João B Pesquero

Universidade Federal de São Paulo, San Paulo, São Paulo, Brazil

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Publications (193)736.3 Total impact

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    ABSTRACT: Several deleterious effects may occur when intense and exhaustive exercise (IE) is not well-planned. This study aimed to investigate the effects of a short duration IE on body chemical composition and hypothalamic-pituitary-adrenal (HPA) axis. C57Bl/6 mice were distributed into four groups (10 mice per group): control (C-4D and C-10D), 4 days (E-4D), and 10 days of IE (E-10D). IE program consisted of a daily running session at 85 % of maximum speed until the animal reached exhaustion. Body weight as well as total body water, fat and protein content were determined from animal carcasses. HPA activation was assessed by plasma corticosterone levels measured by radioimmunoassay and the weight of both the adrenal glands and thymus. Plasma corticosterone levels increased by 64 % in both the E-4D and E-10D groups. The weight of the adrenal glands augmented by 74 % and 45 %, at 4 and 10 days of IE, respectively, whereas thymus weight diminished by 15 % only in the E-10D group. Total carcass fat content decreased by 20 % only at 4 days IE, whereas protein content decreased by 20 % in both E-4D and E-10D groups. A relationship between corticosterone plasma levels and loss of body protein content in both E-4D and E-10D groups was observed (R(2)=0.999). We concluded that IE may be related to HPA axis activation associated with remodeling of body chemical composition in C57BL/6 mice.
    Physiological research / Academia Scientiarum Bohemoslovaca 06/2014; · 1.53 Impact Factor
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    ABSTRACT: Focal and segmental glomerulosclerosis (FSGS) is one of the most important renal diseases related to end stage renal failure. Bradykinin has been implicated in the pathogenesis of renal inflammation whereas the role of its receptor 2 (B2RBK) in FSGS has not been studied. FSGS was induced in wild type and B2RBK KO mice by a single intravenous injection of Adriamycin (ADM). In order to further modulate the kinin receptors, animals were also treated with B2RBK antagonist HOE-140, and DALBK, B1RBK antagonist. Here, we show that the blockage of B2RBK with HOE-140 protects mice from FSGS development, including podocyte foot process effacement and reestablishment of slit diaphragm-related proteins. However, B2RBK KO mice were not protected from FSGS. These opposite results were due to B1RBK expression. B1RBK was up regulated after ADM injection and it was exacerbated in B2RBK KO animals. Further, HOE-140 treatment down regulated B1RBK receptor. The blockade of B1RBK in B2RBK KO animals promoted FSGS regression, with a less inflammatory phenotype. These results indicate a deleterious role of both kinin receptors in FSGS model and suggest a possible crosstalk of them in disease progression.
    Disease Models and Mechanisms 04/2014; · 4.96 Impact Factor
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    ABSTRACT: Regulation of muscle mass depends on the balance between synthesis and degradation of proteins, which is under control of different signaling pathways regulated by hormonal, neural and nutritional stimuli. Such stimuli are altered in several pathologies such as chronic obstructive pulmonary disease, diabetes, AIDS and cancer (cachexia), as well as in some conditions such as immobilization and aging (sarcopenia), leading to muscle atrophy, which represents a significant contribution to patient morbidity. The kallikrein-kinin system (KKS) is composed of the enzymes kallikreins, which generate active peptides called kinins that activate two G protein-coupled receptors, namely B1 and B2, expressed in a variety of tissues. The local modulation of the KKS may account for its described participation in different diseases, such as those of cardiovascular, renal and central nervous systems, cancer, and many inflammatory processes, including pain. Due to such pleiotropic actions of the KKS by local modulatory events and the probable fine-tuning of associated signaling cascades involved in skeletal muscle catabolic disorders (e.g. NFкB and PI3K/Akt pathways), we hypothesized that KKS could contribute to modulation of intracellular responses in atrophying skeletal muscle. Our data showed that the kinin B1 receptor activation induced a decrease in C2C12 myotubes diameters, activation of NFκB, decrease of Akt phosphorylation levels, and increase in the ubiquitin E3 ligases atrogin-1 and MuRF-1 mRNAs levels. In vivo, we observed an increase of the B1 receptor mRNA levels in an androgen-sensitive model of muscle atrophy. In the same model, blockage of the B1 receptor with a selective antagonist resulted in impairment of atrogin-1 and MuRF-1 expression and IκB phosphorylation. Moreover, knockout of B1 receptor in mice led to an impairment of MuRF-1 mRNA expression after induction of levator ani muscle atrophy. As a conclusion, using pharmacological and gene ablation tools, we have obtained evidence that the B1 receptor plays a significant role in regulation of skeletal muscle proteolysis in the model of levator ani muscle atrophy.
