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BACKGROUND: Ischemic stroke combined with hypertension can increase risks of stroke recurrence and death. AIM: The aim of this study is to investigate the clinical efficacy of clopidogrel bisulfate tablets combined with olmesartan medoxomil in the treatment of ischemic stroke patients with hypertension and the effect of angiotensin II type 1 receptor (AT1R) level on prognosis. METHODS: Ninety ischemic stroke patients with hypertension were chosen for continuous treatment with clopidogrel bisulfate tablets and olmesartan medoxomil for 12 months. The Modified Edinburgh Scandinavian Stroke Scale (MESSS) score, Brunnstrom score, Barthel score, death, recurrence, and progression of cerebrovascular residual lesions were observed and recorded during the treatment period. According to the plasma AT1R expression of the patients before treatment, the patients were divided into a high-AT1R group and low-AT1R group. Then, survival analysis was performed. RESULTS: Compared with pretreatment, the MESSS scores of the patients at the first, second, third, sixth, ninth, and twelfth months after treatment were reduced (p < 0.01) while the Brunnstrom score and Barthel score were prominently boosted (p < 0.01). Compared with the low-AT1R group, patients in the high-AT1R group had higher rates of stroke recurrence and progression of residual cerebrovascular lesions (p < 0.05). CONCLUSION: Clopidogrel bisulfate tablets combined with olmesartan medoxomil has prominent clinical effects in the treatment of ischemic stroke patients with hypertension, evidently improving the prognosis. In addition, the level of AT1R may be a vital factor affecting the prognosis.
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Clopidogrel/administración & dosificación , Hipertensión/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Olmesartán Medoxomilo/administración & dosificación , Receptor de Angiotensina Tipo 1/sangre , Anciano , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Antihipertensivos/administración & dosificación , Biología Computacional , Quimioterapia Combinada , Femenino , Humanos , Hipertensión/sangre , Hipertensión/complicaciones , Accidente Cerebrovascular Isquémico/sangre , Accidente Cerebrovascular Isquémico/complicaciones , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/administración & dosificación , Pronóstico , Resultado del TratamientoRESUMEN
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.
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Autoanticuerpos/sangre , COVID-19/inmunología , SARS-CoV-2/aislamiento & purificación , Glicoproteína de la Espiga del Coronavirus/sangre , Angiotensina II/sangre , Angiotensina II/inmunología , Enzima Convertidora de Angiotensina 2/genética , Autoanticuerpos/inmunología , Autoanticuerpos/aislamiento & purificación , COVID-19/sangre , COVID-19/virología , Femenino , Humanos , Masculino , Peptidil-Dipeptidasa A/sangre , Receptor de Angiotensina Tipo 1/sangre , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/inmunología , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/inmunología , SARS-CoV-2/genética , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/aislamiento & purificaciónRESUMEN
Background: Lung histopathology demonstrates vasculopathy in a subset of deceased COVID19 patients, which resembles histopathology observed in antibody-mediated lung transplant rejection. Autoantibodies against angiotensin II type 1 receptor (AT1R) and Endothelin receptor Type A (ETAR) have been demonstrated in antibody-mediated rejection and may also be associated with severe COVID19 infection. Objective To assess AT1R and ETAR auto-antibodies in COVID19 patients and controls, and explore their association with disease course. Methods: 65 hospitalized patients with COVID19 infection were included. Clinical and laboratory findings were retrospectively assessed. Patients with unfavorable disease course, admitted at the intensive care unit and/or deceased during hospital admission (n=33) were compared to admitted COVID19 patients with favorable disease course (n=32). The presence of antinuclear antibodies (ANA) and auto-antibodies against AT1R or ETAR in peripheral blood were compared between COVID19 with unfavorable and favorable disease course and age matched controls (n=20). Results: The presence of ANA was not significantly different between COVID19 patients with unfavorable (n=7/33; 21%) and favorable disease course (n=6/32; 19%) (p= 0.804) and controls (n=3/20; 15%). Auto-antibodies against AT1R were significantly increased in unfavorable disease course (median 14.59 U/mL, IQR 11.28 - 19.89) compared to favorable disease course (median 10.67 U/mL, IQR 8.55 - 13.0, p< 0.01). ETAR antibody titers were also significantly increased in unfavorable disease course (median 7.21, IQR 5.0 - 10.45) as compared to favorable disease course (median 4.0, IQR 3.0 - 6.0, p <0.05). Conclusion: Auto-antibodies against AT1R and ETAR are significantly increased in COVID19 patients with an unfavorable disease course.
