RESUMO
Changes in renal hemodynamics impact renal function during physiological and pathological conditions. In this context, renal vascular resistance (RVR) is regulated by components of the Renin-Angiotensin System (RAS) and the Kallikrein-Kinin System (KKS). However, the interaction between these vasoactive peptides on RVR is still poorly understood. Here, we studied the crosstalk between angiotensin-(1-7) and kinins on RVR. The right kidneys of Wistar rats were isolated and perfused in a closed-circuit system. The perfusion pressure and renal perfusate flow were continuously monitored. Ang-(1-7) (1.0-25.0â¯nM) caused a sustained, dose-dependent reduction of relative RVR (rRVR). This phenomenon was sensitive to 10â¯nM A-779, a specific Mas receptor (MasR) antagonist. Bradykinin (BK) promoted a sustained and transient reduction in rRVR at 1.25â¯nM and 125â¯nM, respectively. The transient effect was abolished by 4⯵M des-Arg9-Leu8-bradykinin (DALBK), a specific kinin B1 receptor (B1R) antagonist. Accordingly, des-Arg9-bradykinin (DABK) 1⯵M (a B1R agonist) increased rRVR. Interestingly, pre-perfusion of Ang-(1-7) changed the sustained reduction of rRVR triggered by 1.25â¯nM BK into a transient effect. On the other hand, pre-perfusion of Ang-(1-7) primed and potentiated the DABK response, this mechanism being sensitive to A-779 and DALBK. Binding studies performed with CHO cells stably transfected with MasR, B1R, and kinin B2 receptor (B2R) showed no direct interaction between Ang-(1-7) with B1R or B2R. In conclusion, our findings suggest that Ang-(1-7) differentially modulates kinin's effect on RVR in isolated rat kidneys. These results help to expand the current knowledge regarding the crosstalk between the RAS and KKS complex network in RVR.
Assuntos
Angiotensina I , Bradicinina , Fragmentos de Peptídeos , Receptor B1 da Bradicinina , Resistência Vascular , Animais , Cricetinae , Masculino , Ratos , Angiotensina I/farmacologia , Angiotensina I/metabolismo , Angiotensina II/análogos & derivados , Bradicinina/farmacologia , Bradicinina/análogos & derivados , Células CHO , Cricetulus , Sistema Calicreína-Cinina/fisiologia , Sistema Calicreína-Cinina/efeitos dos fármacos , Rim/metabolismo , Rim/efeitos dos fármacos , Cininas/metabolismo , Fragmentos de Peptídeos/farmacologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/metabolismo , Ratos Wistar , Receptor B1 da Bradicinina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Circulação Renal/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Resistência Vascular/efeitos dos fármacosRESUMO
Initiation of the bradykinin generation cascade is responsible for the occurrence of attacks in some types of angioedema without wheals. Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is one such clinical entity. In this paper, we explore the existing evidence that mast cells (MCs) degranulation may contribute to the activation of the kallikrein-kinin system cascade, followed by bradykinin formation and angioedema. We present the multidirectional effects of MC-derived heparin and other polyanions on the major components of the kinin-kallikrein system, particularly on the factor XII activation. Although, bradykinin- and histamine-mediated symptoms are distinct clinical phenomena, they share some common features, such as some similar triggers and a predilection to occur at sites where mast cells reside, namely the skin and mucous membranes. In addition, recent observations indicate a high incidence of hypersensitivity reactions associated with MC degranulation in the HAE-C1-INH patient population. However, not all of these can be explained by IgE-dependent mechanisms. Mast cell-related G protein-coupled receptor-X2 (MRGPRX2), which has recently attracted scientific interest, may be involved in the activation of MCs through a different pathway. Therefore, we reviewed MRGPRX2 ligands that HAE-C1-INH patients may be exposed to in their daily lives and that may affect MCs degranulation. We also discussed the known inter- and intra-individual variability in the course of HAE-C1-INH in relation to factors responsible for possible variability in the strength of the response to MRGPRX2 receptor stimulation. The above issues raise several questions for future research. It is not known to what extent a prophylactic or therapeutic intervention targeting the pathways of one mechanism (mast cell degranulation) may affect the other (bradykinin production), or whether the number of mast cells at a specific body site and their reactivity to triggers such as pressure, allergens or MRGPRX2 agonists may influence the occurrence of HAE-C1-INH attacks at that site.