    Clinical Science 02/2014; · 4.86 Impact Factor
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    ABSTRACT: The current dominance of African runners in long-distance running is an intriguing phenomenon that highlights the close relationship between genetics and physical performance. Many factors in the interesting interaction between genotype and phenotype (eg, high cardiorespiratory fitness, higher hemoglobin concentration, good metabolic efficiency, muscle fiber composition, enzyme profile, diet, altitude training, and psychological aspects) have been proposed in the attempt to explain the extraordinary success of these runners. Increasing evidence shows that genetics may be a determining factor in physical and athletic performance. But, could this also be true for African long-distance runners? Based on this question, this brief review proposed the role of genetic factors (mitochondrial deoxyribonucleic acid, the Y chromosome, and the angiotensin-converting enzyme and the alpha-actinin-3 genes) in the amazing athletic performance observed in African runners, especially the Kenyans and Ethiopians, despite their environmental constraints.
    Open Access Journal of Sports Medicine 01/2014; 5:123-127.
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    ABSTRACT: Cisplatin is a chemotherapeutic agent that causes severe renal dysfunction. The kinin B1 receptor has been associated with the migration of immune cells to injured tissue as well as with renal inflammation. To examine the role of the kinin B1 receptor in cisplatin-induced acute kidney injury, we used kinin B1 receptor knockout mice and treatment with a receptor antagonist before and after cisplatin administration. Cisplatin injection caused exacerbation of renal macrophage and neutrophil migration, higher levels of serum creatinine and blood urea, upregulation of B1 receptor mRNA and an increase in pro-inflammatory cytokines expression. B1 receptor knockout mice exhibited a reduction in serum creatinine and blood urea levels, diminished apoptosis, and decreased cisplatin-induced upregulation of inflammatory components. Moreover, treatment with the B1 receptor antagonist prior to cisplatin administration normalized serum creatinine, blood urea levels, protected from acute tubular necrosis, apoptosis-related genes, and prevented upregulation of pro-inflammatory cytokines. Thus, we propose that kinins have an important role in cisplatin-induced acute kidney injury by impairing immune cells migration to renal tissue during cisplatin nephrotoxicity. Kinin B1 receptor is upregulated after cisplatin exposure. Kinin B1 receptor deficiency diminishes the nephrotoxicity caused by cisplatin. Kinin B1 receptor deficiency ameliorates the inflammatory response. Kinin B1 receptor deficiency diminishes apoptosis caused by cisplatin. Kinin B1 receptor antagonism ameliorates renal function after cisplatin injection.
    Journal of Molecular Medicine 12/2013; · 4.77 Impact Factor
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    ABSTRACT: Renal cell carcinoma (RCC) is characterized by high vascular endothelial growth factor (VEGF) production and, consequently, excessive angiogenesis. Several strategies have been developed to target angiogenesis as a method for treating metastatic RCC (mRCC). Endostatin (ES) is a C-terminal fragment of collagen XVIII that has antiangiogenic activity. The aim of this study was to investigate the predictive value of circulating VEGF-A in a murine model of mRCC after ES gene therapy. ES therapy did not affect the levels of collagen XVIII/ES or ES in the tissue. The circulating level of ES was increased in the control and ES-treated groups (normal vs. control, P<0.05 and ES-treated vs. control, P<0.001), and the intratumoral vessels were significantly decreased (ES-treated vs. control, P<0.05). ES therapy decreased the VEGF mRNA levels. The tissue and circulating levels of VEGF in the control group were significantly higher than normal (P<0.01 and P<0.05, respectively). Treatment with ES significantly reduced the VEGF concentrations in both compartments (P<0.001 for tissue and P<0.05 for plasma). Our findings indicate that in addition to the directly targeted tumor vessels, ES exerts its antitumor effect by down-regulating VEGF gene expression in renal tumor cells. Additionally, our findings point to the predictive value of VEGF for ES therapy.
