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1.
Medicine (Baltimore) ; 99(31): e21492, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756181

RESUMO

Activation of the renin angiotensin system and renal oxidative stress (OS) are critical contributors in the progression of chronic kidney disease(CKD). Recent studies have confirmed that the angiotensin-converting enzyme 2-angiotensin (1-7)-Mas(ACE2/Ang(1-7)/Mas) axis, the important components of renin angiotensin system, protected kidneys against damage by antagonizing angiotensin II and attenuating OS in rats with several nephropathy models, but its effect needs to be further evaluated in clinic. In this study, we aimed to detected serum ACE2/Ang (1-7)/Mas axis, OS conditions and described its clinical associations in patients with CKD at different stages.A total of 48 patients with CKD and 6 healthy controls (CT) were enrolled, and serum angiotensin converting enzyme (ACE), ACE2, Ang (1-7), 8-hydroxy-2'-deoxyguanosine (8-OHdG) were determined by ELISA. Serum extracellular glutathione peroxidase(eGSH-Px) activity and renal functions were determined by the biochemical method.Serum ACE and ACE2 levels in CKD stages 3 to 5 and serum Ang(1-7) levels in CKD stages 4 to 5 without Ang II receptor blockers treatment significantly increased compared to those in the CT group. However, ACE2 was decreased and Ang(1-7) level increased in early CKD stage with Ang II receptor blockers treatment. Higher serum 8-OHdG levels and lower eGSH-Px activity were noted in CKD stages 4 to 5. Serum 8-OHdG level was correlated with serum ACE2, Ang(1-7) expression. Estimated glomerular filtration rate (eGFR) was correlated with serum ACE, ACE2, Ang(1-7), 8-OHdG, Hcy levels and serum eGSH-Px activity. Multiple-regression analysis eGFR was predicted by ACE, Hcy, eGSH-Px, and also can be predicted by ACE2, Ang(1-7), Hcy in CT subgroup.The ACE2/Ang(1-7)/Mas axis is associated with OS, and both them were associated with eGFR in the progression of CKD. Activation of ACE2/Ang(1-7)/Mas axis may have renoprotective effect and can be a potential therapeutic target in patients with early CKD stages.


Assuntos
Angiotensina II/sangue , Angiotensina I/sangue , Estresse Oxidativo/fisiologia , Fragmentos de Peptídeos/sangue , Peptidil Dipeptidase A/sangue , Insuficiência Renal Crônica/sangue , 8-Hidroxi-2'-Desoxiguanosina/sangue , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Sistema Renina-Angiotensina/fisiologia
2.
Front Immunol ; 11: 1472, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32655579

RESUMO

Severe acute respiratory syndrome coronavirus 2 has spread rapidly around the globe. However, despite its high pathogenicity and transmissibility, the severity of the associated disease, COVID-19, varies widely. While the prognosis is favorable in most patients, critical illness, manifested by respiratory distress, thromboembolism, shock, and multi-organ failure, has been reported in about 5% of cases. Several studies have associated poor COVID-19 outcomes with the exhaustion of natural killer cells and cytotoxic T cells, lymphopenia, and elevated serum levels of D-dimer. In this article, we propose a common pathophysiological denominator for these negative prognostic markers, endogenous, angiotensin II toxicity. We hypothesize that, like in avian influenza, the outlook of COVID-19 is negatively correlated with the intracellular accumulation of angiotensin II promoted by the viral blockade of its degrading enzyme receptors. In this model, upregulated angiotensin II causes premature vascular senescence, leading to dysfunctional coagulation, and immunity. We further hypothesize that angiotensin II blockers and immune checkpoint inhibitors may be salutary for COVID-19 patients with critical illness by reversing both the clotting and immune defects (Graphical Abstract).


