disease outcomes. The greater risk of infection that may hypothetically derive from enhanced ACE2 expression is not clear since the functionality of the enzyme seems to be as important as the abundance. Thus, the greater abundance of ACE2 in adipose tissue of obese subjects may be counterbalanced by its lower activation. In addition, a protective role of ACE2 overexpression has also been suggested, associated with the increase in anti-inflammatory factors that it may produce.


Assuntos
Tecido Adiposo/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Obesidade/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Animais , Dieta , Humanos , Sistema Renina-Angiotensina/fisiologia , Índice de Gravidade de Doença
9.
Trials ; 22(1): 573, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34454580

RESUMO

BACKGROUND: SARS-CoV-2 binds to membrane-bound angiotensin-converting enzyme 2 (ACE2) which may result in downregulation of membrane-bound ACE2. ACE2 is a key regulator of the renin-angiotensin system (RAS) and is responsible for degrading angiotensin II and thereby counteracting its pro-inflammatory, pro-fibrotic effects mediated through the angiotensin II type 1 receptor (AT1R). As AT1R is directly blocked by angiotensin receptor blockers (ARBs), these agents may offer a safe, low-cost solution for reducing COVID-19 respiratory outcomes. METHODS AND DISCUSSION: CLARITY is a pragmatic, adaptive, two-arm, multi-centre, comparative effectiveness phase III randomised controlled trial that examines whether ARBs reduce COVID-19 severity among high-risk patients. Recruiting in India and Australia, the trial will compare treatment with a maximum tolerated daily dose of an ARB to standard of care. Treatment allocation is blinded in India but open-label in Australia due to interruptions to placebo supply in the latter. The primary endpoint is a 7-point ordinal scale of clinical states, ranging from no limitation of activities (category 1) to death (category 7), assessed on day 14. Secondary outcomes include the 7-point scale assessed at day 28 and 28- and 90-day mortality. The design adapts the sample size based on accumulating data via frequent interim analyses and the use of predictive probability to determine whether the current sample size is sufficient or continuing accrual would be futile. The trial commenced recruitment on 18 August 2020. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04394117 . Registered on 19 May 2020. Clinical Trial Registry of India: CTRI/2020/07/026831).


Assuntos
Antagonistas de Receptores de Angiotensina , COVID-19 , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Humanos , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistema Renina-Angiotensina , SARS-CoV-2
10.
Cells ; 10(7)2021 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-34359922

RESUMO

Since the end of 2019, the medical-scientific community has been facing a terrible pandemic caused by a new airborne viral agent known as SARS-CoV2. Already in the early stages of the pandemic, following the discovery that the virus uses the ACE2 cell receptor as a molecular target to infect the cells of our body, it was hypothesized that the renin-angiotensin-aldosterone system was involved in the pathogenesis of the disease. Since then, numerous studies have been published on the subject, but the exact role of the renin-angiotensin-aldosterone system in the pathogenesis of COVID-19 is still a matter of debate. RAAS represents an important protagonist in the pathogenesis of COVID-19, providing the virus with the receptor of entry into host cells and determining its organotropism. Furthermore, following infection, the virus is able to cause an increase in plasma ACE2 activity, compromising the normal function of the RAAS. This dysfunction could contribute to the establishment of the thrombo-inflammatory state characteristic of severe forms of COVID-19. Drugs targeting RAAS represent promising therapeutic options for COVID-19 sufferers.


