RESUMEN

Cerebral malaria (CM) induced by Plasmodium falciparum is a devastating neurological complication that may lead the patient to coma and death. This study aimed to protect Plasmodium-infected C57BL6 mice from CM by targeting the angiotensin II type 1 (AT1) receptor, which is considered the common connecting link between hypertension and CM. In CM, AT-1 mediates blood-brain barrier (BBB) damage through the overexpression of ß-catenin. The AT-1-inhibiting drugs, such as irbesartan and losartan, were evaluated for the prevention of CM. The effectiveness of these drugs was determined by the down regulation of ß-catenin, TCF, LEF, ICAM-1, and VCAM-1 in the drug-treated groups. The expression levels of VE-cadherin and vinculin, essential for the maintenance of BBB integrity, were found to be restored in the drug-treated groups. The pro-inflammatory cytokine levels were decreased, and the anti-inflammatory cytokine levels increased with the treatment. As a major highlight, the mean survival time of treated mice was found to be increased even in the absence of treatment with an anti-malarial agent. The combination of irbesartan or losartan with the anti-malarial agent α/ß-arteether has contributed to an 80% cure rate, which is higher than the 60% cure rate observed with α/ß-arteether alone treatment.

Asunto(s)

Modelos Animales de Enfermedad , Irbesartán , Malaria Cerebral , Ratones Endogámicos C57BL , Animales , Ratones , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Artemisininas/farmacología , Artemisininas/uso terapéutico , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/parasitología , Barrera Hematoencefálica/efectos de los fármacos , Citocinas/metabolismo , Irbesartán/farmacología , Irbesartán/uso terapéutico , Losartán/farmacología , Losartán/uso terapéutico , Malaria Cerebral/tratamiento farmacológico , Malaria Cerebral/parasitología , Receptor de Angiotensina Tipo 1/metabolismo , Angiotensinas/metabolismo

RESUMEN

The polymorphisms of the Renin-Angiotensin System are related to many disorders like diabetes, cardiovascular disease, and different types of cancer. Among all the polymorphisms related to AGTR1, A1166C has been associated with several disorders, including cardiovascular diseases and breast cancer. This study was conducted to discover the association of AGTR1 polymorphism (A1166C) Renin-Angiotensin and its effect on the development and progression of breast cancer in the Pakistani population. One hundred forty participants, including seventy diagnosed breast cancer patients and seventy healthy individuals, were included in this study and genotyped with an allele-specific polymerase chain reaction. The most frequent genotype in healthy participants and breast cancer patients was CC. An insignificant (p value>0.05) risk of breast cancer was found with A1166C polymorphism in codominant (CC vs. AA OR=1.200 [0.256-5.631] and AC vs. AA 0.941 [OR=0.223-3.976]), dominant (OR=1.00 [0.240-4.167]), recessive (OR=1.230 [0.593-2.552]) and additive models (OR=1.028 [0.533-1.983]) of general population genotypes. Nonetheless, when the AA genotype was considered a reference group, a significant association was found between AC and CC genotypes and invasive ductal and ductal carcinoma development in breast cancer patients. In conclusion, this study demonstrated no significant association between AGTR1 (A1166C) polymorphism and breast cancer risk.

Asunto(s)

Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Angiotensina II/genética , Pakistán/epidemiología , Polimorfismo Genético , Sistema Renina-Angiotensina/genética , Genotipo , Predisposición Genética a la Enfermedad

RESUMEN

OBJECTIVES: To evaluate the effect of autologous stem cell transplantation (aSCT) on functional antibodies (abs) to the angiotensin II type-1-receptor (AT1R) and topoisomerase-I (topo-I) in SSc-patients and to analyse their prognostic relevance. MATERIAL AND METHODS: Forty-three SSc-patients in whom aSCT was performed were analysed. Thirty-one patients had a favourable outcome after aSCT (group 1), 12 patients showed no response or relapse (group 2). Patients' sera were tested for anti-AT1R and anti-topo-I antibodies by ELISA and in a luminometric assay (LA) using AT1R-expressing Huh7-cells for inhibitory or stimulatory anti-AT1R antibodies before and after aSCT (4-217 months, median 28 months). Anti-topo-I antibodies were also analysed for their capacity to inhibit enzyme function. RESULTS: A total of 70% of the SSc patients had anti-topo-I- and 51% anti-AT1R antibodies in the ELISA before aSCT. In all instances, anti-topo-I antibodies inhibited topo-I-enzyme function. In the LA, 40% had stimulatory and 12% inhibitory anti-AT1R antibodies. Anti-topo-I- and anti-AT1R-reactivity (ELISA) significantly decreased after aSCT. Before aSCT, anti-topo-I-reactivity was significantly higher in group 2 patients than in group 1 patients (P < 0.001), while there was no difference between both groups for anti-AT1R antibodies detected by ELISA. Stimulatory anti-AT1R antibodies detected by LA were confined to group 1-patients. CONCLUSIONS: Reactivity of functionally active anti-AT1R antibodies was not influenced by aSCT, while anti-topo-I antibodies decreased after aSCT. The fact that anti-topo-I antibodies inhibited enzyme function in all instances supports the hypothesis of a pathogenetic role of the topo-I antigen/antibody-system in SSc. High anti-topo-I reactivity before aSCT was associated with an unfavourable, presence of stimulatory anti-AT1R antibodies with a favourable course after aSCT.