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Autoanticuerpos/sangre , COVID-19/inmunología , Receptor de Angiotensina Tipo 1/inmunología , Receptor de Endotelina A/inmunología , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/sangre , Femenino , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Países Bajos , Receptor de Angiotensina Tipo 1/sangre , Receptor de Endotelina A/sangre , Estudios Retrospectivos , Medición de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
Preeclampsia (PE) remains a leading cause of maternal and neonatal morbidity and mortality. Numerous studies have shown that women with PE develop autoantibody, termed angiotensin II type 1 receptor autoantibody (AT1-AA), and key features of the disease result from it. Emerging evidence has indicated that inflammatory cell necrosis, such as pyroptosis, could lead to autoantigen exposure and stimulate autoantibody production. Caspase-1, the central enzyme of inflammasome and key target of pyroptosis, may play roles in AT1R exposure and AT1-AA production. Exploring endogenous regulator that could inhibit AT1-AA production by targeting pyroptosis will be essential for treating PE. Lipoxin A4 (LXA4), endogenous dual anti-inflammatory and proresolving lipid mediator, may inhibit AT1-AA production via modulating caspase-1. Thus, we explore whether caspase-1 is essential for AT1-AA production and LXA4 inhibits AT1-AA via modulating caspase-1. PE patients and mice developed AT1-AA associated with caspase-1 activation. Caspase-1 deletion leaded to AT1-AA decrease in PE mice. Consistent with these findings, we confirmed caspase-1 activation, trophoblast pyroptosis and AT1R exposure in PE mice and trophoblast model, while caspase-1 deficiency showed decreased trophoblast pyroptosis and AT1R exposure in vitro and in vivo. Interestingly, LXA4 could suppress AT1-AA production via regulating caspase-1 as well as enhancing phagocytosis of dead trophoblasts by macrophages. These results suggest that caspase-1 promotes AT1-AA production via inducing trophoblast pyroptosis and AT1R exposure, while LXA4 suppresses AT1-AA production via modulating caspase-1, supporting caspase-1 serving as a therapeutic target for attenuating AT1-AA and LXA4 protecting patients from AT1-AA and PE.
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Autoanticuerpos/metabolismo , Caspasa 1/metabolismo , Lipoxinas/farmacología , Preeclampsia/inmunología , Piroptosis/efectos de los fármacos , Receptor de Angiotensina Tipo 1/inmunología , Trofoblastos/efectos de los fármacos , Antagonistas de Receptores de Angiotensina , Animales , Autoanticuerpos/genética , Autoanticuerpos/inmunología , Caspasa 1/sangre , Caspasa 1/deficiencia , Caspasa 1/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Células Cultivadas , Citocinas/metabolismo , Femenino , Humanos , Lipopolisacáridos/farmacología , Lipoxinas/sangre , Lipoxinas/deficiencia , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Preeclampsia/sangre , Preeclampsia/metabolismo , Embarazo , Piroptosis/genética , Piroptosis/inmunología , ARN Interferente Pequeño , Receptor de Angiotensina Tipo 1/sangre , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Bazo/crecimiento & desarrollo , Bazo/inmunología , Bazo/patología , Trofoblastos/metabolismoRESUMEN
Preeclampsia not only seriously endangers maternal and fetal health during pregnancy but may incur many sequelae in postpartum women such as reduced visual acuity. Agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA) is closely associated with preeclampsia. The aim of the present study is to determine whether AT1-AA is associated with retinal impairment during the course of preeclampsia. A preeclampsia model was established by injecting AT1-AA into pregnant rats via the tail vein. Changes in the retinal histological structure were observed. Cell apoptosis and cytokines including reactive oxygen species (ROS), as well as apoptosis-related proteins such as Bcl-2, Bax, and caspase-3 were detected. In addition, flash electroretinograms obtained at different postpartum days were analyzed. Compared with the control group, the retinal structure became edematous and the cell density was reduced significantly in preeclampsia group. The cell apoptosis rate was increased significantly. In addition, the content of ROS, the levels of Bax and caspase-3 in the retina were increased, while the content of Bcl-2 was reduced significantly. Continuous observation of the electroretinograms showed loss of retinal ganglion cells postpartum. The present study demonstrated that AT1-AA induced retinal cell apoptosis by promoting ROS release and activating caspase, suggesting that the increased postpartum susceptibility of preeclamptic women to retinopathy is related to AT1-AA-induced cell apoptosis.
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Citocinas/inmunología , Preeclampsia/inmunología , Especies Reactivas de Oxígeno/inmunología , Receptor de Angiotensina Tipo 1/inmunología , Retina/inmunología , Adulto , Animales , Apoptosis/inmunología , Proteínas Reguladoras de la Apoptosis/inmunología , Proteínas Reguladoras de la Apoptosis/metabolismo , Autoanticuerpos/inmunología , Autoanticuerpos/metabolismo , Citocinas/metabolismo , Femenino , Humanos , Preeclampsia/sangre , Preeclampsia/metabolismo , Embarazo , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Receptor de Angiotensina Tipo 1/administración & dosificación , Receptor de Angiotensina Tipo 1/sangre , Retina/efectos de los fármacos , Retina/metabolismo , Retina/patología , Adulto JovenRESUMEN
BACKGROUND: Transplant glomerulopathy (TG) is an important cause of late graft loss. The role of angiotensin type 1-receptor antibodies (AT1 R-Ab) in TG is not known. METHODS: All the TG cases (N = 137) between January 2007 and December 2014 (N = 1410) were analyzed. Donor-specific anti-HLA antibodies (DSA) at the time of biopsy and AT1 R-Ab IgG (positive, >17 UI/mL; "at risk," 10-17 UI/mL; negative, <10 UI/mL) in pre-transplant sera (PT-Ab) and at biopsy time (BT-Ab) were studied. RESULTS: AT1 R-PT-Ab+ and AT1 R-BT-Ab+ patients were 16.5% (51.5% "at risk") and 11.5% (27.4% "at risk"), respectively. Clinical correlations were found between AT1 R-Ab and HCV infection, number of transplants, and age. Considering Banff scores, ptc was higher in DSA+ patients vs AT1 R-PT-Ab+ (P = 0.002) or AT1 R-BT-Ab+ (P = 0.001) without differences in g and chronicity score (ci + ct); cg showed lower scores in DSA+ patients vs AT1 R-BT-Ab+ (P = 0.001). Graft survival was not influenced by the presence of AT1 R-Ab, AT1-R-Ab titer or MFI, but we observed a longer graft survival in patients with both AT1 R-BT-Ab+ or "at risk" and DSA+ vs patients positive only for DSA (P = 0.02), for AT1 R-BT-Ab (P = 0.019) or AT1 R-BT-Ab "at risk" (P = 0.039). CONCLUSION: AT1 R-Ab showed no independent prognostic role in TG in this pilot analysis.