Assuntos
Angiotensina II/sangue , Betacoronavirus/metabolismo , Infecções por Coronavirus/sangue , Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/sangue , Pneumonia Viral/fisiopatologia , Regulação para Cima , Fatores Etários , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Encéfalo/imunologia , Encéfalo/metabolismo , Senescência Celular/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Estado Terminal , Citocinas/metabolismo , Dopamina/metabolismo , Regulação para Baixo , Humanos , Imunoterapia/métodos , Mitocôndrias/metabolismo , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Prognóstico , Sistema Renina-Angiotensina/imunologia
3.
Medicine (Baltimore) ; 99(27): e20943, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629698

RESUMO

Angiotensin II mediates exercise-induced hypertension (EIH), which adversely impacts future cardiovascular health. There is paucity of data on the association between EIH and angiotensin II in well-trained middle-aged marathoners. Therefore, we investigated the renin-angiotensin-aldosterone-system and total nitric oxide activity in middle-aged marathoners with EIH.Seventy middle-aged marathoners were divided into 3 groups: normal blood pressure ([NBPG] [n = 21]), EIH group ([EIHG] [n = 35]), and complex hypertension group ([CHG] [n = 14]). We defined NBPG as resting systolic BP/diastolic BP (SBP/DBP) of ≤140/90 mm Hg and maximal exercise SBP of ≤210 mm Hg, EIHG as resting SBP/DBP ≤140/90 mm Hg and maximal exercise SBP of ≥210 mm Hg, and CHG as resting SBP/DBP ≥140/90 mm Hg and maximal exercise SBP of ≥210 mm Hg. Renin-angiotensin-aldosterone-system and NO levels were measured before and 30 minutes after the graded exercise test.Renin level was elevated while angiotensin level was reduced after 30 minutes of graded exercise test. There was no change in angiotensin I and angiotensin converting enzyme levels. Comparing the groups, renin level was only elevated in the CHG during recovery, while aldosterone level was higher than the baseline level in the recovery phase in all groups. Angiotensin I level remained unchanged in all groups. Angiotensin II level reduced significantly in the NBPG group but remained at the baseline in the EIHG and CHG groups. NO level was unchanged in the NBPG group but reduced in the EIHG and CHG groups after exercise. At 3 minutes of recovery, SBP was the highest in the NBPG group, followed by the EIHG and CHG groups (P < .05).In conclusion, angiotensin II activity and reduced NO level are associated with EIH in middle-aged long-distance runners. Angiotensin II inhibitors may; therefore, be the more appropriate antihypertensive medication for runners with EIH.


Assuntos
Angiotensina II/sangue , Exercício Físico , Hipertensão/fisiopatologia , Óxido Nítrico/sangue , Corrida , Adulto , Pressão Sanguínea , Humanos , Hipertensão/sangue , Masculino , Pessoa de Meia-Idade , Sistema Renina-Angiotensina
4.
Gen Physiol Biophys ; 39(3): 203-204, 2020 May.
Artigo em Inglês | MEDLINE | ID: covidwho-595142

RESUMO

Renin-angiotensin system (RAS) inhibition supposedly increases the expression of angiotensin converting enzyme 2, serving as a binding site for SARS-CoV-2. Concerns arose regarding therapy with RAS inhibition during the COVID-19 pandemic. However, the pharmacological restraining the classical RAS axis might be beneficial due to the reduction of deleterious effects of angiotensin II and enhancement of the anti-inflammatory angiotensin 1-7 pathway. Unless large controlled studies are performed, RAS inhibition remains the cornerstone therapy in populations with cardiovascular disorders.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Sistema Renina-Angiotensina , Angiotensina II/sangue , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Betacoronavirus/patogenicidade , Betacoronavirus/fisiologia , Doenças Cardiovasculares/complicações , Infecções por Coronavirus/tratamento farmacológico , Humanos , Pandemias , Peptidil Dipeptidase A , Pneumonia Viral/tratamento farmacológico , Internalização do Vírus/efeitos dos fármacos
6.
J Mol Cell Cardiol ; 145: 84-87, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32562701