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 05/2013; · 2.24 Impact Factor
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    ABSTRACT: Abstract A role for the kinin B1 receptor in energy-homeostatic processes was implicated by previous works. Notably the studies where kinin B1 receptor knockout mice (B1-/-) are observed to have impaired adiposity, impaired leptin and insulin production, lower feed efficiency, protection from liver steatosis and diet induced obesity when fed a high fat diet (HFD). More particularly, in a model where the B1 receptor is expressed exclusively in the adipose tissue, it rescues the plasma insulin concentration and the weight gain seen in wild type mice. Taking into consideration that leptin participates in the formation of hypothalamic nuclei, which modulate energy expenditure, and feeding behavior, we hypothesized that these brain regions could also be altered in B1-/- mice. We observed for the first time a difference in the gene expression pattern of CART (cocaine-and-amphetamine related transcript) in the LHA (lateral hypothalamic area) resulting from the deletion of the kinin B1 receptor gene. The correlation between CART expression in the LHA and the thwarting of diet-induced obesity corroborates independent correlations between CART and obesity. Further it seems to indicate that the mechanism underlying the 'lean' phenotype of B1-/- mice is not solely stemming from changes in peripheral tissues but may also receive contributions from changes in the hypothalamic machinery involved in energy homeostasis processes.
    Biological Chemistry 03/2013; · 2.68 Impact Factor
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    ABSTRACT: Fabry disease (FD) is an X-linked inborn error of glycosphingolipid catabolism that results from mutations in the alpha-galactosidase A (GLA) gene. Evaluating the enzymatic activity in male individuals usually performs the diagnosis of the disease, but in female carriers the diagnosis should be based on DNA sequencing (DS), since enzyme assays is often inconclusive due to inactivation of chromosome X. This work presents genotyping of GLA gene in 568 individuals from 102 families with suspect of FD. In addition, we developed a simple and noninvasive diagnosis by sequencing the messenger RNA (mRNA). In parallel, we correlated the expression of GLA gene by real time PCR. Furthermore, this protocol using RNA extracted from leukocytes avoids the use of biopsies, decreases the amount of fragments to be sequenced, and should open up new perspectives for a more accurate diagnosis and early treatment of Fabry disease.
    Molecular Genetics and Metabolism 02/2013; 108(2):S93. · 2.83 Impact Factor
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    ABSTRACT: Multiple sclerosis (MS) is a progressive, demyelinating inflammatory disease of the human central nervous system (CNS). While the primary symptoms of MS affect motor function, it is now recognized that chronic pain is a relevant symptom that affects both animals and MS patients. There is evidence that glial cells, such as astrocytes, play an important role in the development and maintenance of chronic pain. Kinins, notably bradykinin (BK) acting through B1 (B1R) and B2 (B2R) receptors, play a central role in pain and inflammatory processes. However, it remains unclear whether kinin receptors are involved in neuropathic pain in MS. Here we investigated by genetic and pharmacological approaches the role of kinin receptors in neuropathic pain behaviors induced in the experimental autoimmune encephalomyelitis (EAE) mouse model. Our results showed that gene deletion or antagonism of kinin receptors, especially B1R, significantly inhibited both tactile and thermal hypersensitivity in EAE animals. By contrast, animals with EAE and treated with a B1R selective agonist displayed a significant increase in tactile hypersensitivity. We also observed a marked increase in B1R mRNA and protein level in the mouse spinal cord 14 days after EAE immunization. Blockade of B1R significantly suppressed the levels of mRNAs for IL-17, IFN-γ, IL-6, CXCL-1/KC, COX-2 and NOS2, as well as glial activation in the spinal cord. Of note, the selective B1 antagonist DALBK consistently prevented IFN-induced up-regulation of TNF-α and IL-6 release in astrocytes culture. Finally, both B1R and B2R antagonists significantly inhibited COX-2 and NOS2 expression in primary astrocytes culture. The B1R was co-localized with immunomarker of astrocytes in the spinal cord of EAE-treated animals. The above data constitute convincing experimental evidence indicating that both kinin receptors, especially the B1 subtype, exert a critical role in the establishment of persistent hypersensitivity observed in the EAE model, an action that seems to involve a central inflammatory process, possibly acting on astrocytes. Thus, B1 selective antagonists or drugs that reduce kinin release may have the potential to treat neuropathic pain in patients suffering from MS.