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Autoanticuerpos/sangre , Glomerulonefritis Membranosa/diagnóstico , Rechazo de Injerto/diagnóstico , Antígenos HLA/sangre , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Receptor de Angiotensina Tipo 1/sangre , Adolescente , Adulto , Anciano , Autoanticuerpos/inmunología , Femenino , Estudios de Seguimiento , Glomerulonefritis Membranosa/sangre , Glomerulonefritis Membranosa/etiología , Rechazo de Injerto/sangre , Rechazo de Injerto/etiología , Supervivencia de Injerto , Antígenos HLA/inmunología , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Receptor de Angiotensina Tipo 1/inmunología , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: Both the adrenergic and renin-angiotensin systems contribute to orthostatic circulatory homeostasis, which is impaired in postural orthostatic tachycardia syndrome (POTS). Activating autoantibodies to the α1-adrenergic and ß1/2-adrenergic receptors have previously been found in sera from patients with POTS. We hypothesized that patients with POTS might also harbor activating autoantibodies to the angiotensin II type 1 receptor (AT1R) independently of antiadrenergic autoimmunity. This study examines a possible pathophysiological role for AT1R autoantibodies in POTS. METHODS AND RESULTS: Serum immunoglobulin G from 17 patients with POTS, 6 patients with recurrent vasovagal syncope, and 10 normal controls was analyzed for the ability to activate AT1R and alter AT1R ligand responsiveness in transfected cells in vitro. Of 17 subjects with POTS, 12 demonstrated significant AT1R antibody activity in immunoglobulin G purified from their serum. No significant AT1R antibody activity was found in the subjects with vasovagal syncope or healthy subjects. AT1R activation by POTS immunoglobulin G was specifically blocked by the AT1R blocker losartan. Moreover, POTS immunoglobulin G significantly shifted the angiotensin II dosage response curve to the right, consistent with an inhibitory effect. All subjects with POTS were positive for one or both autoantibodies to the AT1R and α1-adrenergic receptor. CONCLUSIONS: Most patients with POTS harbor AT1R antibody activity. This supports the concept that AT1R autoantibodies and antiadrenergic autoantibodies, acting separately or together, may exert a significant impact on the cardiovascular pathophysiological characteristics in POTS.
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Autoanticuerpos/sangre , Autoinmunidad , Síndrome de Taquicardia Postural Ortostática/fisiopatología , Receptor de Angiotensina Tipo 1/inmunología , Adolescente , Adulto , Autoanticuerpos/inmunología , Femenino , Humanos , Masculino , Síndrome de Taquicardia Postural Ortostática/sangre , Síndrome de Taquicardia Postural Ortostática/inmunología , Receptor de Angiotensina Tipo 1/sangre , Vasoconstricción/fisiología , Adulto JovenRESUMEN
Background: We analysed in a carefully phenotyped cohort of paediatric patients the association of serum angiotensin II type 1 receptor antibodies (AT1R-Ab) with specific histological lesions and with graft function and survival in conjunction with overall and complement-binding donor-specific human leucocyte antigen donor-specific antibodies (HLA-DSA). Methods: Sera of 62 patients at the time of renal graft biopsy for clinical indication >1 year post-transplant were assessed for AT1R-Ab by enzyme-linked immunosorbent assay (ELISA) and for DSA and C1q-fixing DSA by single-antigen bead technology. Results: Serum AT1R-Ab concentration was significantly higher in antibody-mediated rejection (ABMR) than in T-cell-mediated rejection or control. By receiver operating characteristic (ROC) curve analysis, the optimal AT1R-Ab cut-off value discriminating between patients with features of ABMR and those without was 9.5 U/mL. A total of 6 of 28 patients (21.4%) with ABMR were only positive for AT1R-Ab. Patients with AT1R-Ab and HLA-DSA double positivity had a significantly higher vascular micro-inflammation score than DSA-negative patients. The 5-year graft survival was only 59% in the AT1R-Ab-positive group compared with 87% in the AT1R-Ab-negative group. Patients with AT1R-Ab and HLA-DSA double positivity tended to have a more rapid decline of estimated glomerular filtration rate (eGFR) than patients who were only positive for AT1R-Ab or HLA-DSA. In a multivariate Cox regression model of non-invasive factors, C1q-positive HLA-DSA, eGFR and AT1R-Ab positivity were significantly associated with accelerated graft function decline. Conclusions: Serum AT1R-Ab positivity in the context of an indication biopsy >1 year post-transplant is associated with the histopathology of ABMR and is an independent non-invasive risk factor for adverse graft outcome.
