Navegando por Autor "Bader, Michael"
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Item Altered renal response to acute volume expansion in transgenic rats harboring the human tissue kallikrein gene.(2005) Passaglio, Kátia Tomagnini; Baltatu, Ovidiu; Machado, Raquel do Pilar; Reis, Adelina Martha dos; Pesquero, João Bosco; Bader, Michael; Santos, Robson Augusto Souza dosThe renal response to acute volume expansion was investigated in transgenic (TGR) rats harboring the human tissue kallikrein gene. After a primer injection of 0.9% NaCl (3 ml/100 g, i.v), Sprague–Dawley (SD) or TGR rats received a continuous infusion of 0.9% NaCl (15 Al/ 100 g/min, i.a.) through a catheter placed into the carotid artery. Acute volume expansion was produced by a second injection of 0.9% NaCl (2 ml/100 g, i.v.) 65 min after the first injection. Plasma vasopressin (AVP) and atrial natriuretic peptide (ANP) concentration was measured before and within 10 min of volume expansion. TGR animals presented a blunted response to acute volume expansion evidenced by an attenuated increase in total and fractional water and sodium excretion. Before or after volume expansion, plasma AVP and ANP did not differ between SD and TGR. Pre-treatment with the BK-B2 antagonist HOE-140 (7.5 Ag/100 g. i.a) partially improved the renal response of TGRs and severely blunted the response in SD rats. These data show that TGR (hKLK1) rats have an impaired renal response to acute volume expansion that can not be accounted for by changes in the release of AVP or ANP.Item Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas.(2003) Santos, Robson Augusto Souza dos; Silva, Ana Cristina Simões e; Maric, Christine; Rabelo, Denise Maria Rover da Silva; Machado, Raquel do Pilar; Buhr, Insa de; Walther, Silvia Heringer; Pinheiro, Sérgio Veloso Brant; Lopes, Miriam Teresa Paz; Bader, Michael; Mendes, Elizabeth Pereira; Lemos, Virgina Soares; Santos, Maria José Campagnole dos; Schultheiss, Heinz-Peter; Speth, Robert; Walther, ThomasThe renin–angiotensin system plays a critical role in blood pressure control and body fluid and electrolyte homeostasis. Besides angiotensin (Ang) II, other Ang peptides, such as Ang III [Ang-(2–8)], Ang IV [Ang-(3–8)], and Ang-(1–7) may also have important biological activities. Ang-(1–7) has become an angiotensin of interest in the past few years, because its cardiovascular and baroreflex actions counteract those of Ang II. Unique angiotensin-binding sites specific for this heptapeptide and studies with a selective Ang-(1–7) antagonist indicated the existence of a distinct Ang-(1–7) receptor. We demonstrate that genetic deletion of the G proteincoupled receptor encoded by the Mas protooncogene abolishes the binding of Ang-(1–7) to mouse kidneys. Accordingly, Mas-deficient mice completely lack the antidiuretic action of Ang-(1–7) after an acute water load. Ang-(1–7) binds to Mas-transfected cells and elicits arachidonic acid release. Furthermore, Mas-deficient aortas lose their Ang-(1–7)-induced relaxation response. Collectively, these findings identify Mas as a functional receptor for Ang-(1–7) and provide a clear molecular basis for the physiological actions of this biologically active peptide.Item Angiotensin-(1-7) receptor Mas is an essential modulator of extracellular matrix protein expression in the heart.(2012) Gava, Elisandra; Castro, Carlos Henrique de; Ferreira, Anderson José; Colleta, Heloísa; Melo, Marcos Barrouin; Alenina, Natalia; Bader, Michael; Oliveira, Laser Antônio Machado de; Santos, Robson Augusto Souza dosIn this study we investigated the effects of genetic deletion of the Angiotensin-(1-7) receptor Mas or the Angiotensin II receptor AT2 on the expression of specific extracellular matrix (ECM) proteins in atria, right ventricles and atrioventricular (AV) valves of neonatal and adult mice. Quantification of collagen types I, III and VI and fibronectin was performed using immunofluorescence-labeling and confocal microscopy. Picrosirius red staining was used for the histological assessment of the overall collagen distribution pattern. ECM proteins, metalloproteinases (MMP), ERK1/2 and p38 levels were quantified by western blot analysis. Gelatin zymography was used to evaluate the activity ofMMP-2 andMMP-9. We observed that the relative levels of collagen types I and III and fibronectin are significantly higher in both the right ventricle and AV valves of neonatal Mas−/− mouse hearts (e.g., collagen type I: 85.28±6.66 vs 43.50±4.41 arbitrary units in the right ventricles of Mas+/+ mice). Conversely, the level of collagen type VI was lower in the right ventricle and AV valves of Mas−/− mice. Adult Mas−/− mouse hearts presented similar patterns as observed in neonates. No significant differences in ECMprotein level were detected in atria. Likewise, no changes in ECM levels were observed in AT2 knockout mouse hearts. Although deletion of Mas induced a significant reduction in the level of the active form of MMP-2 in neonate hearts and a reduction of both MMP-2 and MMP-9 in adult Mas−/− mice, no significant differences were observed inMMP enzymatic activities when compared to controls. The levels of the active, phosphorylated forms of ERK1/2 and p38 were higher in hearts of both neonatal and adult Mas−/− mice. These observations suggest that Mas is involved in the selective expression of specific ECMproteins within both the ventricular myocardium and AV valves. The changes in the ECM profile may alter the connective tissue framework and contribute to the decreased cardiac performance observed in Mas−/− mice.Item Discovery and characterization of Alamandine : a novel component of the Renin-Angiotensin system.