    Neurobiology of Disease 02/2013; · 5.62 Impact Factor
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    ABSTRACT: AIM: The pathophysiology of periodontal diseases involves aspects of immunity and bone remodelling. Considering the role of the kinin B1 receptor (Bdkrb1) in inflammation and healing, the purpose of this study was to evaluate the contribution of Bdkrb1 to the pathogenesis of periodontitis. MATERIAL AND METHODS: We used a model of ligature-induced experimental periodontitis (LIEP) in mice lacking Bdkrb1 (Bdkrb1(-/-) ) to test the role of this receptor in bone loss and cytokine secretion by lymph nodes cells. Angiotensin-converting enzyme inhibitor (ACEi) was used as a pharmacological strategy to support the genetic model. Also, autonomous effect of Bdkrb1 deletion was evaluated in osteoclasts precursors from bone marrow. RESULTS: Bdkrb1(-/-) mice exhibit increased bone loss and IL-17 secretion in response to LIEP when compared to wild type. LIEP does not modify TNF-α, IFN-γ and IL-10 levels in Bdkrb1(-/-) mice after 21 days. Bone marrow cells from Bdkrb1(-/-) displayed increased differentiation into functional osteoclasts with consistent artificial calcium phosphate degradation. Furthermore, treatment of mice with ACEi prevented bone destruction. CONCLUSION: Bdkrb1 participates in the pathogenesis of LIEP bone loss possibly through mechanisms that involve modulation of the TH 17 response, thereby demonstrating its role in the development of periodontitis.
    Journal Of Clinical Periodontology 02/2013; · 3.69 Impact Factor
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    ABSTRACT: Endothelial cells from microvasculature are directly involved in a large number of vascular diseases; however, culture of these cells is problematic since most methodologies employ proteolytic enzymes or mechanical techniques, leading to cell damage and contamination of endothelial cultures with other cellular types. Besides, primary cultured cells have a short life span in vitro and undergo replicative senescence after 3-4 passages, limiting long-term studies. In the present work we report the generation of a spontaneously immortalized endothelial culture obtained from mice pulmonary capillaries. Firstly, primary (3(th) passage) and immortalized cultures (100(th)) were established. Further, monoclonal populations were obtained by serial dilutions from immortalized cultures. Cells were analyzed according to: 1) morphological appearance, 2) expression of specific endothelial markers by fluorescent staining [von Willebrand Factor (vWF), endothelial nitric oxide synthase (eNOS), angiotensin converting enzyme (ACE) and Ulex europaeus (UEA-1)] and by flow citometry (endoglin, VE-cadherin and VCAM-1), and 3) release of nitric oxide (NO), assessed by the specific fluorescent dye DAF-2DA, and prostacyclin (PGI(2)), quantified by enzyme immune assay. In both cultures cells grew in monolayers and presented cobblestone appearance at confluence. The positive staining to vWF, eNOS, ACE and UEA-1 was detected in cloned as well as in early-passage cultured cells. Similarly, cultures presented equal expression of endoglin, VE-cadherin and VCAM-1. Values of NO and PGI(2) levels did not differ between cultures. From these results we confirm that the described spontaneously immortalized endothelial cell line is able to unlimited growth and retains typical morphological and functional properties exhibited by primary cultured cells. Therefore, the endothelial cell line described in the present study can become a suitable tool in the field of endothelium research and can be useful to investigate production of endothelial mediators, angiogenesis and inflammation.
    Experimental Cell Research 02/2013; · 3.56 Impact Factor
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    ABSTRACT: Kinins B(1) and B(2) receptors (B(1)R and B(2)R) are classically associated with inflammation, but our group has recently demonstrated new roles for B(1)R in metabolism using a knockout model (B(1) (-/-)). B(1) (-/-) mice display improvement on leptin and insulin sensitivity and is protected from high fat diet (HFD)-induced obesity. Here, we evaluate the hepatic effects of the B(1)R ablation and its role on hepatic function. Despite no expression of hepatic B(1)R, HFD-induced hepatic lipid accumulation was lower than in control animals. B(1) (-/-) mice also presented lower hepatic lipogenesis and SCD1 protein content in the liver. When stimulated with exogenous leptin, B(1) (-/-) mice exhibited increased hepatic pJAK2. Similarly, leptin signaling was enhanced in the liver of ob/ob-B(1) (-/-) mice, as demonstrated by increased levels of pSTAT3 compared to ob/ob. Plasma concentrations of intercellular adhesion molecule 1, fetuin A, leukemia inhibitory factor, tissue inhibitor of metalloprotease-1, resistin, and oncostatin M were reduced in B(1) (-/-). Finally, B(1) (-/-) mice have increased gene expression of hepatic B(2) receptor, but no difference in leptin receptor expression. Our results show that B(1) (-/-) mice are protected from non-alcoholic fatty liver disease (NAFLD) after HFD treatment. Since B(1)R expression was not observed in the liver after HFD, we propose that the cross talk between the adipose tissue and the liver, mainly through leptin, is an important factor contributing to the observed results. Besides that, several other inflammatory mediators already correlated with NAFLD or liver function were found to be altered in our model. Taken together, our data suggest that B(1)R plays an important role in hepatic steatosis development.