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Anticuerpos/efectos adversos , Rechazo de Injerto/mortalidad , Supervivencia de Injerto , Antígenos HLA/inmunología , Trasplante de Riñón/efectos adversos , Receptor de Angiotensina Tipo 1/inmunología , Receptores de Trasplantes/estadística & datos numéricos , Adolescente , Adulto , Anticuerpos/inmunología , Niño , Femenino , Tasa de Filtración Glomerular , Rechazo de Injerto/etiología , Rechazo de Injerto/patología , Humanos , Masculino , Receptor de Angiotensina Tipo 1/sangre , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Tasa de Supervivencia , Donantes de TejidosRESUMEN
BACKGROUND/AIMS: Heavy ethanol consumption is a risk factor for hypertension and prompts organ damage. There is no information regarding the impact of long-term heavy ethanol consumption on kidney structure and function linking to their hypertensive effects nor the repercussions after withdrawal. METHODS: Rats were exposed to ethanol for 24 weeks and, afterwards, a group was assigned to withdrawal for 8 weeks. Blood pressure (BP) was measured and serum biochemical parameters were quantified. Glomerular volume density, areal density of glomerular tuft and renal corpuscles were determined. Angiotensin II type 1 receptor (AT1R) protein expression was evaluated. RESULTS: Twenty-four weeks of ethanol consumption causes atrophy of renal corpuscles and glomeruli and reduces the volume of glomeruli. Glomerular changes induced by ethanol consumption were still evident after withdrawal. Renal AT1R levels were increased in ethanol-treated rats and returned to control levels during withdrawal. Ethanol consumption also induced an increase in BP, uric acid and albumin levels. Upon withdrawal, systolic and mean arterial pressures decreased, but were still higher than in controls rats. CONCLUSION: Ethanol consumption induces changes in glomerular morphology associated with increased BP and AT1R expression. Long-term withdrawal was inefficient to restore the structural integrity of renal corpuscles and in lowering systolic pressure.
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Consumo de Bebidas Alcohólicas/efectos adversos , Presión Sanguínea/efectos de los fármacos , Riñón/efectos de los fármacos , Animales , Etanol/efectos adversos , Riñón/patología , Glomérulos Renales/patología , Ratas , Receptor de Angiotensina Tipo 1/sangre , Síndrome de Abstinencia a Sustancias , Factores de TiempoRESUMEN
INTRODUCTION: The definition of antibody-mediated rejection (AMR) is based on serologic (presence and/or development of donor-specific anti-HLA antibodies [DSAs]) and histologic (C4d deposition and endothelial damage) criteria. However, several cases of AMR have been described without C4d deposition, and other cases of histologic AMR without DSAs, which could be driven by other non-HLA alloantibodies such as anti-MICA or anti-angiotensin II type I receptor (AT1R). Here we studied clinical and histologic humoral rejection in kidney transplant recipients without evidence of anti-HLA antibodies. MATERIALS AND METHODS: Fifteen kidney transplant recipients with AMR defined as C4d+ and/or histologic g+ptc without anti-HLA antibodies in screening test were studied. Sera at the moment of biopsy and 2 months earlier were studied for anti-HLA antibodies by Luminex, in neat, diluted 1/160, and sera after treatment with dithiothreitol (DTT) and confirmed by single-antigen test. The anti-AT1R was measured by enzyme-linked immunosorbent assay. RESULTS: A lack of anti-HLA and MICA antibodies was confirmed after anti-HLA screening test in all conditions (neat, diluted, and DTT-treated) and de novo development of AT1R antibodies was ruled out. Nevertheless, after single-antigen test, 3 patients were identified with a weak reaction against class I antigen and another 4 patients against class II antigen. Due to the lack of locus-C typing in the donors, the DSA assignment cannot be confirmed, whereas anti-HLA class II antigens were DSA. CONCLUSIONS: A low sensitivity in the screening of anti-HLA antibody testing was observed. Our results suggest performing single-antigen test in seronegative patients with clinical humoral rejection after screening to confirm the presence of DSA.