RESUMO

We believe that, in parallel to the attempts for direct blockade of the SARS-CoV-2 penetration into host cell and repurposing drugs, finding new therapeutic strategies for patients with lung injury or cardiovascular complications/coagulopathies associated with COVID-19 should be paid particular attention. Apelin or its receptor agonists are of great potential treatment for COVID-19 through suppressing angiotensin-converting enzyme (ACE) and angiotensin II (Ang-II) production, as well as, down-regulating angiotensin receptor 1 (AT1R) and ACE2 up-regulation. These drugs have potential to improve acute lung injury and cardiovascular/coagulopathy complications in COVID-19 which are associated with elevated Ang-II/Ang(1-7) ratio.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Receptores de Apelina/uso terapêutico , Apelina/uso terapêutico , Betacoronavirus/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Angiotensina I/metabolismo , Angiotensina II/biossíntese , Angiotensina II/sangue , Animais , Apelina/metabolismo , Receptores de Apelina/agonistas , Receptores de Apelina/metabolismo , Infecções por Coronavirus/virologia , Reposicionamento de Medicamentos/métodos , Humanos , Camundongos , Pandemias , Fragmentos de Peptídeos/metabolismo , Pneumonia Viral/virologia , Receptor Tipo 1 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/imunologia
8.
Gen Physiol Biophys ; 39(3): 203-204, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32525813

RESUMO

Renin-angiotensin system (RAS) inhibition supposedly increases the expression of angiotensin converting enzyme 2, serving as a binding site for SARS-CoV-2. Concerns arose regarding therapy with RAS inhibition during the COVID-19 pandemic. However, the pharmacological restraining the classical RAS axis might be beneficial due to the reduction of deleterious effects of angiotensin II and enhancement of the anti-inflammatory angiotensin 1-7 pathway. Unless large controlled studies are performed, RAS inhibition remains the cornerstone therapy in populations with cardiovascular disorders.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Sistema Renina-Angiotensina , Angiotensina II/sangue , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Betacoronavirus/patogenicidade , Betacoronavirus/fisiologia , Doenças Cardiovasculares/complicações , Infecções por Coronavirus/tratamento farmacológico , Humanos , Pandemias , Peptidil Dipeptidase A , Pneumonia Viral/tratamento farmacológico , Internalização do Vírus/efeitos dos fármacos
9.
Cardiovasc Diabetol ; 19(1): 56, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32375786

RESUMO

BACKGROUND: The intracellular ROCK signaling pathway is an important modulator of blood pressure and of cardiovascular and renal remodeling when Rho-kinase activity is increased. Besides, in preclinical models of diabetes, ROCK activation has also a role in abnormal glucose metabolism as well as in subsequent vascular and myocardial dysfunction. In humans, there are a few data assessing ROCK activation in patients with type 2 diabetes mellitus (T2D) and no studies assessing upstream/downstream components of the ROCK pathway. We assessed here levels of ROCK activation and some of the RhoA/ROCK cascade molecules in peripheral blood mononuclear cells (PBMCs) in T2D patients under current treatment. METHODS: Cross-sectional observational study comparing 28 T2D patients under current antidiabetic treatment with 31 consecutive healthy subjects, matched by age and gender. Circulating levels of malondialdehyde, angiotensin II and inflammatory cytokines IL-6 and IL-8 were determined in all subjects. ROCK activation in PMBCs, upstream and downstream cascade proteins, and levels of the proinflammatory molecules VCAM, ICAM-1 and IL-8 were determined in their PMBCs by Western blot. RESULTS: Compared to healthy controls, ROCK activation in T2D patients measured by 2 direct ROCK targets in PBMCs was increased by 420 and 570% (p < 0001) and it correlated significantly with serum glucose levels. p38 MAPK phosphorylation (downstream from ROCK) and JAK-2 (upstream from ROCK) were significantly higher in the T2D patients by 580% and 220%, respectively. In T2D patients, significantly increased PBMC levels of the proinflammatory molecules VCAM-1, ICAM-1 and IL-8 were observed compared to control subjects (by 180%, 360% and 260%, respectively). Circulating levels of Ang II and MDA were significantly higher in T2D patients by 29 and 63%, respectively. CONCLUSIONS: T2D patients under treatment with glucose-lowering drugs, antihypertensive treatment as well as with statins have significantly increased ROCK activation in their circulating leukocytes along with higher phosphorylation of downstream cascade proteins despite pharmacologic treatment, along with increased plasma angiotensin II and MDA levels. ROCK inhibition might have an additional role in the prevention and treatment of T2D.