    Journal of Molecular Medicine 02/2013; · 4.77 Impact Factor
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    ABSTRACT: Atualmente, um fenômeno interessante capaz de demonstrar a estreita relação entre a genética, o ambiente e o desempenho físico, é a dominância dos corredores africanos (quenianos e etíopes) nas corridas de longa distância. Nesse sentido, alguns fatores (o estilo de vida na infância, a motivação psicológica para o sucesso econômico e social, o tipo de dieta, o tipo de treinamento físico, o biótipo, o perfil fisiológico e bioquímico e o background genético) da intrigante e complexa interação entre o genótipo e fenótipo têm sido propostos na tentativa de Vancini et al.: Desempenho esportivo e genética www.brjb.com.br Brazilian Journal of Biomotricity explicar o extraordinário sucesso esportivo dos corredores africanos. Dessa forma, objetivo do presente artigo de atualização é abordar alguns dos fatores responsáveis por esse fenômeno do desempenho atlético no restrito universo dos corredores quenianos e etíopes.
    02/2013;
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    ABSTRACT: Bradykinin (BK) and des-Arg(9)-bradykinin (DBK) of kallikrein-kinin system exert its effects mediated by the B(2) (B(2)R) and B(1) (B(1)R) receptors, respectively. It was already shown that the deletion of kinin B(1)R or of B(2)R induces upregulation of the remaining receptor subtype [10,12,16,28,36]. However studies on overexpression of B(1)R or B(2)R in transgenic animals have supported the importance of the overexpressed receptor but the expression of the another receptor subtype has not been determined [17,19,33]. Previous study described a marked vasodilatation and increased susceptibility to endotoxic shock which was associated with increased mortality in response to DBK in thoracic aorta from transgenic rat overexpressing the kinin B(1)R (TGR(Tie(2)B(1))) exclusively in the endothelium. In another study, mice overexpressing B(1)R in multiple tissues were shown to present high susceptibility to inflammation and to lipopolysaccharide-induced endotoxic shock. Therefore the role of B(2)R was investigated in the thoracic aorta isolated from TGR(Tie(2)B(1)) rats overexpressing the B(1)R exclusively in the vascular endothelium. Our findings provided evidence for highly increased expression level of the B(2)R in the transgenic rats. It was reported that under endotoxic shock, these rats exhibited exaggerated hypotension, bradycardia and mortality. It can be suggested that the high mortality during the pathogenesis of endotoxic shock provoked in the transgenic TGR(Tie(2)B(1)) rats could be due to the enhanced expression of B(2)R associated with the overexpression of the B(1)R.
    Peptides 01/2013; · 2.52 Impact Factor
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    ABSTRACT: Melanoma is a very aggressive tumor that does not respond well to standard therapeutic approaches, such as radio- and chemotherapies. Furthermore, acquiring the ability to metastasize in melanoma and many other tumor types is directly related to incurable disease. The B1 kinin receptor participates in a variety of cancer-related pathophysiological events, such as inflammation and angiogenesis. Therefore, we investigated whether this G protein-coupled receptor plays a role in tumor progression. We used a murine melanoma cell line that expresses the kinin B1 receptor and does not express the kinin B2 receptor to investigate the precise contribution of activation of the B1 receptor in tumor progression and correlated events using various in vitro and in vivo approaches. Activation of the kinin B1 receptor in the absence of B2 receptor inhibits cell migration in vitro and decreases tumor formation in vivo. Moreover, tumors formed from cells stimulated with B1-specific agonist showed several features of decreased aggressiveness, such as smaller size and infiltration of inflammatory cells within the tumor area, higher levels of pro-inflammatory cytokines implicated in the host anti-tumor immune response, lower number of cells undergoing mitosis, a poorer vascular network, no signs of invasion of surrounding tissues or metastasis and increased animal survival. Our findings reveal that activation of the kinin B1 receptor has a host protective role during murine melanoma tumor progression, suggesting that the B1 receptor could be a new anti-tumor GPCR and provide new opportunities for therapeutic targeting.