Assuntos
Bradicinina , Degranulação Celular , Mastócitos , Receptores Acoplados a Proteínas G , Receptores de Neuropeptídeos , Humanos , Mastócitos/imunologia , Mastócitos/metabolismo , Bradicinina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Animais , Angioedema/metabolismo , Angioedema/imunologia , Angioedema/etiologia , Proteínas do Tecido Nervoso/metabolismo , Sistema Calicreína-Cinina/fisiologiaRESUMO
BACKGROUND: The kallikrein-kinin system is a key regulatory cascade involved in blood pressure maintenance, hemostasis, inflammation and renal function. Currently, approved drugs remain limited to the rare disease hereditary angioedema. However, growing interest in this system is indicated by an increasing number of promising drug candidates for further indications. METHODS: To provide an overview of current drug development, a two-stage literature search was conducted between March and December 2023 to identify drug candidates with targets in the kallikrein-kinin system. First, drug candidates were identified using PubMed and Clinicaltrials.gov. Second, the latest publications/results for these compounds were searched in PubMed, Clinicaltrials.gov and Google Scholar. The findings were categorized by target, stage of development, and intended indication. RESULTS: The search identified 68 drugs, of which 10 are approved, 25 are in clinical development, and 33 in preclinical development. The three most studied indications included diabetic retinopathy, thromboprophylaxis and hereditary angioedema. The latter is still an indication for most of the drug candidates close to regulatory approval (3 out of 4). For the emerging indications, promising new drug candidates in clinical development are ixodes ricinus-contact phase inhibitor for thromboprophylaxis and RZ402 and THR-149 for the treatment of diabetic macular edema (all phase 2). CONCLUSION: The therapeutic impact of targeting the kallikrein-kinin system is no longer limited to the treatment of hereditary angioedema. Ongoing research on other diseases demonstrates the potential of therapeutic interventions targeting the kallikrein-kinin system and will provide further treatment options for patients in the future.
Assuntos
Descoberta de Drogas , Sistema Calicreína-Cinina , Humanos , Sistema Calicreína-Cinina/fisiologia , Desenvolvimento de Medicamentos , AnimaisRESUMO
Heart failure (HF) is a pervasive clinical challenge characterized by compromised cardiac function and reduced quality of life. The kinin-kallikrein system (KSS), a multifaceted peptide cascade, has garnered substantial attention due to its potential role in HF. Through activation of B1 and/or B2 receptors and downstream signaling, kinins modulate various physiological processes, including inflammation, coagulation, pain, blood pressure control, and vascular permeability. Notably, aberrations in KKS components have been linked to HF risk. The elevation of vasodilatory bradykinin (BK) due to kallikrein activity reduces preload and afterload, while concurrently fostering sodium reabsorption inhibition. However, kallikrein's conversion of prorenin to renin leads to angiotensinsII upregulation, resulting in vasoconstriction and fluid retention, alongside increased immune cell activity that fuels inflammation and cardiac remodeling. Importantly, prolonged KKS activation resulting from volume overload and tissue stretch contributes to cardiac collagen loss. The conventional renin-angiotensin-aldosterone system (RAAS) inhibitors used in HF management may inadvertently intensify KKS activity, exacerbating collagen depletion and cardiac remodeling. It is crucial to balance the KKS's role in acute cardiac damage, which may temporarily enhance function and metabolic parameters against its detrimental long-term effects. Thus, KKS blockade emerges as a promising strategy to impede HF progression. By attenuating the link between immune system function and tissue damage, KKS inhibition can potentially reduce cardiac remodeling and alleviate HF symptoms. However, the nuanced roles of BK in various acute conditions necessitate further investigation into the sustained benefits of kallikrein inhibitors in patients with chronic HF.