Assuntos
Diabetes Mellitus Tipo 2/enzimologia , Leucócitos Mononucleares/enzimologia , Quinases Associadas a rho/sangue , Idoso , Angiotensina II/sangue , Anti-Hipertensivos/uso terapêutico , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ativação Enzimática , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipoglicemiantes/uso terapêutico , Molécula 1 de Adesão Intercelular/sangue , Interleucina-8/sangue , Janus Quinase 2/sangue , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Transdução de Sinais , Molécula 1 de Adesão de Célula Vascular/sangue , Proteínas Quinases p38 Ativadas por Mitógeno/sangue
11.
Sci China Life Sci ; 63(3): 364-374, 2020 03.
Artigo em Inglês | MEDLINE | ID: covidwho-693

RESUMO

The outbreak of the 2019-nCoV infection began in December 2019 in Wuhan, Hubei province, and rapidly spread to many provinces in China as well as other countries. Here we report the epidemiological, clinical, laboratory, and radiological characteristics, as well as potential biomarkers for predicting disease severity in 2019-nCoV-infected patients in Shenzhen, China. All 12 cases of the 2019-nCoV-infected patients developed pneumonia and half of them developed acute respiratory distress syndrome (ARDS). The most common laboratory abnormalities were hypoalbuminemia, lymphopenia, decreased percentage of lymphocytes (LYM) and neutrophils (NEU), elevated C-reactive protein (CRP) and lactate dehydrogenase (LDH), and decreased CD8 count. The viral load of 2019-nCoV detected from patient respiratory tracts was positively linked to lung disease severity. ALB, LYM, LYM (%), LDH, NEU (%), and CRP were highly correlated to the acute lung injury. Age, viral load, lung injury score, and blood biochemistry indexes, albumin (ALB), CRP, LDH, LYM (%), LYM, and NEU (%), may be predictors of disease severity. Moreover, the Angiotensin II level in the plasma sample from 2019-nCoV infected patients was markedly elevated and linearly associated to viral load and lung injury. Our results suggest a number of potential diagnosis biomarkers and angiotensin receptor blocker (ARB) drugs for potential repurposing treatment of 2019-nCoV infection.


Assuntos
Angiotensina II/sangue , Betacoronavirus/patogenicidade , Biomarcadores/sangue , Infecções por Coronavirus/diagnóstico , Lesão Pulmonar , Pneumonia Viral/etiologia , Síndrome do Desconforto Respiratório do Adulto/etiologia , Carga Viral , Adulto , Idoso , Análise Química do Sangue , Criança , Infecções por Coronavirus/complicações , Infecções por Coronavirus/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/patologia , Índice de Gravidade de Doença
12.
Sci China Life Sci ; 63(3): 364-374, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32048163

RESUMO

The outbreak of the 2019-nCoV infection began in December 2019 in Wuhan, Hubei province, and rapidly spread to many provinces in China as well as other countries. Here we report the epidemiological, clinical, laboratory, and radiological characteristics, as well as potential biomarkers for predicting disease severity in 2019-nCoV-infected patients in Shenzhen, China. All 12 cases of the 2019-nCoV-infected patients developed pneumonia and half of them developed acute respiratory distress syndrome (ARDS). The most common laboratory abnormalities were hypoalbuminemia, lymphopenia, decreased percentage of lymphocytes (LYM) and neutrophils (NEU), elevated C-reactive protein (CRP) and lactate dehydrogenase (LDH), and decreased CD8 count. The viral load of 2019-nCoV detected from patient respiratory tracts was positively linked to lung disease severity. ALB, LYM, LYM (%), LDH, NEU (%), and CRP were highly correlated to the acute lung injury. Age, viral load, lung injury score, and blood biochemistry indexes, albumin (ALB), CRP, LDH, LYM (%), LYM, and NEU (%), may be predictors of disease severity. Moreover, the Angiotensin II level in the plasma sample from 2019-nCoV infected patients was markedly elevated and linearly associated to viral load and lung injury. Our results suggest a number of potential diagnosis biomarkers and angiotensin receptor blocker (ARB) drugs for potential repurposing treatment of 2019-nCoV infection.