Asunto(s)

Trasplante de Células Madre Hematopoyéticas , Esclerodermia Sistémica , Humanos , Autoanticuerpos , Trasplante Autólogo , Esclerodermia Sistémica/complicaciones , Ensayo de Inmunoadsorción Enzimática , ADN-Topoisomerasas de Tipo I

RESUMEN

Pregnant women with either pre-existing or gestational diabetes mellitus are at increased risk of preeclampsia as well as future cardiovascular disease. The renin-angiotensin system is dysregulated in both diabetes mellitus and preeclampsia. In preeclampsia, maternal levels of circulating agonistic autoantibodies against the angiotensin II Type I receptor (AT1-AAs) are increased. Circulating AT1-AAs are thought to contribute to both the pathophysiology of preeclampsia and the increased risk of future cardiovascular disease. Studies exploring AT1-AA in diabetes outside pregnancy suggest their potential for both metabolic and cardiovascular pathogenicity. No studies have investigated AT1-AAs in diabetic pregnancies. We hypothesized elevated maternal circulating AT1-AA levels in pregnancies complicated by any type of diabetes mellitus. Third-trimester maternal serum from 39 women (controls: n = 10; type 1 diabetes: n = 9; type 2 diabetes: n = 10; gestational diabetes=10) were analyzed for AT1-AA using an established bioassay method. Circulating AT1-AAs were present in 70% (7/10) of the controls and 83% (24/29) of the diabetes group (P = 0.399). Presence of AT1-AA was correlated to hsCRP levels (P = 0.036), but neither with maternal circulating angiogenic factors (soluble fms-like tyrosine kinase-1 and placental growth factor), nor with maternal or fetal characteristics indicative of metabolic disease or placental dysfunction. Our study is the first to demonstrate presence of circulating AT1-AAs in pregnant women with any type of diabetes. Our findings suggest AT1-AAs presence in pregnancy independently of placental dysfunction, nuancing the current view on their pathogenicity. Whether AT1-AAs per se contribute to increased risk of adverse pregnancy outcomes and future cardiovascular disease remains currently unanswered.

Asunto(s)

Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Preeclampsia , Embarazo , Femenino , Humanos , Angiotensina II , Autoanticuerpos , Factor de Crecimiento Placentario , Placenta , Resultado del Embarazo

RESUMEN

Preeclampsia (PE) is a multisystem disease that affects the health of both the pregnant women and the fetus during pregnancy. Agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA) play a significant role in the pathogenesis of PE. This study aimed to determine the effects of Angiotensin 1-7 (Ang 1-7) and its analogue AVE0991 on AT1-AA-induced PE model. Pregnant mice were divided into five groups: the normal pregnant group, AT1-AA-induced preeclampsia group, and AT1-AA-induced preeclampsia group treated with Losartan, Ang 1-7, and AVE0991, respectively. AT1-AA-induced PE model was established on gestational day 13 by tail intravenous injection of purified AT1-AA polyclonal antibody from serum of guinea pigs. Blood urea nitrogen (BUN), urine albumin and urinary creatinine were measured on day 18 of pregnancy. The systolic blood pressure (SBP) was measured from gestational day 13 to day 18. Renal structure changes were observed via light and electron microscopy. Compared with the normal pregnant group (NP group), AT1-AA-induced preeclampsia group (PE group) exhibited elevated blood pressure and proteinuria, consistent with the characteristics of PE. Ang 1-7 or AVE0991 treatment decreased blood pressure without showing renoprotective effects. The findings indicated that Ang 1-7 and its analogue reduced blood pressure but aggravated renal damage in AT1-AA-induced PE mice.