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Autoanticuerpos/inmunología , Rechazo de Injerto/inmunología , Antígenos HLA/sangre , Trasplante de Riñón/efectos adversos , Adulto , Autoanticuerpos/sangre , Biopsia , Ensayo de Inmunoadsorción Enzimática , Femenino , Antígenos HLA/inmunología , Antígenos de Histocompatibilidad Clase II/sangre , Antígenos de Histocompatibilidad Clase II/inmunología , Prueba de Histocompatibilidad/métodos , Humanos , Riñón/inmunología , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Receptor de Angiotensina Tipo 1/sangre , Receptor de Angiotensina Tipo 1/inmunologíaRESUMEN
With increased industrial development, cadmium is an increasingly important environmental pollutant. Studies have identified various adverse effects of cadmium on human beings. However, the relationships between cadmium pollution and the pathogenesis of preeclampsia remain elusive. The objective of this study is to explore the effects of cadmium on immune system among preeclamptic patients and rats. The results showed that the cadmium levels in the peripheral blood of preeclamptic patients were significantly higher than those observed in normal pregnancy. Based on it, a novel rat model of preeclampsia was established by the intraperitoneal administration of cadmium chloride (CdCl2) (0.125 mg of Cd/kg body weight) on gestational days 9-14. Key features of preeclampsia, including hypertension, proteinuria, placental abnormalities and small foetal size, appeared in pregnant rats after the administration of low-dose of CdCl2. Cadmium increased immunoglobulin production, mainly angiotensin II type 1-receptor-agonistic autoantibodies (AT1-AA), by increasing the expression of activation-induced cytosine deaminase (AID) in B cells. AID is critical for the maturation of antibody and autoantibody responses. In addition, angiotensin II type 1-receptor-agonistic autoantibody, which emerged recently as a potential pathogenic contributor to PE, was responsible for the deposition of complement component 5 (C5) in kidneys of pregnant rats via angiotensin II type 1 receptor (AT1R) activation. C5a is a fragment of C5 that is released during C5 activation. Selectively interfering with C5a signalling by a complement C5a receptor-specific antagonist significantly attenuated hypertension and proteinuria in Cd-injected pregnant rats. Our results suggest that cadmium induces immune abnormalities that may be a key pathogenic contributor to preeclampsia and provide new insights into treatment strategies of preeclampsia.
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Autoanticuerpos/sangre , Cadmio/efectos adversos , Exposición a Riesgos Ambientales/efectos adversos , Contaminantes Ambientales/efectos adversos , Preeclampsia/inducido químicamente , Receptor de Angiotensina Tipo 1/sangre , Animales , Linfocitos B/metabolismo , Cadmio/sangre , Complemento C5/metabolismo , Citosina Desaminasa/metabolismo , Femenino , Humanos , Hipertensión/inducido químicamente , Riñón/efectos de los fármacos , Riñón/metabolismo , Placenta/efectos de los fármacos , Placenta/metabolismo , Preeclampsia/sangre , Preeclampsia/inmunología , Embarazo , Proteinuria/inducido químicamente , Ratas , Ratas WistarRESUMEN
Preeclampsia is a low-grade systemic inflammatory condition in which oxidative stress and endothelial dysfunction occurs. Plasma levels of soluble receptor for vascular endothelial growth factor (VEGFR)-1, also known as sFlt1 (soluble fms-like tyrosine kinase 1), an antiangiogenic factor have been reported to be elevated in preeclampsia. It was reported that pregnant mice deficient in catechol-O-methyltransferase (COMT) activity show a preeclampsia-like phenotype due to a deficiency or absence of 2-methoxyoestradiol (2-ME), a natural metabolite of estradiol that is elevated during the third trimester of normal human pregnancy. Additionally, autoantibodies (AT1-AAs) that bind and activate the angiotensin II receptor type 1 a (AT1 receptor) also have a role in preeclampsia. None of these abnormalities are consistently seen in all the patients with preeclampsia and some of them are not specific to pregnancy. Preeclampsia could occur due to an imbalance between pro- and antiangiogenic factors. VEGF, an angiogenic factor, is necessary for the transport of polyunsaturated fatty acids (PUFAs) to endothelial cells. Hence reduced VEGF levels decrease the availability of PUFAs to endothelial cells. This leads to a decrease in the formation of anti-inflammatory and angiogenic factors: lipoxins, resolvins, protectins, and maresins from PUFAs. Lipoxins, resolvins, protectins, maresins, and PUFAs suppress insulin resistance; activation of leukocytes, platelets, and macrophages; production of interleukin-6 and tumor necrosis factor-α; and oxidative stress and endothelial dysfunction; and enhance production of prostacyclin and nitric oxide (NO). Estrogen enhances the formation of lipoxin A4 and NO. PUFAs also augment the production of NO and inhibit the activity of angiotensin-converting enzyme and antagonize the actions of angiotensin II. Thus, PUFAs can prevent activation of angiotensin II receptor type 1 a (AT1 receptor). Patients with preeclampsia have decreased plasma phospholipid concentrations of arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), the precursors of lipoxins (from AA), resolvins (from EPA and DHA), and protectins (from DHA) and prostaglandin E1 (PGE1 from DGLA: dihomo-γ-linolenic acid) and prostacyclin (PGI2 derived from AA). Based on these evidences, it is proposed that preeclampsia may occur due to deficiency of PUFAs and their anti-inflammatory products: lipoxins, resolvins, protectins, and maresins.