Assuntos
Angiotensina II/sangue , Betacoronavirus/patogenicidade , Biomarcadores/sangue , Infecções por Coronavirus/diagnóstico , Lesão Pulmonar , Pneumonia Viral/etiologia , Síndrome do Desconforto Respiratório do Adulto/etiologia , Carga Viral , Adulto , Idoso , Análise Química do Sangue , Criança , Infecções por Coronavirus/complicações , Infecções por Coronavirus/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/patologia , Índice de Gravidade de Doença
13.
Bull Exp Biol Med ; 168(3): 305-308, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31938910

RESUMO

The concentrations of the key factors of molecular pathogenesis of prehypertension (angiotensin II, HLDF24, S100b, endothelin, autoantibodies to these molecules, and VEGF) were analyzed in subjects with optimal BP (<120/80 mm Hg) and prehypertension (120-139/80-89 mm Hg). Comparative and correlation analysis of the levels of these molecules was performed. A statistically significant decrease in HLDF24 level in prehypertension in comparison optimal BP was observed. Specific features and interactions between the studied factors in optimal BP and in prehypertension were studied. The mechanisms underlying the observed associations between serum concentration of HLFF24 and the development of prehypertension were discussed.


Assuntos
Biomarcadores/sangue , Proteínas de Neoplasias/sangue , Fragmentos de Peptídeos/sangue , Pré-Hipertensão/sangue , Angiotensina II/sangue , Autoanticorpos/sangue , Pressão Sanguínea/fisiologia , Endotelinas/sangue , Feminino , Humanos , Hipertensão/sangue , Masculino , Pessoa de Meia-Idade , Subunidade beta da Proteína Ligante de Cálcio S100/sangue
14.
Acta Biochim Biophys Sin (Shanghai) ; 52(1): 38-48, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31836883

RESUMO

Obstructive sleep apnea is characterized by chronic intermittent hypoxia (CIH), which is a risk factor for renal peritubular capillary (PTC) loss, and angiotensin II receptor blockers can alleviate PTC loss. However, the mechanism by which losartan (an angiotensin II receptor blocker) reduces CIH-induced PTC loss and attenuates kidney damage is still unknown. Thus, in this study, we examined the protective effects of losartan against CIH-induced PTC loss and explored the underlying mechanisms in rat CIH model. The immunohistochemical staining of CD34 and morphological examination showed that CIH reduced PTC density and damaged tubular epithelial cells. Immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), real-time quantitative PCR, and western blot analysis results revealed that CIH increased the expression of hypoxia inducible factor-1α (HIF-1α), angiotensin II (Ang II), angiotensin II type 1 receptor (AT1R), pro-angiogenesis factor vascular endothelial growth factor (VEGF), and anti-angiogenesis factor thrombospondin-1 (TSP-1) in the renal cortex of rats. CIH may up-regulate VEGF expression and simultaneously increase TSP-1 production. By histopathological, immunohistochemistry, ELISA, RT-qPCR, and western blot analysis, we found that the expressions of renal renin-angiotensin system (RAS), HIF-1α, VEGF, and TSP-1 were decreased, and PTC loss and tubular epithelial cell injury were attenuated with losartan treatment. Losartan ameliorated CIH-induced PTC loss by modulating renal RAS to improve the crosstalk between endothelial cells and tubular epithelial cells and subsequently regulate the balance of angiogenesis factors. Our study provided novel insights into the mechanisms of CIH-induced kidney damage and indicated that losartan could be a potential therapeutic agent for renal protection by alleviating CIH-induced PTC loss.