Asunto(s)

Preeclampsia , Femenino , Embarazo , Ratones , Humanos , Cobayas , Animales , Preeclampsia/inducido químicamente , Presión Sanguínea , Receptor de Angiotensina Tipo 1 , Angiotensina I/efectos adversos

RESUMEN

Promiscuous G protein-coupled receptors (GPCRs) engage multiple Gα subtypes with different efficacies to propagate signals in cells. A mechanistic understanding of Gα selectivity by GPCRs is critical for therapeutic design, since signaling can be restrained by ligand-receptor complexes to preferentially engage specific G proteins. However, details of GPCR selectivity are unresolved. Here, we investigated cognate G protein selectivity using the prototypical promiscuous Gαq/11 and Gα12/13 coupling receptors, angiotensin II type I receptor (AT1R) and prostaglandin F2α receptor (FP), bioluminescence resonance energy transfer-based G protein and pathway-selective sensors, and G protein knockout cells. We determined that competition between G proteins for receptor binding occurred in a receptor- and G protein-specific manner for AT1R and FP but not for other receptors tested. In addition, we show that while Gα12/13 competes with Gαq/11 for AT1R coupling, the opposite occurs for FP, and Gαq-mediated signaling regulated G protein coupling only at AT1R. In cells, the functional modulation of biased ligands at FP and AT1R was contingent upon cognate Gα availability. The efficacy of AT1R-biased ligands, which poorly signal through Gαq/11, increased in the absence of Gα12/13. Finally, we show that a positive allosteric modulator of Gαq/11 signaling that also allosterically decreases FP-Gα12/13 coupling, lost its negative modulation in the absence of Gαq/11 coupling to FP. Together, our findings suggest that despite preferential binding of similar subsets of G proteins, GPCRs follow distinct selectivity rules, which may contribute to the regulation of ligand-mediated G protein bias of AT1R and FP.

Asunto(s)

Subunidades alfa de la Proteína de Unión al GTP G12-G13 , Subunidades alfa de la Proteína de Unión al GTP Gq-G11 , Receptor de Angiotensina Tipo 1 , Receptores de Prostaglandina , Subunidades alfa de la Proteína de Unión al GTP G12-G13/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Células HEK293 , Humanos , Ligandos , Receptor de Angiotensina Tipo 1/metabolismo , Receptores de Prostaglandina/metabolismo

RESUMEN

As survival in breast cancer patients from newer therapies increases, concerns for chemotherapy-induced cardiotoxicity (CIC) have offset some of these benefits, manifesting as a decline in left ventricular ejection fraction (LVEF). Patients receiving anthracycline-based chemotherapy followed by trastuzumab are at risk for CIC. Previous research evaluating whether clinical biomarkers predict cardiotoxicity has been inconsistent. Recently, angiotensin II type 1 receptor (ATR1) and endothelin 1 (ET1) have been shown to play a role in breast tumor growth. We evaluated ATR1 and ET1 expression in breast cancer tissue and its association with CIC. A total of 33 paraffin-embedded breast tissue specimens from women with breast cancer treated with anthracycline-based chemotherapy and trastuzumab were analyzed by immunohistochemistry (IHC) and qRT-PCR. We found that ET1 expression was increased in patients with an LVEF ≤ 50% (p = 0.032) with a lower LVEF correlating with higher ET1 expression (r = 0.377, p = 0.031). In patients with a change in LVEF of greater than 10%, greater ET1 expression was noted compared to those without a change in LVEF (p = 0.017). Increased ET1 expression in breast tumor tissue is associated with reduced LVEF. Future studies need to examine whether ET1 may be a tissue biomarker that helps predict the risk of developing CIC in women with breast cancer.

RESUMEN

Angiotensin (Ang) III, a biologically active peptide of the renin angiotensin system (RAS) is predominantly known for its central effects on blood pressure. Our understanding of the RAS has evolved from the simplified, classical RAS, a hormonal system regulating blood pressure to a complex system affecting numerous biological processes. Ang II, the main RAS peptide has been widely studied, and its deleterious effects when overexpressed is well-documented. However, other components of the RAS such as Ang III are not well studied. This review examines the molecular and biological actions of Ang III and provides insight into Ang III's potential role in metabolic diseases.