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Inhibidores de la Angiogénesis/sangre , Citocinas/sangre , Eicosanoides/sangre , Ácidos Grasos Insaturados/sangre , Inflamación/sangre , Preeclampsia/etiología , Factor A de Crecimiento Endotelial Vascular/sangre , Animales , Endotelio Vascular/metabolismo , Ácidos Grasos Insaturados/deficiencia , Femenino , Humanos , Preeclampsia/sangre , Embarazo , Receptor de Angiotensina Tipo 1/sangre , Factor A de Crecimiento Endotelial Vascular/deficienciaRESUMEN
BACKGROUND: Whether biomechanical force on the heart can induce exosome secretion to modulate cardiovascular function is not known. We investigated the secretion and activity of exosomes containing a key receptor in cardiovascular function, the angiotensin II type I receptor (AT1R). METHODS AND RESULTS: Exosomes containing AT1Rs were isolated from the media overlying AT1R-overexpressing cells exposed to osmotic stretch and from sera of mice undergoing cardiac pressure overload. The presence of AT1Rs in exosomes was confirmed by both electron microscopy and radioligand receptor binding assays and shown to require ß-arrestin2, a multifunctional adaptor protein essential for receptor trafficking. We show that functional AT1Rs are transferred via exosomes in an in vitro model of cellular stretch. Using mice with global and cardiomyocyte conditional deletion of ß-arrestin2, we show that under conditions of in vivo pressure overload the cellular source of the exocytosis of exosomes containing AT1R is the cardiomyocyte. Exogenously administered AT1R-enriched exosomes target cardiomyocytes, skeletal myocytes, and mesenteric resistance vessels and are sufficient to confer blood pressure responsiveness to angiotensin II infusion in AT1R knockout mice. CONCLUSIONS: AT1R-enriched exosomes are released from the heart under conditions of in vivo cellular stress to likely modulate vascular responses to neurohormonal stimulation. In the context of the whole organism, the concept of G protein-coupled receptor trafficking should consider circulating exosomes as part of the reservoir of functional AT1Rs.
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Exosomas/química , Miocitos Cardíacos/química , Receptor de Angiotensina Tipo 1/sangre , Estrés Mecánico , Animales , Arrestinas/deficiencia , Arrestinas/genética , Arrestinas/fisiología , Presión Sanguínea , Constricción , Exosomas/fisiología , Femenino , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Electrónica , Células Musculares/metabolismo , Miocitos Cardíacos/ultraestructura , Presión Osmótica , Transporte de Proteínas , Interferencia de ARN , ARN Interferente Pequeño/farmacología , Ensayo de Unión Radioligante , Receptor de Angiotensina Tipo 1/deficiencia , Receptor de Angiotensina Tipo 1/genética , Resistencia Vascular , beta-ArrestinasRESUMEN
BACKGROUND: Solid-phase immunoassays have improved detection sensitivity for donor-specific HLA antibody (DSHA) and permitted the accurate diagnosis of antibody-mediated rejection (AMR). However, DSHA is not always sufficient to explain the cause of AMR. Consequently, a means of assessing non-HLA antibodies is required to determine the cause of AMR. The aim of the present study was to evaluate the clinical implications of antibodies (Abs) targeting angiotensin II type I receptor (AT1R) in recipients with AMR but without serum DSHA. METHODS: Non-HLA AMR cases diagnosed between January 2011 and June 2014 were included. Levels of anti-AT1R Abs (U/mL) were quantified by using AT1R assay kits (One Lambda, Calif, United States) with collected sera pretransplantation and at biopsy (cut-off value: 15 U/mL). RESULTS: Seventy-two patients were diagnosed with AMR during the above-mentioned period. Of them, 12 recipients (16.7%) had no DSHA. The sera of these 12 patients were tested (2 patients were only checked at time of biopsy). Nine patients (9/10) were presensitized for anti-AT1R Abs (median, 25.0 U/mL; range, 12.9 to 50.0 U/mL). Ten patients (10/12) were anti-AT1R- positive at time of biopsy (median, 23.2 U/mL; range, 11.4 to 50.0 U/mL). The mean time from transplantation to biopsy was 73 months. Eight patients experienced acute AMR, and 4 developed chronic AMR. Four patients showed negative C4d staining in peritubular capillaries (4/12). Patients were treated with plasmapheresis, low-dose intravenous immunoglobulin, and/or rituximab. CONCLUSIONS: AT1R Abs may play a significant role in AMR without detectable DSHA. Pretransplantation detection of AT1R Abs may be helpful for assessing the risk for non-HLA AMR.