(2013) Lautner, Roberto Queiroga; Villela, Daniel Campos; Silva, Rodrigo Araújo Fraga da; Silva, Neiva Caldeira; Braga, Thiago Verano; Fraga, Fabiana Costa; Jankowski, Joachim; Jankowski, Vera; Sousa, Frederico Barros de; Alzamora, Andréia Carvalho; Soares, Everton Rocha; Barbosa, Claudiane Maria; Kjeldsen, Frank; Oliveira, Aline Cristina; Braga, Janaina Félix; Savergnini, Silvia Silveira Quintão; Etelvino, Gisele Maia; Peluso, Antonio Augusto Bastos; Silva, Danielle Gomes Passos; Ferreira, Anderson José; Alves, Fabiana; Martins, Almir de Sousa; Raizada, Mohan K.; Paula, Renata Dutra de; Santos, Daisy Motta; Klempin, Friederike; Pimenta, Adriano Monteiro de Castro; Alenina, Natalia; Sinisterra Millán, Ruben Dario; Bader, Michael; Santos, Maria José Campagnole dos; Santos, Robson Augusto Souza dosThe renin–angiotensin system (RAS) is a key regulator of the cardiovascular system, electrolyte, and water balance. Here, we report identification and characterization of alamandine, a new heptapeptide generated by catalytic action of angiotensin-converting enzyme-2 angiotensin A or directly from angiotensin-(1–7). To characterize a novel component of the RAS, alamandine. Using mass spectrometry we observed that alamandine circulates in human blood and can be formed from angiotensin-(1–7) in the heart. Alamandine produces several physiological actions that resemble those produced by angiotensin-(1–7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein–coupled receptor, member D. Binding of alamandine to Mas-related G-protein–coupled receptor, member D is blocked by D-Pro7-angiotensin-(1–7), the Mas-related G-protein–coupled receptor, member D ligand β-alanine and PD123319, but not by the Mas antagonist A-779. In addition, oral administration of an inclusion compound of alamandine/β-hydroxypropyl cyclodextrin produced a long-term antihypertensive effect in spontaneously hypertensive rats and antifibrotic effects in isoproterenol-treated rats. Alamandine had no noticeable proliferative or antiproliferative effect in human tumoral cell lines. The identification of these 2 novel components of the RAS, alamandine and its receptor, provides new insights for the understanding of the physiological and pathophysiological role of the RAS and may help to develop new therapeutic strategies for treating human cardiovascular diseases and other related disorders.Item Identification of a novel agonist-like autoantibody in preeclamptic patients.(2016) Velloso, Elizabeth Portugal; Pimentel, Renata Lúcia; Braga, Janaina Félix; Cabral, Antônio Carlos Vieira; Reis, Zilma Silveira Nogueira; Bader, Michael; Santos, Robson Augusto Souza dos; Wallukat, GerdBACKGROUND Recent studies have shown that preeclampsia (PE) is associated with the presence of autoantibodies (AABs) that activate the angiotensin II AT1 receptor, which could contribute to many of the symptoms of PE. METHODS To investigate the frequency and the targets of AABs in preeclamptic women (31 cases) and healthy pregnant normotensive women (29 cases) in Brazil, antibodies from serum samples were detected by a bioassay using spontaneously beating neonatal rat cardiomyocytes in culture. In the cardiomyocytes, the agonistic AABs induce a positive or negative chronotropic response, mimicking the corresponding receptor agonists. The specificity of the AAB response was identified by specific receptor antagonists. RESULTS Thirty preeclamptic patients (97%) presented AABs against the angiotensin II AT1 receptor. The agonistic effect of the AAB was blocked by irbesartan and neutralized by a peptide corresponding to the second extracellular loop of this receptor. Strikingly, we discovered that all sera from the severe preeclamptic patients (16 cases) contained a novel agonist- like AAB directed against the endothelin-1 ETA receptor in addition to the AABs against the angiotensin II AT1 receptor. This AAB was selectively blocked by the antagonist BQ-123, antagonized by the protein kinase C (PKC) inhibitor Calphostin C and neutralized by peptides corresponding to the second extracellular loop of the endothelin-1 ETA receptor subtype. CONCLUSIONS We described, for the first time, the presence of endothelin-1 ETA receptor AABs in PE. Our results suggest that the presence of both agonistic AABs may be involved in the pathogenesis of severe PE.Item The ACE2/Angiotensin-(1-7)/MAS axis of the renin-angiotensin system : focus on Angiotensin-(1-7).(2018) Santos, Robson Augusto Souza dos; Sampaio, Walkyria Oliveira; Alzamora, Andréia Carvalho; Santos, Daisy Motta; Alenina, Natalia; Bader, Michael; Santos, Maria José Campagnole dosThe renin-angiotensin system (RAS) is a key player in the control of the cardiovascular system and hydroelectrolyte balance, with an influence on organs and functions throughout the body. The classical view of this system saw it as a sequence of many enzymatic steps that culminate in the production of a single biologically active metabolite, the octapeptide angiotensin (ANG) II, by the angiotensin converting enzyme (ACE). The past two decades have revealed new functions for some of the intermediate products, beyond their roles as substrates along the classical route. They may be processed in alternative ways by enzymes such as the ACE homolog ACE2. One effect is to establish a second axis through ACE2/ANG-(1–7)/MAS, whose end point is the metabolite ANG- (1–7). ACE2 and other enzymes can form ANG-(1–7) directly or indirectly from either the decapeptide ANG I or from ANG II. In many cases, this second axis appears to counteract or modulate the effects of the classical axis. ANG-(1–7) itself acts on the receptor MAS to influence a range of mechanisms in the heart, kidney, brain, and other tissues. This review highlights the current knowledge about the roles of ANG-(1–7) in physiology and disease, with particular emphasis on the brain.