Asunto(s)

Angiotensina III , Sistema Renina-Angiotensina , Angiotensina II/genética , Angiotensina II/metabolismo , Angiotensina III/genética , Presión Sanguínea/fisiología , Encéfalo/metabolismo , Sistema Renina-Angiotensina/fisiología

RESUMEN

New avenues for glioblastoma therapy are required due to the limited mortality benefit of the current treatments. The renin-angiotensin system (RAS) exhibits local actions and works as a paracrine system in different tissues and tumors, including glioma. The glioblastoma cell lines U-87 MG and T98G overexpresses Angiotensin II (Ang II)/Angiotensin II type I receptor (AGTR1) signaling, which enhances in vitro and in vivo local estrogen production through a direct up-regulation of the aromatase gene promoters p I.f and p I.4. In addition, Ang II/AGTR1 signaling transactivates estrogen receptor-α in a ligand-independent manner through mitogen-activated protein kinase (MAPK) activation. The higher aromatase mRNA expression in patients with glioblastoma was associated with the worst survival prognostic, according to The Cancer Genome Atlas (TCGA). An intrinsic immunosuppressive glioblastoma tumor milieu has been previously documented. We demonstrate how Ang II treatment in glioblastoma cells increases programmed death-ligand 1 (PD-L1) expression reversed by combined exposure to Losartan (LOS) in vitro and in vivo. Our findings highlight how LOS, in addition, antagonizes the previously documented neoangiogenetic, profibrotic, and immunosuppressive effects of Ang II and drastically inhibits its stimulatory effects on local estrogen production, sustaining glioblastoma cell growth. Thus, Losartan may represent an adjuvant pharmacological tool to be repurposed prospectively for glioblastoma treatment.

RESUMEN

The renin-angiotensin system (RAS) controls not only systemic functions, such as blood pressure, but also local tissue-specific events. Previous studies have shown that angiotensin II receptor type 1 (AT1R) and type 2 (AT2R), two RAS components, are expressed in chondrocytes. However, the angiotensin II (ANG II) effects exerted through these receptors on chondrocyte metabolism are not fully understood. In this study, we investigated the effects of ANG II and AT1R blockade on chondrocyte proliferation and differentiation. Firstly, we observed that ANG II significantly suppressed cell proliferation and glycosaminoglycan content in rat chondrocytic RCS cells. Additionally, ANG II decreased CCN2, which is an anabolic factor for chondrocytes, via increased MMP9. In Agtr1a-deficient RCS cells generated by the CRISPR-Cas9 system, Ccn2 and Aggrecan (Acan) expression increased. Losartan, an AT1R antagonist, blocked the ANG II-induced decrease in CCN2 production and Acan expression in RCS cells. These findings suggest that AT1R blockade reduces ANG II-induced chondrocyte degeneration. Interestingly, AT1R-positive cells, which were localized on the surface of the articular cartilage of 7-month-old mice expanded throughout the articular cartilage with aging. These findings suggest that ANG II regulates age-related cartilage degeneration through the ANG II-AT1R axis.

Asunto(s)

Angiotensina II/farmacología , Condrocitos/efectos de los fármacos , Agrecanos/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Diferenciación Celular , Línea Celular Tumoral , Proliferación Celular , Células Cultivadas , Condrocitos/citología , Condrocitos/metabolismo , Condrocitos/fisiología , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Femenino , Humanos , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo

RESUMEN

Portal hypertension, defined as increased pressure in the portal vein, develops as a consequence of increased intrahepatic vascular resistance due to the dysregulation of liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), frequently arising from chronic liver diseases. Extrahepatic haemodynamic changes contribute to the aggravation of portal hypertension. The pathogenic complexity of portal hypertension and the unsuccessful translation of preclinical studies have impeded the development of effective therapeutics for patients with cirrhosis, while counteracting hepatic and extrahepatic mechanisms also pose a major obstacle to effective treatment. In this review article, we will discuss the following topics: i) cellular and molecular mechanisms of portal hypertension, focusing on dysregulation of LSECs, HSCs and hepatic microvascular thrombosis, as well as changes in the extrahepatic vasculature, since these are the major contributors to portal hypertension; ii) translational/clinical advances in our knowledge of portal hypertension; and iii) future directions.