Assuntos
COVID-19/metabolismo , Sistema Renina-Angiotensina , SARS-CoV-2/fisiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/tratamento farmacológico , COVID-19/patologia , Descoberta de Drogas , Humanos , Terapia de Alvo Molecular , Sistema Renina-Angiotensina/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos
11.
Genes (Basel) ; 12(7)2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34356070

RESUMO

Chronic inflammatory lung diseases are characterized by uncontrolled immune response in the airways as their main pathophysiological manifestation. The lack of specific diagnostic and therapeutic biomarkers for many pulmonary diseases represents a major challenge for pulmonologists. The majority of the currently approved therapeutic approaches are focused on achieving disease remission, although there is no guarantee of complete recovery. It is known that angiotensin-converting enzyme 2 (ACE2), an important counter-regulatory component of the renin-angiotensin-aldosterone system (RAAS), is expressed in the airways. It has been shown that ACE2 plays a role in systemic regulation of the cardiovascular and renal systems, lungs and liver by acting on blood pressure, electrolyte balance control mechanisms and inflammation. Its protective role in the lungs has also been presented, but the exact pathophysiological mechanism of action is still elusive. The aim of this study is to review and discuss recent findings about ACE2, including its potential role in the pathophysiology of chronic inflammatory lung diseases:, i.e., chronic obstructive pulmonary disease, asthma, and pulmonary hypertension. Additionally, in the light of the coronavirus 2019 disease (COVID-19), we will discuss the role of ACE2 in the pathophysiology of this disease, mainly represented by different grades of pulmonary problems. We believe that these insights will open up new perspectives for the future use of ACE2 as a potential biomarker for early diagnosis and monitoring of chronic inflammatory lung diseases.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Asma/diagnóstico , Teste para COVID-19 , COVID-19/enzimologia , Hipertensão Pulmonar/diagnóstico , Pulmão/enzimologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Asma/enzimologia , Asma/genética , COVID-19/genética , Humanos , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/genética , Inflamação/diagnóstico , Inflamação/enzimologia , Inflamação/genética , Pulmão/patologia , Doença Pulmonar Obstrutiva Crônica/enzimologia , Doença Pulmonar Obstrutiva Crônica/genética , Sistema Renina-Angiotensina
12.
Pharmazie ; 76(8): 342-350, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34412732

RESUMO

Angiotensin-2 converting enzyme (ACE2), a key element of the renin-angiotensin-system (RAS), is not only the direct target of infection by the human SARS-Cov-2 virus but is at the same the root for the complex pathogenetic events of COVID-19. From a pharmaceutical perspective, several established classes of medicines are involved in different phases of the disease. From their known mechanisms of action, a comprehensive understanding of COVID-19 will be hopefully soon delineated. A set of proven medicines is available to cope at least with some of the pathologies involved. To arrive back to normal life, vaccinations and broad consideration of hygienic measures are to be complemented by effective medicines to treat airborne viral infections. Therapeutic schemes based on a comprehensive understanding of the disease will include drug combinations made up from both established drugs as well as novel drugs presently under development.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/tratamento farmacológico , Sistema Renina-Angiotensina/fisiologia , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Desenvolvimento de Medicamentos , Humanos , SARS-CoV-2/efeitos dos fármacos
13.
Molecules ; 26(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34279439

RESUMO

COVID-19 is a pandemic disease caused by the SARS-CoV-2 virus, which is potentially fatal for vulnerable individuals. Disease management represents a challenge for many countries, given the shortage of medicines and hospital resources. The objective of this work was to review the medicinal plants, foods and natural products showing scientific evidence for host protection against various types of coronaviruses, with a focus on SARS-CoV-2. Natural products that mitigate the symptoms caused by various coronaviruses are also presented. Particular attention was placed on natural products that stabilize the Renin-Angiotensin-Aldosterone System (RAAS), which has been associated with the entry of the SARS-CoV-2 into human cells.


Assuntos
Produtos Biológicos/farmacologia , Coronavirus/efeitos dos fármacos , Fitoterapia/métodos , Extratos Vegetais/farmacologia , SARS-CoV-2/efeitos dos fármacos , Antivirais/metabolismo , Antivirais/farmacologia , Produtos Biológicos/metabolismo , COVID-19/tratamento farmacológico , COVID-19/virologia , Humanos , Pandemias , Extratos Vegetais/metabolismo , Plantas/química , Sistema Renina-Angiotensina/efeitos dos fármacos
14.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199409