    PLoS ONE 01/2013; 8(5):e64453. · 3.73 Impact Factor
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    ABSTRACT: Angiotensins (Angs) modulate blood pressure, hydro-electrolyte composition, and antinociception. Although Ang (5–8) has generally been considered to be inactive, we show here that Ang (5–8) was the smallest Ang to elicit dose-dependent responses and receptor-mediated antinociception in the rat ventrolateral periaqueductal gray matter (vlPAG). Ang (5–8) antinociception seems to be selective, because it did not alter blood pressure or act on vascular or intestinal smooth muscle cells. The non-selective Ang-receptor (Ang-R) antagonist saralasin blocked Ang (5–8) antinociception, but selective antagonists of Ang-R types I, II, IV, and Mas did not, suggesting that Ang (5–8) may act via an unknown receptor. Endopeptidase EP 24.11 and amastatin-sensitive aminopeptidase from the vlPAG catalyzed the synthesis (from Ang II or Ang III) and inactivation of Ang (5–8), respectively. Selective inhibitors of neuronal-nitric oxide (NO) synthase, soluble guanylyl cyclase (sGC) and a non-selective opioid receptor (opioid-R) inhibitor blocked Ang (5–8)-induced antinociception. In conclusion, Ang (5–8) is a new member of the Ang family that selectively and strongly modulates antinociception via NO–sGC and endogenous opioid in the vlPAG.
    Neuroscience 12/2012; 231:315–327. · 3.12 Impact Factor
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    ABSTRACT: Somatic angiotensin I-converting enzyme (ACE)has two homologous active sites (N and C domains) that show differences in various biochemical properties.In a previous study, we described the use of positionals canning synthetic combinatorial (PS-SC) libraries of fluorescence resonance energy transfer (FRET) peptides to define the ACE C-domain versus N-domain substrate specificity and developed selective substrates for the C-domain(Bersanetti et al., 2004). In the present work, we used the results from the PS-SC libraries to define the N-domain preferences and designed selective substrates for this domain. The peptide Abz-GDDVAK(Dnp)-OH presented the most favorable residues for N-domain selectivity in the P 3 to P 1 ′ positions. The fluorogenic analog Abz-DVAK(Dnp)-OH (Abz = ortho -aminobenzoic acid; Dnp = 2,4-dinitrophenyl)showed the highest selectivity for ACE N-domain( k cat /K m = 1.76 μ m -1 · s -1) . Systematic reduction of the peptide length resulted in a tripeptide that was preferentially hydrolyzed by the C-domain. The binding of Abz-DVAK(Dnp)-OH to the active site of ACE N-domain was examined using a combination of conformational analysis and molecular docking. Our results indicated that the binding energies for the N-domain-substrate complexes were lower than those for the C-domain-substrate, suggesting that the former complexes are more stable.
    Biological Chemistry 12/2012; 393(12):1547-54. · 2.68 Impact Factor
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    ABSTRACT: Bradykinin is not only important for inflammation and blood pressure regulation, but also involved in neuromodulation and neuroprotection. Here we describe novel functions for bradykinin and the kinin-B2 receptor (B2BkR) in differentiation of neural stem cells. In the presence of the B2BkR antagonist HOE-140 during rat neurosphere differentiation, neuron-specific β3-tubulin and enolase expression was reduced together with an increase in glial protein expression, indicating that bradykinin-induced receptor activity contributes to neurogenesis. In agreement, HOE-140 affected in the same way expression levels of neural markers during neural differentiation of murine P19 and human iPS cells. Kinin-B1 receptor agonists and antagonists did not affect expression levels of neural markers, suggesting that bradykinin-mediated effects are exclusively mediated via B2BkR. Neurogenesis was augmented by bradykinin and captopril in middle and late stages of the differentiation process. Chronic treatment with HOE-140 diminished eNOS and nNOS as well as M1-M4 muscarinic receptor expression and also affected purinergic receptor expression and activity. Neurogenesis, gliogenesis and neural migration were altered during differentiation of neurospheres isolated from B2BkR knockout mice. Whole-mount in situ hybridization revealed the presence of B2BkR mRNA throughout the nervous system in mouse embryos, and less β3-tubulin and more glial proteins were expressed in developing and adult B2BkR knockout mice brains. As underlying transcriptional mechanism for neural fate determination, HOE-140 induced up-regulation of Notch and Stat3 gene expression. Since pharmacological treatments did not affect cell viability and proliferation, we conclude that bradykinin-induced signaling provides a switch for neural fate determination and specification of neurotransmitter receptor expression.