RESUMEN

Autoantibody against the angiotensin II type I receptor (AT1-AA) has been found in the serum of patients with diabetes mellitus (DM). However, it remains unclear whether AT1-AA induces ß-cell apoptosis and participates in the development of DM. In this study, an AT1-AA-positive rat model was set up by active immunization, and AT1-AA IgG was purified. INS-1 cells were treated with AT1-AA, and cell viability, apoptosis, and autophagy-related proteins were detected by Cell Counting Kit-8 assay, flow cytometry, and western blot analysis, respectively. Results showed that existence of AT1-AA impaired the islet function and increased the apoptosis of pancreatic islet cells in rats, and the autophagy level in rat pancreatic islet tissues tended to increase gradually with the prolongation of immunization time. AT1-AA markedly reduced INS-1 cell viability, promoted cell apoptosis, and decreased insulin secretion in vitro. In addition, the autophagy level was gradually increased along with the prolongation of AT1-AA treatment time. Meanwhile, it was determined that treatment with autophagy inhibitor 3-methyladenine and angiotensin II type 1 receptor (AT1R) blocker telmisartan could improve insulin secretion and apoptosis in vitro and in vivo. In conclusion, it is deduced that upregulation of autophagy contributed to the AT1-AA-induced ß-cell apoptosis and islet dysfunction, and AT1R mediated the signal transduction.

Asunto(s)

Apoptosis/efectos de los fármacos , Autoanticuerpos/inmunología , Autoanticuerpos/farmacología , Autofagia/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Diabetes Mellitus Experimental/inmunología , Inmunoglobulina G/inmunología , Inmunoglobulina G/farmacología , Células Secretoras de Insulina/metabolismo , Receptor de Angiotensina Tipo 1/inmunología , Adenina/análogos & derivados , Adenina/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Apoptosis/inmunología , Autoanticuerpos/aislamiento & purificación , Autofagia/inmunología , Línea Celular Tumoral , Supervivencia Celular/inmunología , Inmunización/métodos , Inmunoglobulina G/aislamiento & purificación , Secreción de Insulina/efectos de los fármacos , Secreción de Insulina/inmunología , Masculino , Ratas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Telmisartán/farmacología , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/inmunología

RESUMEN

BACKGROUND: Selecting angiotensin converting enzyme inhibitor (ACEI) or angiotensin II type I receptor blocker (ARB) in patients diagnosed as acute myocardial infarction (AMI) with non-obstructive coronary arteries (MINOCA) is not established. The purpose of this study is to compare the clinical effect of ACEI vs. ARB in MINOCA patients. METHODS AND RESULTS: A total of 273 patients between November 2011 to June 2015, diagnosed with MINOCA who were registered in the Korea Acute Myocardial Infarction Registry - National Institute of Health were enrolled. Patients were divided into ACEI (n = 112) and ARB groups (n = 161). The primary endpoint was cumulative incidence of major adverse cardiac events (MACE) defined as cardiac death, recurrent MI, any new revascularization during 2 years clinical follow-up. Secondary endpoint was heart failure requiring re-hospitalization. Propensity score matching analysis was done. The incidence of primary endpoint was similar (10.4% vs. 15.6%, HR: 0.65; 95% CI: 0.29-1.47; p = 0.301) among both groups. However, the incidence of recurrent MI was significantly lower in ACEI group compared to ARB group (2.1% vs. 10.4%, HR: 0.18, 95% CI: 0.04-0.86; p = 0.031). CONCLUSIONS: In the present study, the risk and incidence of MACE was similar between ACEI and ARB therapy in MINOCA patients. However, ACEI significantly reduced the risk of recurrent MI. Further larger scale multi-center randomized clinical trials are needed to clarify the proper use of renin-angiotensin-aldosterone system blocker in these patients.

Asunto(s)

Infarto del Miocardio , Intervención Coronaria Percutánea , Angiotensina II , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Vasos Coronarios , Humanos , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/epidemiología , Sistema de Registros , República de Corea/epidemiología

RESUMEN

INTRODUCTION: There is controversy concerning the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II type-I receptor blockers (ARB) for treating hypertensive patients with Covid-19. It has been hypothesized that these drugs might increase the risk of severe Covid-19, but some authors suggested that blocking the renin-angiotensin system might actually decrease this risk. METHODS: Retrospective cohort study of all the consecutive hypertensive patients with confirmed SARS-CoV-2 infection in a health area. The outcome variable was hospitalization because of severe Covid-19. RESULTS: 539 subjects were diagnosed of SARS-CoV-2 infection. Of these, 157 (29.1%) had hypertension and were included in the study. Sixty-nine cases (43.9%) were hospitalized because of severe Covid-19. In multivariable analysis older age, diabetes and hypertensive myocadiopathy were related to a higher risk of hospital admission. ARB treatment was associated with a significantly lower risk of hospitalization (HR: 0.29, 95% CI: 0.10 - 0.88). A similar albeit not significant trend was observed for ACEI. CONCLUSION: ARB or ACEI treatment was not associated with a worse clinical outcome in consecutive hypertensive patients infected by SARS-CoV-2.