RESUMO

Diabetic nephropathy (DN) is characterized by albuminuria, loss of renal function, renal fibrosis and infiltration of macrophages originating from peripheral monocytes inside kidneys. DN is also associated with intrarenal overactivation of the renin-angiotensin system (RAS), an enzymatic cascade which is expressed and controlled at the cell and/or tissue levels. All members of the RAS are present in the kidneys and most of them are also expressed in monocytes/macrophages. This review focuses on the control of monocyte recruitment and the modulation of macrophage polarization by the RAS in the context of DN. The local RAS favors the adhesion of monocytes on renal endothelial cells and increases the production of monocyte chemotactic protein-1 and of osteopontin in tubular cells, driving monocytes into the kidneys. There, proinflammatory cytokines and the RAS promote the differentiation of macrophages into the M1 proinflammatory phenotype, largely contributing to renal lesions of DN. Finally, resolution of the inflammatory process is associated with a phenotype switch of macrophages into the M2 anti-inflammatory subset, which protects against DN. The pharmacologic interruption of the RAS reduces albuminuria, improves the trajectory of the renal function, decreases macrophage infiltration in the kidneys and promotes the switch of the macrophage phenotype from M1 to M2.


Assuntos
Quimiocina CCL2/genética , Nefropatias Diabéticas/genética , Osteopontina/genética , Sistema Renina-Angiotensina/genética , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Ativação de Macrófagos/genética , Macrófagos/metabolismo , Macrófagos/patologia , Monócitos/metabolismo , Monócitos/patologia
15.
Int J Mol Sci ; 22(14)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34299027

RESUMO

Soluble Fms-like tyrosine kinase-1 (sFlt-1) is increased in pre-eclampsia. The proton pump inhibitor (PPI) lowers sFlt-1, while angiotensin increases it. To investigate whether PPIs lower sFlt-1 by suppressing placental renin-angiotensin system (RAS) activity, we studied gene expression and protein abundance of RAS components, including megalin, a novel endocytic receptor for prorenin and renin, in placental tissue obtained from healthy pregnant women and women with early-onset pre-eclampsia. Renin, ACE, ACE2, and the angiotensin receptors were expressed at identical levels in healthy and pre-eclamptic placentas, while both the (pro)renin receptor and megalin were increased in the latter. Placental prorenin levels were upregulated in pre-eclamptic pregnancies. Angiotensinogen protein, but not mRNA, was detectable in placental tissue, implying that it originates from maternal blood. Ex vivo placental perfusion revealed a complete washout of angiotensinogen, while prorenin release remained constant. The PPI esomeprazole dose-dependently reduced megalin/(pro)renin receptor-mediated renin uptake in Brown Norway yolk sac epithelial cells and decreased sFlt-1 secretion from placental villous explants. Megalin inhibition blocked angiotensinogen uptake in epithelial cells. In conclusion, our data suggest that placental RAS activity depends on angiotensinogen taken up from the maternal systemic circulation. PPIs might interfere with placental (pro)renin-AGT uptake/transport, thereby reducing angiotensin formation as well as angiotensin-induced sFlt-1 synthesis.


Assuntos
Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Placenta/patologia , Pré-Eclâmpsia/patologia , Inibidores da Bomba de Prótons/farmacologia , Sistema Renina-Angiotensina , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Placenta/efeitos dos fármacos , Placenta/metabolismo , Pré-Eclâmpsia/tratamento farmacológico , Pré-Eclâmpsia/metabolismo , Gravidez
16.
J Am Heart Assoc ; 10(15): e021154, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34320843