Assuntos
Indutores da Angiogênese/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Capilares/patologia , Hipóxia/complicações , Losartan/farmacologia , Substâncias Protetoras/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina II/sangue , Animais , Peso Corporal/efeitos dos fármacos , Creatinina/sangue , Células Epiteliais/efeitos dos fármacos , Hipóxia/etiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Córtex Renal/irrigação sanguínea , Córtex Renal/metabolismo , Masculino , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo , Apneia Obstrutiva do Sono/complicações , Trombospondina 1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
15.
Hypertension ; 75(1): 163-172, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760886

RESUMO

Primary aldosteronism is recognized as the most frequent cause of secondary hypertension, and its screening is expected to become a routine evaluation in most patients with hypertension. The interference of antihypertensive therapies with the aldosterone-to-renin ratio during screening process is a major confounder. Renin-angiotensin-aldosterone system Triple-A analysis is a novel liquid chromatography/tandem mass spectrometry diagnostic assay that allows simultaneous quantification of aldosterone, equilibrium Ang I (angiotensin I), and Equilibrium Ang II in a single sample of serum. We performed a comparative evaluation of the diagnostic performance of the aldosterone-to-Ang II ratio and 5 renin-based diagnostic ratios, differing in methods to determine aldosterone levels and renin activity in a cohort of 110 patients with hypertension (33 patients with confirmed primary aldosteronism and 77 with essential hypertension). All ratios showed comparable areas under the curves ranging between 0.924 and 0.970 without significant differences between each other. The evaluation of the Ang II-to-Ang I ratio revealed persistent drug intake in some patients as cause for suppressed renin-based diagnostic ratios, while aldosterone-to-Ang II ratio remained unaffected. The Youden index optimal cutoff value for the aldosterone-to-Ang II ratio was 6.6 ([pmol/L]/[pmol/L]) with a sensitivity of 90% and a specificity of 93%, proving noninferiority compared with the aldosterone-to-renin ratio while pointing to the potential for an interference-free application in patients under ACE (angiotensin-converting enzyme) inhibitor therapy. This study shows for the first time the accuracy and reliability of renin-angiotensin-aldosterone system triple-A analysis for the screening of primary aldosteronism that can be applied in clinical routine.


Assuntos
Aldosterona/sangue , Angiotensina II/sangue , Angiotensina I/sangue , Hipertensão Essencial/diagnóstico , Hiperaldosteronismo/diagnóstico , Sistema Renina-Angiotensina , Adulto , Hipertensão Essencial/sangue , Feminino , Humanos , Hiperaldosteronismo/sangue , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem
16.
BMC Infect Dis ; 19(1): 866, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31638922

RESUMO

BACKGROUND: Hand, foot and mouth disease (HFMD) remains a burdensome health issue in mainland China. Enterovirus71 (EV-A71) is the main pathogen of severe HFMD. Continuous hemofiltration improves fluid overload, restores kidney function and alleviates inflammatory reactions. The aim of the present study was to evaluate the effects of continuous veno-venous hemodiafiltration (CVVHDF) on severe HFMD caused by EV-A71(EV-A71-HFMD) in a pediatric intensive care unit (PICU). METHODS: A retrospective observational study was performed in a tertiary university PICU from January 2012 to December 2016. Children with severe EV-A71-HFMD complicated by cardiopulmonary failure were included. The patients were divided into a CVVHDF group and a conventional therapy (control) group (non-CVVHDF). The demographics, characteristics, and outcomes between the groups were collected and analyzed. RESULTS: Twenty-nine patients with severe EV-A71-HFMD were enrolled. The 28-day mortality was 17.6% (3/17) in the CVVHDF group and 33.3% (4/12) in the non-CVVHDF group, with no statistical significance between the two groups (P = 0.403). The median interval between CVVHDF initiation and PICU admission was 6 (4,8.5) hrs, and the median duration of CVVHDF was 48 (36, 64) hrs. The left ventricular ejection fraction (LVEF) and cardiac index (CI) in the CVVHDF group were improved after treatment. The plasma levels of catecholamines and renin-angiotensin-aldosterone system (RAAS) substances in the CVVHDF group were significantly decreased after treatment. The decreased catecholamines and RAAS substances included adrenalin (169.8 [145.5, 244.6] vs. 148.0 [109.0, 208.1] ng/L, P = 0.033), dopamine (152.7 [97.0, 191.1] vs. 96.0 [68.0, 160.9] ng/L, P = 0.026), angiotensin II (185.9 [125.2, 800.0] vs. 106.0 [90.8, 232.5] ng/L, P = 0.047), aldosterone (165.7 [94.0, 353.3] vs. 103.3 [84.3, 144.3] ng/L, P = 0.033), and renin (1.12 [0.74, 3.45] vs. 0.79 [0.52, 1.25] µg/L/h, P = 0.029), CONCLUSIONS: CVVHDF reduced the levels of catecholamines and RAAS substances and improved cardiovascular function. Continuous hemodiafiltration may represent a potential therapy in patients with severe EV-A71-HFMD complicated with cardiopulmonary failure.