Asunto(s)

Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversos , COVID-19/epidemiología , Hipertensión/tratamiento farmacológico , SARS-CoV-2 , Factores de Edad , Anciano , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Cardiomiopatías/complicaciones , Complicaciones de la Diabetes , Femenino , Hospitalización , Humanos , Masculino , Análisis Multivariante , Pronóstico , Estudios Retrospectivos

RESUMEN

INTRODUCTION: Chronic active antibody-mediated rejection (cAMR) is a major determinant of late allograft failure. Rituximab/immunoglobulins (IVIg) + plasma exchange (PLEX) showed controversial results in cAMR treatment. Tocilizumab (TCZ), a humanized anti-interleukin 6 receptor antibody, has been recently used as rescue therapy in patients non-responsive to rituximab/IVIg/PLEX with favorable outcomes. Whether TCZ acts "per se" or requires a priming effect from previous treatments is currently unknown. METHODS: Fifteen patients with cAMR were treated with TCZ as a first-line therapy and followed for a median time of 20.7 months. RESULTS: Despite the majority of patients experiencing advanced transplant glomerulopathy (TG) at diagnosis (60% with cg3), glomerular filtration rate and proteinuria stabilized during the follow-up, with a significant reduction in donor-specific antibodies. Protocol biopsies after 6 months demonstrated significant amelioration of microvascular inflammation and no TG, C4d deposition, or IF/TA progression. Gene-expression and immunofluorescence analysis showed upregulation of three genes (TJP-1, AKR1C3, and CASK) involved in podocyte, mesangial, and tubular restoration. CONCLUSION: Tocilizumab adopted as a first-line approach in cAMR was associated with early serological and histological improvements and functional stabilization even in advanced TG, suggesting a role for the use of TCZ alone with the avoidance of unnecessary previous immunosuppressants.

Asunto(s)

Trasplante de Riñón , Anticuerpos Monoclonales Humanizados/uso terapéutico , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/etiología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto , Humanos , Rituximab/uso terapéutico

RESUMEN

The vasoconstricting effect of angiotensin II (Ang II) is mediated by Ang II type I receptor (AT1R); blocking or blunting AT1R is a key strategy for the development of antihypertensive drugs. Our previous study showed that the blood pressure lowering the activity of egg white hydrolysate (EWH) in spontaneously hypertensive rats was due to the downregulation of aortic AT1R expression, which promoted us to further identify the AT1R downregulating peptides in the present study. The protein expression of AT1R in a rat aortic vascular smooth muscle cell line A7r5 cells was used for the activity test. The hydrolysate was fractionated stepwise by C18 Sep-Pack cartridge and reverse-phase chromatography, and the peptide sequences were characterized by LC-MS/MS. Peptides including ITKPNDVYS, VVGSAEAGVDAAS, AVHAAHAEINEAGRE, AGREVVGSAEAGVD, and VVGSAEAGVD, were identified. ITKPNDVYS showed the most potent peptide for lowering the level of AT1R in A7r5 cells. These results suggested that ITKPNDVYS is the responsible peptide for lowering the AT1R level in EWH. PRACTICAL APPLICATIONS: A new peptide ITKPNDVYS was identified as a downregulator of AT1R from egg white hydrolysate, which provides a new approach for the development of food protein-derived antihypertensive peptides as nutraceuticals or functional food ingredients.