Assuntos
Insuficiência Cardíaca , Sistema Calicreína-Cinina , Calicreínas , Cininas , Sistema Renina-Angiotensina , Humanos , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Sistema Calicreína-Cinina/fisiologia , Cininas/metabolismo , Calicreínas/metabolismo , Sistema Renina-Angiotensina/fisiologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais , Bradicinina/metabolismoRESUMO
Atmospheric particulate matter (PM) perturbs hematological homeostasis by targeting the plasma kallikrein-kinin system (KKS), causing a cascade of zymogen activation events. However, the causative components involved in PM-induced hematological effects are largely unknown. Herein, the standard reference materials (SRMs) of atmospheric PM, including emissions from the diesel (2975), urban (1648a), and bituminous coal (2693), were screened for their effects on plasma KKS activation, and the effective constituent contributing to PM-induced KKS activation was further explored by fraction isolation and chemical analysis. The effects of three SRMs on KKS activation followed the order of 2975 > 1648a > 2693, wherein the fractions of 2975 isolated by acetone and water, together with the insoluble particulate residues, exerted significant perturbations in the hematological homeostasis. The soot contents in the SRMs and corresponding isolated fractions matched well with their hematological effects, and the KKS activation could be dependent on the soot surface oxidation degree. This study, for the first time, uncovered the soot content in atmospheric PM with different origins contributed to the distinct effects on plasma KKS activation. The finding would be of utmost importance for the health risk assessment on inhaled airborne fine PM, given its inevitable contact with human circulatory system.
Assuntos
Poluentes Atmosféricos , Sistema Calicreína-Cinina , Material Particulado , Humanos , Sistema Calicreína-Cinina/fisiologia , Fuligem , Poluentes Atmosféricos/análiseRESUMO
Vasoactive peptides often serve a multitude of functions aside from their direct effects on vasodynamics. This article will review the existing literature on two vasoactive peptides and their involvement in skin homeostasis: adiponectin and-as the main representative of the kallikrein-kinin system-bradykinin. Adiponectin is the most abundantly expressed adipokine in the human organism, where it is mainly localized in fat depots including subcutaneous adipose tissue, from where adiponectin can exert paracrine effects. The involvement of adiponectin in skin homeostasis is supported by a number of studies reporting the effects of adiponectin in isolated human keratinocytes, sebocytes, fibroblasts, melanocytes, and immune cells. Regarding skin pathology, the potential involvement of adiponectin in psoriasis, atopic dermatitis, scleroderma, keloid, and melanogenesis is discussed in this article. The kallikrein-kinin system is composed of a variety of enzymes and peptides, most of which have been identified to be expressed in the skin. This also includes the expression of bradykinin receptors on most skin cells. Bradykinin is one of the very few hormones that is targeted by treatment in routine clinical use in dermatology-in this case for the treatment of hereditary angioedema. The potential involvement of bradykinin in wound healing, psoriasis, and melanoma is further discussed in this article. This review concludes with a call for additional preclinical and clinical studies to further explore the therapeutic potential of adiponectin supplementation (for psoriasis, atopic dermatitis, wound healing, scleroderma, and keloid) or pharmacological interference with the kallikrein-kinin system (for wound healing, psoriasis, and melanoma).