Assuntos
Doenças Cardiovasculares/terapia , Terapia de Substituição Renal Contínua , Enterovirus Humano A , Doença de Mão, Pé e Boca/terapia , Doença de Mão, Pé e Boca/virologia , Unidades de Terapia Intensiva Pediátrica , Doença Pulmonar Obstrutiva Crônica/terapia , Aldosterona/sangue , Angiotensina II/sangue , Doenças Cardiovasculares/complicações , Catecolaminas/sangue , Pré-Escolar , China , Feminino , Seguimentos , Doença de Mão, Pé e Boca/sangue , Doença de Mão, Pé e Boca/complicações , Hemodiafiltração/métodos , Humanos , Lactente , Masculino , Doença Pulmonar Obstrutiva Crônica/complicações , Renina/sangue , Sistema Renina-Angiotensina/fisiologia , Estudos Retrospectivos , Volume Sistólico , Resultado do Tratamento
17.
Can J Physiol Pharmacol ; 97(12): 1115-1123, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31613143

RESUMO

Cyclosporine, an immunosuppressive drug, exhibits a toxic effect on renal and vascular systems. The present study investigated whether resveratrol treatment alleviates renal and vascular injury induced by cyclosporine. Cyclosporine (25 mg/kg per day, s.c.) was given for 7 days to rats either alone or in combination with resveratrol (10 mg/kg per day, i.p.). Relaxation and contraction responses of aorta were examined. Serum levels of blood urea nitrogen, creatinine, angiotensin II, and angiotensin 1-7 were measured. Histopathological examinations as well as immunostaining for 4-hydroxynonenal and nitrotyrosine were performed in the kidney. RNA expressions of renin-angiotensin system components were also measured in renal and aortic tissues. Cyclosporine decreased the endothelium-dependent relaxation and increased vascular contraction in the aorta. It caused renal tubular degeneration and increased immunostaining for 4-hydroxynonenal, an oxidative stress marker. Cyclosporine also caused upregulations of the vasoconstrictive renin-angiotensin system components in renal (angiotensin-converting enzyme) and aortic (angiotensin II type 1 receptor) tissues. Resveratrol co-treatment prevented the cyclosporine-related deteriorations. Moreover, it induced the expressions of vasodilatory effective angiotensin-converting enzyme 2 and angiotensin II type 2 receptor in aorta and kidney, respectively. We conclude that resveratrol may be effective in preventing cyclosporine-induced renal tubular degeneration and vascular dysfunction at least in part by modulating the renin-angiotensin system.