Asunto(s)

Hipertensión , Receptor de Angiotensina Tipo 1 , Angiotensina II , Animales , Cromatografía Liquida , Clara de Huevo , Hipertensión/tratamiento farmacológico , Péptidos/farmacología , Ratas , Espectrometría de Masas en Tándem

RESUMEN

The enormous growth in drug discovery paradigm has necessitated continuous exploration of new methods for drug-protein interaction analysis. To enhance the role of these methodologies in designing rational drugs, this work extended an immobilized angiotensin II type I receptor (AT1R) based affinity chromatography in antihypertensive compound identification. We fused haloalkane dehalogenase at C-terminus of AT1R and expressed the fusion receptor in E. coli. The expressed receptor was covalently immobilized onto 8.0 µm microspheres by mixing the cell lysate with 6-chlorocaproic acid-modified amino polystyrene microspheres. The immobilized AT1R was utilized for thermodynamic and kinetic interaction analysis between the receptor and four specific ligands. Following confirmation of these interactions by molecular docking, we identified puerarin and rosmarinic acid by determining their binding to the receptor. Azilsartan, candesartan, valsartan and olmesartan displayed two kinds of binding sites to AT1R by injection amount-dependent method. By molecular docking, we recognize the driving forces of the interaction as electrostatic interaction, hydrogen bonds and van der Waals force. The dissociation rate constants (kd) of azilsartan, candesartan, valsartan and olmesartan to AT1R were 0.01138 ± 0.003, 0.05142 ± 0.003, 0.07547 ± 0.004 and 0.01310 ± 0.005 min-1 by peak profiling assay. Comparing with these parameters, puerarin and rosmarinic acid presented lower affinity (KA: 0.12 × 104 and 1.5 × 104/M) and slower kinetics (kd: 0.6864 ± 0.03 and 0.3005 ± 0.01 min-1) to the receptor. These results, taking together, indicated that the immobilized AT1R has the capacity to probe antihypertensive compounds.

Asunto(s)

Antihipertensivos/metabolismo , Ensayos Analíticos de Alto Rendimiento/métodos , Receptor de Angiotensina Tipo 1/metabolismo , Antihipertensivos/química , Bencimidazoles/química , Bencimidazoles/metabolismo , Sitios de Unión , Compuestos de Bifenilo , Cromatografía de Afinidad , Cinamatos/metabolismo , Depsidos/metabolismo , Imidazoles/química , Imidazoles/metabolismo , Proteínas Inmovilizadas/química , Proteínas Inmovilizadas/metabolismo , Isoflavonas/metabolismo , Cinética , Ligandos , Simulación del Acoplamiento Molecular , Oxadiazoles/química , Oxadiazoles/metabolismo , Receptor de Angiotensina Tipo 1/química , Receptor de Angiotensina Tipo 1/genética , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/metabolismo , Tetrazoles/química , Tetrazoles/metabolismo , Termodinámica , Valsartán/química , Valsartán/metabolismo , Ácido Rosmarínico

RESUMEN

Recent evidence indicates that elevated placental adenosine signaling contributes to preeclampsia (PE). However, the molecular basis for the chronically enhanced placental adenosine signaling in PE remains unclear. Here, we report that hypoxia-inducible factor-1α (HIF-1α) is crucial for the enhancement of placental adenosine signaling. Utilizing a pharmacologic approach to reduce placental adenosine levels, we found that enhanced adenosine underlies increased placental HIF-1α in an angiotensin receptor type 1 receptor agonistic autoantibody (AT1 -AA)-induced mouse model of PE. Knockdown of placental HIF-1α in vivo suppressed the accumulation of adenosine and increased ecto-5'-nucleotidase (CD73) and adenosine A2B receptor (ADORA2B) in the placentas of PE mouse models induced by AT1 -AA or LIGHT, a TNF superfamily cytokine (TNFSF14). Human in vitro studies using placental villous explants demonstrated that increased HIF-1α resulting from ADORA2B activation facilitates the induction of CD73, ADORA2B, and FLT-1 expression. Overall, we demonstrated that (a) elevated placental HIF-1α by AT1 -AA or LIGHT upregulates CD73 and ADORA2B expression and (b) enhanced adenosine signaling through upregulated ADORA2B induces placental HIF-1α expression, which creates a positive feedback loop that promotes FLT-1 expression leading to disease development. Our results suggest that adenosine-based therapy targeting the malicious cycle of placental adenosine signaling may elicit therapeutic effects on PE.