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Rechazo de Injerto/inmunología , Antígenos HLA/inmunología , Isoanticuerpos/inmunología , Trasplante de Riñón , Receptor de Angiotensina Tipo 1/inmunología , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Femenino , Rechazo de Injerto/sangre , Antígenos HLA/sangre , Humanos , Inmunoensayo , Isoanticuerpos/sangre , Masculino , Persona de Mediana Edad , Receptor de Angiotensina Tipo 1/sangre , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: The purpose of this study was to investigate the inhibitory effects of long-term electroacupuncture at BaiHui (DU20) and ZuSanLi (ST36) on cardiovascular remodeling in spontaneously hypertensive rats (SHR) and underlying mechanisms. METHODS: 6-weeks-old SHR or Wistar male rats were randomly, divided into 6 groups: the control group (SHR/Wistar), the non-acupoint electroacupuncture stimulation group (SHR-NAP/Wistar-NAP) and the electroacupuncture stimulation at DU20 and ST36 group (SHR-AP/Wistar-AP), 24 rats in each group. Rats were treated with or without electroacupuncture at DU20 and ST36, once every other day for a period of 8 weeks. The mean arterial pressure (MAP) was measured once every 2 weeks. By the end of the 8th week, the left ventricular structure and function were assessed by echocardiography. The content of angiotensin II (Ang II), endothelin-1 (ET-1) and nitric oxide (NO) in the plasma was determined using enzyme-linked immunosorbent assay. Histological studies on the heart and the ascending aorta were performed. The expression of angiotensin II type 1 receptor (AT1R), endothelin-1 type A receptor (ETAR), eNOS and iNOS in rat myocardium and ascending aorta was investigated by Western blotting. RESULTS: The MAP in SHR increased linearly over the observation period and significantly reduced following electroacupuncture as compared with sham control SHR rats, while no difference in MAP was observed in Wistar rats between electroacupuncture and sham control. The aortic wall thickness, cardiac hypertrophy and increased collagen level in SHR were attenuated by long term electroacupuncture. The content of Ang II, ET-1 in the plasma decreased, but the content of NO increased after electroacupuncture stimulation in SHR. Long term electroacupuncture significantly inhibited the expression of AT1R, ETAR and iNOS, whereas increased eNOS expression, in myocardium and ascending aorta of SHR. CONCLUSIONS: The long term electroacupuncture stimulation at DU20 and ST36 relieves the increased MAP and cardiovascular abnormality in both structure and function in SHR, this beneficial action is most likely mediated via modulation of AT1R-AT1R-ET-1-ETAR and NOS/NO pathway.
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Aorta/patología , Presión Sanguínea , Cardiomegalia/terapia , Electroacupuntura , Hipertensión/terapia , Miocardio/patología , Remodelación Vascular , Puntos de Acupuntura , Angiotensina II/sangre , Angiotensina II/metabolismo , Animales , Aorta/metabolismo , Colágeno/metabolismo , Endotelina-1/sangre , Endotelina-1/metabolismo , Ensayo de Inmunoadsorción Enzimática , Hipertensión/sangre , Masculino , Miocardio/metabolismo , Óxido Nítrico/sangre , Óxido Nítrico Sintasa/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Ratas Wistar , Receptor de Angiotensina Tipo 1/sangre , Receptor de Angiotensina Tipo 1/metabolismoRESUMEN
BACKGROUND: Autoantibodies specific to the angiotensin II type I receptor (anti-AT1-AR) have been implicated in the pathology of congestive heart failure (CHF). Anti-AT1-AR may be associated with left ventricular function in CHF patients treated with perindopril. METHODS: Synthetic angiotensin II type 1 receptor (AT1-R) peptides served as the target antigen. ELISA was used to screen the sera of 156 CHF patients, which were divided into positive and negative groups based on their anti-AT1-AR reactivity. Echocardiography and a 6-minute walk test were performed at baseline and after one year of perindopril therapy. The end-point events were compared over a 5-year follow-up. RESULTS: Final analysis covered 138 patients, including 82 positive and 56 negative. The frequency and geometric mean titre of anti-AT1-AR were significantly lower in the positive group after one year of treatment (all P < 0.01, from 100% to 73.2% and from 1:125.3 ± 1.0 to 1:69.2 ± 1.1). Of these, 22 patients showed no antibodies. Both groups showed improvement in left ventricular end-diastole, end-systolic dimensions, ejection fraction, and a 6-minute walk test by perindopril in combination with standard treatment regime for one year (all P < 0.01). However, the 82 patients positive for anti-AT1-AR showed more pronounced improvement than the 56 negative patients (all P < 0.05). However, after 5 years of follow-up, the rate of all causes and cardiovascular mortality attributable to any cause and the re-hospitalisation rate showed no significant differences between the two groups (all P > 0.05). CONCLUSIONS: Perindopril treatment significantly decreased the frequency and geometric mean titre in patients positive for anti-AT1-AR, even to complete ablation. These patients showed greater improvement in left ventricular remodeling and heart function than negative that in patients after one year of perindopril treatment in combination with standard treatment, but no significant differences in endpoint events were observed in the following 5 years. Anti-AT1-AR might be a useful biomarker of over-activation of the renin-angiotensin-aldosterone system for clinical medication.