Assuntos
Adiponectina , Bradicinina , Homeostase , Sistema Calicreína-Cinina , Dermatopatias , Fenômenos Fisiológicos da Pele , Adiponectina/fisiologia , Sistema Calicreína-Cinina/fisiologia , Bradicinina/fisiologia , Humanos , Dermatopatias/metabolismoRESUMO
Heart transplantation remains the definitive treatment for end stage heart failure. Because availability is limited, risk stratification of candidates is crucial for optimizing both organ allocations and transplant outcomes. Here we utilize proteomics prior to transplant to identify new biomarkers that predict post-transplant survival in a multi-institutional cohort. Microvesicles were isolated from serum samples and underwent proteomic analysis using mass spectrometry. Monte Carlo cross-validation (MCCV) was used to predict survival after transplant incorporating select recipient pre-transplant clinical characteristics and serum microvesicle proteomic data. We identified six protein markers with prediction performance above AUROC of 0.6, including Prothrombin (F2), anti-plasmin (SERPINF2), Factor IX, carboxypeptidase 2 (CPB2), HGF activator (HGFAC) and low molecular weight kininogen (LK). No clinical characteristics demonstrated an AUROC > 0.6. Putative biological functions and pathways were assessed using gene set enrichment analysis (GSEA). Differential expression analysis identified enriched pathways prior to transplant that were associated with post-transplant survival including activation of platelets and the coagulation pathway prior to transplant. Specifically, upregulation of coagulation cascade components of the kallikrein-kinin system (KKS) and downregulation of kininogen prior to transplant were associated with survival after transplant. Further prospective studies are warranted to determine if alterations in the KKS contributes to overall post-transplant survival.
Assuntos
Transplante de Coração , Sistema Calicreína-Cinina , Coagulação Sanguínea , Transplante de Coração/efeitos adversos , Humanos , Sistema Calicreína-Cinina/fisiologia , Cininogênios/metabolismo , ProteômicaRESUMO
The COVID-19 pandemic is rapidly spreading, and health care systems are being overwhelmed with the huge number of cases, with a good number of cases requiring intensive care. It has become imperative to develop safe and effective treatment strategies to improve survival. In this regard, understanding the pathogenesis of COVID-19 is highly important. Many hypotheses have been proposed, including the ACE/angiotensin-II/angiotensin receptor 1 pathway, the complement pathway, and the angiotensin-converting enzyme 2/mitochondrial assembly receptor (ACE2/MasR) pathway. SARS-CoV-2 binds to the ACE2 on the cell surface, downregulating the ACE2, and thus impairs the inactivation of bradykinin and des-Arg9-bradykinin. Bradykinin, a linear nonapeptide, is extensively distributed in plasma and different tissues. Kininogens in plasma and tissue are the main sources of the two vasoactive peptides called bradykinin and kallidin. However, the role of the dysregulated bradykinin pathway is less explored in the pathogenesis of COVID-19. Understanding the pathogenesis of COVID-19 is crucial for the development of new effective treatment approaches which interfere with these pathways. In this review, we have tried to explore the interaction between SARS-CoV-2, ACE2, bradykinin, and its metabolite des-Arg9-bradykinin in the pathogenesis of COVID-19.
Assuntos
Bradicinina/fisiologia , COVID-19/etiologia , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/fisiologia , Humanos , Sistema Calicreína-Cinina/fisiologia , Receptores da Bradicinina/fisiologia , Tratamento Farmacológico da COVID-19RESUMO
Mast cells (MCs) have relevant participation in inflammatory and vascular hyperpermeability events, responsible for the action of the kallikrein-kinin system (KKS), that affect patients inflicted by the severe form of COVID-19. Given a higher number of activated MCs present in COVID-19 patients and their association with vascular hyperpermeability events, we investigated the factors that lead to the activation and degranulation of these cells and their harmful effects on the alveolar septum environment provided by the action of its mediators. Therefore, the pyroptotic processes throughout caspase-1 (CASP-1) and alarmin interleukin-33 (IL-33) secretion were investigated, along with the immunoexpression of angiotensin-converting enzyme 2 (ACE2), bradykinin receptor B1 (B1R) and bradykinin receptor B2 (B2R) on post-mortem lung samples from 24 patients affected by COVID-19. The results were compared to 10 patients affected by H1N1pdm09 and 11 control patients. As a result of the inflammatory processes induced by SARS-CoV-2, the activation by immunoglobulin E (IgE) and degranulation of tryptase, as well as Toluidine Blue metachromatic (TB)-stained MCs of the interstitial and perivascular regions of the same groups were also counted. An increased immunoexpression of the tissue biomarkers CASP-1, IL-33, ACE2, B1R and B2R was observed in the alveolar septum of the COVID-19 patients, associated with a higher density of IgE+ MCs, tryptase+ MCs and TB-stained MCs, in addition to the presence of intra-alveolar edema. These findings suggest the direct correlation of MCs with vascular hyperpermeability, edema and diffuse alveolar damage (DAD) events that affect patients with a severe form of this disease. The role of KKS activation in events involving the exacerbated increase in vascular permeability and its direct link with the conditions that precede intra-alveolar edema, and the consequent DAD, is evidenced. Therapy with drugs that inhibit the activation/degranulation of MCs can prevent the worsening of the prognosis and provide a better outcome for the patient.
Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/patologia , Permeabilidade Capilar , Sistema Calicreína-Cinina/fisiologia , Pulmão/patologia , Mastócitos/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Autopsia , COVID-19/imunologia , COVID-19/virologia , Caspase 1/metabolismo , Feminino , Humanos , Interleucina-33/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/virologia , Masculino , Mastócitos/metabolismo , Mastócitos/virologia , Pessoa de Meia-Idade , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/patogenicidadeRESUMO
During severe inflammatory and infectious diseases, various mediators modulate the equilibrium of vascular tone, inflammation, coagulation and thrombosis. This Review describes the interactive roles of the renin-angiotensin system, the complement system, and the closely linked kallikrein-kinin and contact systems in cell biological functions such as vascular tone and leakage, inflammation, chemotaxis, thrombosis and cell proliferation. Specific attention is given to the role of these systems in systemic inflammation in the vasculature and tissues during hereditary angioedema, cardiovascular and renal glomerular disease, vasculitides and COVID-19. Moreover, we discuss the therapeutic implications of these complex interactions, given that modulation of one system may affect the other systems, with beneficial or deleterious consequences.
Assuntos
Proteínas do Sistema Complemento , Sistema Renina-Angiotensina , Trombose , COVID-19 , Humanos , Inflamação , Sistema Calicreína-Cinina/fisiologiaRESUMO
This review aims to summarize the main pathophysiological events involved in the development of hereditary angioedema (OMIM#106100). Hereditary angioedema is a rare genetic disease inherited in an autosomal dominant manner and caused by a loss of control over the plasma contact system or kallikrein-kinin system, which results in unrestrained bradykinin generation or signaling. In patients with hereditary angioedema, BK binding to endothelial cells leads to recurrent episodes of swelling at subcutaneous or submucosal tissues that can be life threatening when affecting the upper respiratory tract. The disease can either present with hypocomplementemia owing to the presence of pathogenic variants in the gene encoding complement C1 inhibitor (hereditary angioedema with C1-inhibitor deficiency) or present with normocomplementemia and associate with elevated estrogen levels owing to gain-of-function variants in the genes encoding coagulation proteins involved in the kallikrein-kinin system (namely, coagulation FXII [FXII-associated hereditary angioedema], plasminogen [PLG-associated hereditary angioedema], and high-molecular-weight kininogen [KNG1-associated hereditary angioedema]). Moreover, in recent years, novel pathogenic variants have been described in the genes encoding angiopoietin 1 (ANGPT1-associated hereditary angioedema) and myoferlin (MYOF-associated hereditary angioedema), which further expand the pathophysiological picture of hereditary angioedema.