Assuntos
Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Ciclosporina/efeitos adversos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Resveratrol/farmacologia , Angiotensina II/sangue , Animais , Citoproteção/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , NADPH Oxidase 4/genética , RNA Mensageiro/genética , Ratos , Ratos Wistar , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
18.
Eur J Pharmacol ; 862: 172638, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491403

RESUMO

Angiotensin-1 converting enzyme inhibitors (ACEIs) improve insulin sensitivity. Inhibitors of dipeptidyl peptidase-4 (DPP-4) are anti-diabetic drugs with several cardio-renal effects. Both ACE and DPP-4 share common features. Thus, we tested if they could be inhibited by one inhibitor. First, in silico screening was used to investigate the ability of different DPP-4 inhibitors or ACEIs to interact with DPP-4 and ACE. The results of screening were then extrapolated into animal study. Fifty Sprague Dawley rats were randomly assigned into 5 groups treated with vehicle, captopril, enalapril, linagliptin or sitagliptin. Both low and high doses of each drug were tested. Baseline blood samples and samples at days 1, 8, 10, 14 were used to measure plasma DPP-4 and ACE activities and angiotensin II levels. Active glucagon-like peptide-1 (GLP-1) levels were measured after oral glucose challenge. All tested DPP-4 inhibitors could interact with ACE at a relatively reasonable binding energy while most of the ACEIs only interacted with DPP-4 at a predicted high inhibition constant. In rats, high dose of sitagliptin was able to inhibit ACE activity and reduce angiotensin II levels while linagliptin had only a mild effect. ACEIs did not significantly affect DPP-4 activity or prevent GLP-1 degradation. It seems that some DPP-4 inhibitors could inhibit ACE and this could partially explain the cardio-renal effects of these drugs. Further studies are required to determine if such inhibition could take place in clinical settings.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Peptidil Dipeptidase A/metabolismo , Angiotensina II/sangue , Animais , Captopril/farmacologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/sangue , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Enalapril/farmacologia , Feminino , Peptídeo 1 Semelhante ao Glucagon/sangue , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Linagliptina/farmacologia , Peptidil Dipeptidase A/sangue , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Fosfato de Sitagliptina/farmacologia
19.
Life Sci ; 235: 116862, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31513814

RESUMO

Dysregulation of miR-29 has been revealed in multiple diseases, but its role in the development of hypertension and vascular endothelial dysfunction has not been defined. Here, we found that, compared with the wild-type (WT) Wistar rats, miR-29b was robustly upregulated in spontaneously hypertensive rats (SHRs), while CTRP6 was distinctly downregulated. There were two miRNA-responding-elements (MREs) for miR-29 in the 3'-UTR of CTRP6 mRNA, and the luciferase activity assay revealed that miR-29b directly targeted CTRP6 mRNA. Intraventricular injection was applied to deliver the miR-29b mimic or miR-29b inhibitor (4 mg/kg) into SHRs once two weeks from 10th week. Downregulation of miR-29b could increase serum CTRP6 content in SHRs, decrease the arterial systolic pressure, reduce serum concentrations of Ang II and ET-1, and enhance serum NO content. Meanwhile, we demonstrated that inhibition of miR-29b increased the phosphorylation of ERK1/2 to activate PPARγ, an inducer of Ang II. Finally, miR-29b expression was manipulated in, and CTRP6 recombinant protein was applied to incubate with the primary aortic endothelial cells. Inhibition of miR-29b increased CTRP6 expression, improved cell proliferation and migration, suppressed secretion of Ang II and ET-1, and decreased ROS accumulation and LDH release, displaying a similar effect to the CTRP6 recombinant protein. Moreover, the CTRP6 recombinant protein could antagonize the suppressive effect of miR-29b on activation of the ERK/PPARγ axis and function of aortic endothelial cells. In conclusion, miR-29b antagonism can alleviate Ang II-induced hypertension and vascular endothelial dysfunction through activating the CTRP6/ERK/PPARγ axis.


Assuntos
Angiotensina II/efeitos adversos , Células Endoteliais/efeitos dos fármacos , Hipertensão/genética , Hipertensão/prevenção & controle , MicroRNAs/antagonistas & inibidores , Adipocinas/sangue , Angiotensina II/sangue , Animais , Pressão Sanguínea/efeitos dos fármacos , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Regulação para Baixo/efeitos dos fármacos , Endotelina-1/sangue , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , L-Lactato Desidrogenase/metabolismo , Masculino , MicroRNAs/agonistas , MicroRNAs/biossíntese , MicroRNAs/genética , Óxido Nítrico/sangue , Fosforilação/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
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