RESUMO

Background Considering the widespread risk of collider bias and confounding by indication in previous research, the associations between renin-angiotensin aldosterone system (RAAS) inhibitor use and COVID-19 remain unknown. Accordingly, this study tested the hypothesis that RAAS inhibitors influence the summation effect of COVID-19 and its progression to severe outcomes. Methods and Results This nationwide cohort study compared all residents of Sweden, without prior cardiovascular disease, in monotherapy (as of January 1, 2020) with a RAAS inhibitor to those using a calcium channel blocker or a thiazide diuretic. Comparative cohorts were balanced using machine-learning-derived propensity score methods. Of 165 355 people in the analysis (51% women), 367 were hospitalized or died with COVID-19 (246 using a RAAS inhibitor versus 121 using a calcium channel blocker or thiazide diuretic; Cox proportional hazard ratio [HR], 0.97; 95% CI, 0.74-1.27). When each outcome was assessed separately, 335 people were hospitalized with COVID-19 (HR, 0.92; 95% CI, 0.70-1.22), and 64 died with COVID-19 (HR, 1.22; 95% CI, 0.68-2.19). The severity of COVID-19 outcomes did not differ between those using a RAAS inhibitor and those using a calcium channel blocker or thiazide diuretic (ordered logistic regression odds ratio, 1.01; 95% CI, 0.89-1.14). Conclusions Despite potential limitations, this study is among the best available evidence that RAAS inhibitor use in primary prevention does not increase the risk of severe COVID-19 outcomes; presenting strong data from which scientists and policy makers alike can base, with greater confidence, their current position on the safety of using RAAS inhibitors during the COVID-19 pandemic.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , COVID-19 , Hipertensão/tratamento farmacológico , Medição de Risco , Idoso , Anti-Hipertensivos/classificação , Anti-Hipertensivos/uso terapêutico , COVID-19/epidemiologia , COVID-19/prevenção & controle , Bloqueadores dos Canais de Cálcio/uso terapêutico , Feminino , Humanos , Hipertensão/epidemiologia , Hipertensão/prevenção & controle , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Sistema Renina-Angiotensina/efeitos dos fármacos , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Suécia/epidemiologia
17.
Intern Med ; 60(13): 2093-2095, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34193775

RESUMO

Hyperkalemia is a challenging comorbidity to manage in patients with heart failure and chronic kidney disease, particularly when administering renin-angiotensin-aldosterone system inhibitors. We encountered an 88-year-old woman with hypertensive heart failure and chronic kidney disease. A mineralocorticoid receptor antagonist was able to be safely administered despite persistent hyperkalemia when sodium zirconium cyclosilicate, a non-absorbed, non-polymer zirconium silicate compound that preferentially exchanges hydrogen and sodium for potassium and ammonium ions in the gastrointestinal tract, was concomitantly administered. Sodium zirconium cyclosilicate might be a promising therapeutic tool to use in order to administer mineralocorticoid receptor antagonist safely in patients with heart failure, chronic kidney disease, and hyperkalemia.


Assuntos
Insuficiência Cardíaca , Hiperpotassemia , Idoso de 80 Anos ou mais , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Hiperpotassemia/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Potássio , Sistema Renina-Angiotensina , Silicatos/uso terapêutico
18.
Life Sci ; 283: 119841, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34298036

RESUMO

Sympathetic vasomotor overactivity is a major feature leading to the cardiovascular dysfunction related to obesity. Considering that the retroperitoneal white adipose tissue (rWAT) is an important fat visceral depot and receives intense sympathetic and afferent innervations, the present study aimed to evaluate the effects evoked by bilateral rWAT denervation in obese rats. Male Wistar rats were fed with HFD for 8 consecutive weeks and rWAT denervation was performed at the 6th week. Arterial pressure, splanchnic and renal sympathetic vasomotor nerve activities were assessed and inflammation and the components of the renin -angiotensin system were evaluated in different white adipose tissue depots. HFD animals presented higher serum levels of leptin and glucose, an increase in arterial pressure and splanchnic sympathetic nerve activity; rWAT denervation, normalized these parameters. Pro-inflammatory cytokines levels were significantly increased, as well as RAAS gene expression in WAT of HFD animals; rWAT denervation significantly attenuated these changes. In conclusion, HFD promotes vasomotor sympathetic overactivation and inflammation with repercussions on the cardiovascular system. In conclusion, the neural communication between WAT and the brain is fundamental to trigger sympathetic vasomotor activation and this pathway is a possible new therapeutic target to treat obesity-associated cardiovascular dysfunction.