Asunto(s)

Adenosina/metabolismo , Autoanticuerpos/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Placenta/metabolismo , Preeclampsia/metabolismo , ARN Interferente Pequeño/metabolismo , Animales , Autoanticuerpos/genética , Presión Sanguínea/genética , Presión Sanguínea/fisiología , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Immunoblotting , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Preeclampsia/genética , Embarazo , ARN Interferente Pequeño/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo

RESUMEN

INTRODUCTION: There is controversy concerning the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II type-I receptor blockers (ARB) for treating hypertensive patients with Covid-19. It has been hypothesized that these drugs might increase the risk of severe Covid-19, but some authors suggested that blocking the renin-angiotensin system might actually decrease this risk. METHODS: Retrospective cohort study of all the consecutive hypertensive patients with confirmed SARS-CoV-2 infection in a health area. The outcome variable was hospitalization because of severe Covid-19. RESULTS: 539 subjects were diagnosed of SARS-CoV-2 infection. Of these, 157 (29.1%) had hypertension and were included in the study. Sixty-nine cases (43.9%) were hospitalized because of severe Covid-19. In multivariable analysis older age, diabetes and hypertensive myocadiopathy were related to a higher risk of hospital admission. ARB treatment was associated with a significantly lower risk of hospitalization (HR: 0.29, 95% CI: 0.10 - 0.88). A similar albeit not significant trend was observed for ACEI. CONCLUSION: ARB or ACEI treatment was not associated with a worse clinical outcome in consecutive hypertensive patients infected by SARS-CoV-2.

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INTRODUCCIÓN: Existe controversia respecto al uso de los inhibidores de la enzima convertidora de angiotensina (IECA) o los bloqueadores de los receptores tipo I de la angiotensina II (ARA-II) para el tratamiento de la hipertensión arterial en COVID-19. Se ha sugerido que estos fármacos podrían tanto aumentar como reducir el riesgo de COVID-19 grave. PACIENTES Y MÉTODO: Estudio de cohortes retrospectivo de pacientes consecutivos de un área sanitaria, con hipertensión e infección por SARS-CoV-2. Variable de resultados: ingreso hospitalario por COVID-19 grave. RESULTADOS: Fueron diagnosticados 539 sujetos por infección por SARS-CoV-2. De estos, 157 (29,1%) eran hipertensos y se incluyeron en el estudio. Se ingresaron 69 (43,9%) pacientes por COVID-19 grave. En el análisis multivariante, la edad más elevada, la diabetes y la miocardiopatía hipertensiva se relacionaron con el riesgo de ingreso hospitalario. El tratamiento con ARA-II se asoció con un riesgo significativamente más bajo de ingreso (HR: 0,29, IC 95%: 0,10-0,88). Una tendencia similar, aunque no significativa, se encontró para los IECA. CONCLUSIÓN: el tratamiento con ARA-II o IECA no se asoció con una peor evolución clínica en pacientes hipertensos consecutivos infectados por SARS-CoV-2.

RESUMEN

Angiotensin II type I receptor agonistic autoantibodies (AT1-AA) in the plasma of preeclampsia patients can induce apoptosis of cardiomyocytes, and microRNA-21 (miR-21) can exert a protective effect on cardiomyocytes. But whether the pro-apoptotic effect of AT1-AA is associated with miR-21 is unclear. The objective of the present study was to explore whether AT1-AA induced cardiomyocyte apoptosis was related to its inhibitory of miR-21 expression. In vivo studies, the pregnant rats were divided into two groups: Sham group, Model group. The pathology, cell apoptosis, and relative protein expressions were evaluated by hematoxylin and eosin staining, and Western blot assay. The expression of microRNA was detected by gene microarray. In the cell experiment, the neonatal rat cardiomyocytes were divided into four groups: NC group, AT1-AA group, and miR-21 group and AT1-AA+miR-21 group. The cell apoptosis and relative proteins' expressions were measured by flow cytometry and Western blot assay. Results: Compared with the Sham group, miR-21 in the cardiac tissue of the model group was downregulated significantly; the expression of p-JNK, Bax and caspases-3 was increased, the expression of Bcl-2 was decreased, and the Bcl-2/Bax ratio became smaller. The expression of miR-21 in AT1-AA treated cardiomyocytes was only 52% of the control group, with an apoptosis rate of 32.6%. In addition, the expression of pPTEN, pAKT and pFOXO3a in the model group was significantly higher than that in the NC group. The cardiomyocyte apoptosis rate in miR-21 overexpression group was only 23.7%, which was higher than that in the NC group, but significantly lower than that in AT1-AA group. PTEN, AKT and FOXO3a phosporylation in miR-21 overexpression group was also lower than that in AT1-AA group. AT1-AA induced cardiomyocyte apoptosis by downregulating miR-21, and the PTEN/AKT/FOXO3a signal transduction pathway participated in this process. The result of the present study suggests that miR-21 may prove to be a new target for the diagnosis and treatment of preeclampsia and other cardiovascular diseases.