    Journal of Biological Chemistry 11/2012; · 4.65 Impact Factor
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    ABSTRACT: Background Kinins participate in the pathophysiology of obesity and type 2 diabetes by mechanisms which are not fully understood. Kinin B1 receptor knockout mice (B1−/−) are leaner and exhibit improved insulin sensitivity. Methodology/Principal Findings Here we show that kinin B1 receptors in adipocytes play a role in controlling whole body insulin action and glucose homeostasis. Adipocytes isolated from mouse white adipose tissue (WAT) constitutively express kinin B1 receptors. In these cells, treatment with the B1 receptor agonist des-Arg9-bradykinin improved insulin signaling, GLUT4 translocation, and glucose uptake. Adipocytes from B1−/− mice showed reduced GLUT4 expression and impaired glucose uptake at both basal and insulin-stimulated states. To investigate the consequences of these phenomena to whole body metabolism, we generated mice where the expression of the kinin B1 receptor was limited to cells of the adipose tissue (aP2-B1/B1−/−). Similarly to B1−/− mice, aP2-B1/B1−/− mice were leaner than wild type controls. However, exclusive expression of the kinin B1 receptor in adipose tissue completely rescued the improved systemic insulin sensitivity phenotype of B1−/− mice. Adipose tissue gene expression analysis also revealed that genes involved in insulin signaling were significantly affected by the presence of the kinin B1 receptor in adipose tissue. In agreement, GLUT4 expression and glucose uptake were increased in fat tissue of aP2-B1/B1−/− when compared to B1−/− mice. When subjected to high fat diet, aP2-B1/B1−/− mice gained more weight than B1−/− littermates, becoming as obese as the wild types. Conclusions/Significance Thus, kinin B1 receptor participates in the modulation of insulin action in adipocytes, contributing to systemic insulin sensitivity and predisposition to obesity.
    PLoS ONE 09/2012; 7(9). · 3.73 Impact Factor

Publication Stats

3k Citations
736.30 Total Impact Points

Institutions

  • 1998–2014
    • Universidade Federal de São Paulo
      • Departamento de Biofísica
      San Paulo, São Paulo, Brazil
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2005–2013
    • University of São Paulo
      • • Ribeirão Preto School of Medicine (FMRP)
      • • Departament of Geophysics
      • • Department of Biochemistry (IQ)
      São Paulo, Estado de Sao Paulo, Brazil
  • 2001–2013
    • Federal University of Santa Catarina
      • Centro de Ciências Biológicas (CCB)
      Florianópolis, Estado de Santa Catarina, Brazil
  • 2011
    • Universidade Federal do ABC (UFABC)
      • Center of Natural and Human Sciences (CCNH)
      Santo André, Estado de Sao Paulo, Brazil
  • 2006–2011
    • Universidade de Mogi das Cruzes
      Moji das Cruzes, São Paulo, Brazil
  • 2009–2010
    • UFGD - Universidade Federal da Grande Dourados
      Dourados, Estado de Mato Grosso do Sul, Brazil
  • 1999–2010
    • Max-Delbrück-Centrum für Molekulare Medizin
      • Experimental and Clinical Research Center (ECRC)
      Berlín, Berlin, Germany
    • Institut Louis Bachelier
      Lutetia Parisorum, Île-de-France, France
  • 2006–2009
    • Federal University of Rio de Janeiro
      • • Instituto de Ciências Biomédicas (ICB)
      • • Instituto de Biofísica Carlos Chagas Filho (IBCCF)
      Rio de Janeiro, Rio de Janeiro, Brazil
  • 2008
    • Centro Universitário Fundação Santo André
      Santo André, São Paulo, Brazil
    • Unité Inserm U1077
      Caen, Lower Normandy, France
    • Universidade Nove de Julho
      San Paulo, São Paulo, Brazil
  • 2003
    • Universidade Aberta do Brasil
      San Paulo, São Paulo, Brazil
  • 1991–1992
    • Federal University of Minas Gerais
      Cidade de Minas, Minas Gerais, Brazil