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Autoanticuerpos/sangre , Insuficiencia Cardíaca/sangre , Perindopril/uso terapéutico , Receptor de Angiotensina Tipo 1/sangre , Función Ventricular Izquierda/fisiología , Remodelación Ventricular/fisiología , Anciano , Secuencia de Aminoácidos , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Perindopril/farmacología , Estudios Prospectivos , Resultado del Tratamiento , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacosRESUMEN
OBJECTIVE: To determine the effect of AT1 receptor antagonism on skin microcirculation and plasma level of thromboxane A2 (TXA2). METHODS: Healthy women (n=20) maintained 7 days low salt (LS) diet (intake <40 mmol Na/day) without (LS) or together with 50 mg/per day of losartan (a selective AT1 receptor inhibitor) (LS diet+losartan group). Laser Doppler flowmetry (LDF) measurements of changes in post occlusive hyperemic blood flow, plasma concentration of stable TXA2 metabolite thromboxane B2 (TXB2) and plasma renin activity (PRA) aldosterone concentration, electrolytes (Na(+), K(+)), as well as blood pressure and heart rate were determined before and after study protocols. RESULTS: PRA and aldosterone increased significantly after 7 days of both LS diet and LS diet+losartan. LS diet or LS diet+losartan administrations had no significant effect on post-occlusion hyperemia While there was no change in TXB2 after LS diet TXB2 significantly increased after one week of LS+losartan compared to control levels (cTXB2 pg/mL control 101±80 vs. LS diet+losartan 190±116, p<0.05). CONCLUSION: These data suggest that inhibition of AT1 receptors could lead to activation of AT2 receptors, which maintain hyperemia, despite the increased level of vasoconstrictor TXA2. These findings also suggest an important role of crosstalk between renin-angiotensin system (RAS) and arachidonic acid metabolites in the regulation of microcirculation under physiological conditions.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Dieta Hiposódica , Microcirculación/fisiología , Receptor de Angiotensina Tipo 1/sangre , Piel/irrigación sanguínea , Tromboxano A2/sangre , Biomarcadores/sangre , Dieta Hiposódica/métodos , Femenino , Humanos , Losartán/farmacología , Microcirculación/efectos de los fármacos , Piel/efectos de los fármacos , Piel/metabolismo , Tromboxano A2/biosíntesis , Adulto JovenRESUMEN
The current epidemic of obesity and type 2 diabetes is attributed to a high carbohydrate diet, containing mainly high fructose corn syrup and sucrose. More than two thirds of diabetic patients have hypertension. Methylglyoxal is a highly reactive dicarbonyl generated during glucose and fructose metabolism, and a major precursor of advanced glycation end products (AGEs). Plasma methylglyoxal levels are increased in hypertensive rats and diabetic patients. Our aim was to examine the levels of methylglyoxal, mediators of the renin angiotensin system and blood pressure in male Sprague-Dawley rats treated with a high fructose diet (60% of total calories) for 4 months. The thoracic aorta and kidney were used for molecular studies, along with cultured vascular smooth muscle cells (VSMCs). HPLC, Western blotting and Q-PCR were used to measure methylglyoxal and reduced glutathione (GSH), proteins and mRNA, respectively. Fructose treated rats developed a significant increase in blood pressure. Methylglyoxal level and protein and mRNA for angiotensin II, AT1 receptor, adrenergic α1D receptor and renin were significantly increased, whereas GSH levels were decreased, in the aorta and/or kidney of fructose fed rats. The protein expression of the receptor for AGEs (RAGE) and NF-κB were also significantly increased in the aorta of fructose fed rats. MG treated VSMCs showed increased protein for angiotensin II, AT1 receptor, and α1D receptor. The effects of methylglyoxal were attenuated by metformin, a methylglyoxal scavenger and AGEs inhibitor. In conclusion, we report a strong association between elevated levels of methylglyoxal, RAGE, NF-κB, mediators of the renin angiotensin system and blood pressure in high fructose diet fed rats.
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Aorta Torácica/efectos de los fármacos , Carbohidratos de la Dieta/efectos adversos , Fructosa/efectos adversos , Regulación de la Expresión Génica/efectos de los fármacos , Riñón/efectos de los fármacos , Piruvaldehído/sangre , Sistema Renina-Angiotensina/efectos de los fármacos , Angiotensina II/sangre , Angiotensina II/genética , Animales , Aorta Torácica/metabolismo , Aorta Torácica/patología , Presión Sanguínea/efectos de los fármacos , Células Cultivadas , Glutatión/sangre , Riñón/metabolismo , Riñón/patología , Masculino , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , FN-kappa B/sangre , FN-kappa B/genética , Piruvaldehído/farmacología , ARN Mensajero/sangre , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Receptor para Productos Finales de Glicación Avanzada , Receptor de Angiotensina Tipo 1/sangre , Receptor de Angiotensina Tipo 1/genética , Receptores Adrenérgicos alfa 1/sangre , Receptores Adrenérgicos alfa 1/genética , Receptores Inmunológicos/sangre , Receptores Inmunológicos/genética , Renina/sangre , Renina/genética , Sistema Renina-Angiotensina/genéticaRESUMEN
Hypercoagulability, platelet activation, and thrombocytopenia are the chief characteristics of preeclampsia, but their responsible underlying molecular mechanisms remain obscure. Recent studies have demonstrated that the autoantibody against angiotensin II type 1 receptor (AT1-AA) constitutes a novel risk factor for preeclampsia. However, the role of AT1-AA in platelet activation and hypercoagulability in preeclampsia has never been investigated. In the present study, we determined whether AT1-AA promotes platelet aggregation in vitro, and dissected the potential underlying mechanisms. AT1-AA was detected by enzyme-linked immunosorbent assay. After immunoglobulin G fractions purified from the preeclamptic patient positive sera were added to platelets isolated from healthy volunteers, platelet aggregation and intracellular Ca(2+) levels were detected. AT1-AA significantly enhanced in vitro collagen-induced platelet aggregation, an effect blocked by the AT1 receptor antagonist losartan. Additionally, AT1-AA increased and maintained collagen-induced cytosolic calcium concentration throughout the experiment. We demonstrated for the first time that AT1-AA significantly promotes collagen-induced platelet aggregation through angiotensin type 1 receptor activation in vitro, potentially via increased intracellular Ca(2+) concentration, supporting AT1-AA as a potential contributor to the hypercoagulable state of preeclampsia.