Assuntos
Doenças Cardiovasculares , Denervação , Dieta Hiperlipídica/efeitos adversos , Gordura Intra-Abdominal , Obesidade , Nervos Esplâncnicos , Animais , Pressão Sanguínea , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/terapia , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatologia , Gordura Intra-Abdominal/inervação , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/fisiopatologia , Masculino , Obesidade/induzido quimicamente , Obesidade/metabolismo , Obesidade/fisiopatologia , Obesidade/terapia , Ratos , Ratos Wistar , Sistema Renina-Angiotensina , Nervos Esplâncnicos/metabolismo , Nervos Esplâncnicos/patologia , Nervos Esplâncnicos/fisiopatologia
19.
Expert Rev Clin Pharmacol ; 14(9): 1055-1064, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34227913

RESUMO

INTRODUCTION: Hyperkalemia is a common finding in patients with advanced kidney disease for multiple reasons. Renin-Angiotensin-Aldosterone-System Inhibitors (RAASi) that are indicated for slowing down progression of kidney disease are often associated with hyperkalemia which becomes a limiting factor in their use and titration to the maximum dose. Having a safe, effective, tolerable, and affordable potassium binder can help optimize RAAS inhibition in the setting of kidney disease. AREAS COVERED: Although sodium polystyrene sulfonate has been a mainstay of acute management of hyperkalemia for decades, evidence regarding its efficacy is limited, and its chronic use is not routinely recommended for concerns regarding toxicity. The concern of gastrointestinal (GI) adverse effects with sodium polystyrene sulfonate has spurred the development of alternatives. Sodium zirconium cyclosilicate (SZC) is a promising agent that selectively binds potassium in the gut and eliminates it, while being safe for chronic use based on 1 year of data. Even though we do not have head-to-head studies among the three currently available binders, SZC stands out in rapidity of onset and efficacy. EXPERT OPINION: In this review, we summarize the general management of hyperkalemia, including new agents. We review the pre-clinical and clinical data relating to sodium zirconium cyclosilicate.


Assuntos
Hiperpotassemia/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Silicatos/administração & dosagem , Doença Crônica , Progressão da Doença , Relação Dose-Resposta a Droga , Humanos , Hiperpotassemia/etiologia , Resinas de Troca Iônica/administração & dosagem , Resinas de Troca Iônica/efeitos adversos , Resinas de Troca Iônica/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Silicatos/efeitos adversos , Silicatos/farmacologia
20.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209289

RESUMO

The continually evolving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has resulted in a vast number of either acute or chronic medical impairments of a pathophysiology that is not yet fully understood. SARS-CoV-2 tropism for the organs is associated with bilateral organ cross-talks as well as targeted dysfunctions, among which acute kidney injury (AKI) seems to be highly prevalent in infected patients. The need for efficient management of COVID-related AKI patients is an aspect that is still being investigated by nephrologists; however, another reason for concern is a disturbingly high proportion of various types of kidney dysfunctions in patients who have recovered from COVID-19. Even though the clinical picture of AKI and COVID-related AKI seems to be quite similar, it must be considered that regarding the latter, little is known about both the optimal management and long-term consequences. These discrepancies raise an urgent need for further research aimed at evaluating the molecular mechanisms associated with SARS-CoV-2-induced kidney damage as well as standardized management of COVID-related AKI patients. The following review presents a comprehensive and most-recent insight into the pathophysiology, clinical manifestations, recommended patient management, treatment strategies, and post-mortem findings in patients with COVID-related AKI.


Assuntos
Injúria Renal Aguda/diagnóstico , COVID-19/patologia , Injúria Renal Aguda/etiologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Biomarcadores/metabolismo , COVID-19/complicações , COVID-19/tratamento farmacológico , COVID-19/virologia , Taxa de Filtração Glomerular , Humanos , Interleucina-6/metabolismo , Sistema Renina-Angiotensina , Rabdomiólise/etiologia , SARS-CoV-2/isolamento & purificação
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