Assuntos
Angioedemas Hereditários/fisiopatologia , Sistema Calicreína-Cinina/fisiologia , Angioedemas Hereditários/enzimologia , Proteína Inibidora do Complemento C1/metabolismo , Humanos , Peptídeo Hidrolases/farmacocinéticaRESUMO
The 1918 influenza killed approximately 50 million people in a few short years, and now, the world is facing another pandemic. In December 2019, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an international outbreak of a respiratory illness termed coronavirus disease 2019 (COVID-19) and rapidly spread to cause the worst pandemic since 1918. Recent clinical reports highlight an atypical presentation of acute respiratory distress syndrome (ARDS) in COVID-19 patients characterized by severe hypoxemia, an imbalance of the renin-angiotensin system, an increase in thrombogenic processes, and a cytokine release storm. These processes not only exacerbate lung injury but can also promote pulmonary vascular remodeling and vasoconstriction, which are hallmarks of pulmonary hypertension (PH). PH is a complication of ARDS that has received little attention; thus, we hypothesize that PH in COVID-19-induced ARDS represents an important target for disease amelioration. The mechanisms that can promote PH following SARS-CoV-2 infection are described. In this review article, we outline emerging mechanisms of pulmonary vascular dysfunction and outline potential treatment options that have been clinically tested.
Assuntos
Lesão Pulmonar Aguda/patologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/patologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/patologia , Síndrome Respiratória Aguda Grave/patologia , Vasoconstrição/fisiologia , Betacoronavirus , COVID-19 , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/patologia , Sistema Calicreína-Cinina/fisiologia , Pandemias , Sistema Renina-Angiotensina/fisiologia , SARS-CoV-2 , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Vasoconstrição/efeitos dos fármacosRESUMO
Coronavirus disease 2019 (COVID-19) is an infectious disease with fast spreading all over the world caused by the SARS-CoV-2 virus which can culminate in a severe acute respiratory syndrome by the injury caused in the lungs. However, other organs can be also damaged. SARS-CoV-2 enter into the host cells using the angiotensin-converting enzyme 2 (ACE2) as receptor, like its ancestor SARS-CoV. ACE2 is then downregulated in lung tissues with augmented serum levels of ACE2 in SARS-CoV-2 patients. Interestingly, ACE2+ organs reveal the symptomatic repercussions, which are signals of the infection such as dry cough, shortness of breath, heart failure, liver and kidney damage, anosmia or hyposmia, and diarrhea. ACE2 exerts a chief role in the renin-angiotensin system (RAS) by converting angiotensin II to angiotensin-(1-7) that activates Mas receptor, inhibits ACE1, and modulates bradykinin (BK) receptor sensitivity, especially the BK type 2 receptor (BKB2R). ACE2 also hydrolizes des-Arg9-bradykinin (DABK), an active BK metabolite, agonist at BK type 1 receptors (BKB1R), which is upregulated by inflammation. In this opinion article, we conjecture a dialogue by the figure of Sérgio Ferreira which brought together basic science of classical pharmacology and clinical repercussions in COVID-19, then we propose that in the course of SARS-CoV-2 infection: i) downregulation of ACE2 impairs the angiotensin II and DABK inactivation; ii) BK and its metabolite DABK seems to be in elevated levels in tissues by interferences in kallikrein/kinin system; iii) BK1 receptor contributes to the outbreak and maintenance of the inflammatory response; iv) kallikrein/kinin system crosstalks to RAS and coagulation system, linking inflammation to thrombosis and organ injury. We hypothesize that targeting the kallikrein/kinin system and BKB1R pathway may be beneficial in SARS-CoV-2 infection, especially on early stages. This route of inference should be experimentally verified by SARS-CoV-2 infected mice.
Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Sistema Calicreína-Cinina/fisiologia , Modelos Biológicos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/fisiopatologia , Enzima de Conversão de Angiotensina 2 , Animais , COVID-19 , Infecções por Coronavirus/etiologia , Humanos , Sistema Calicreína-Cinina/efeitos dos fármacos , Camundongos , Pandemias , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/etiologia , Receptores Virais/fisiologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , SARS-CoV-2 , Pesquisa Translacional Biomédica , Internalização do Vírus/efeitos dos fármacos , Tratamento Farmacológico da COVID-19RESUMO
Recent studies have shown that the innate and adaptive immune system, together with low-grade inflammation, may play an important role in essential hypertension. In this work, to verify the importance of selected factors for the development of essential hypertension, we created a Petri net-based model and analyzed it. The analysis was based mainly on t-invariants, knockouts of selected fragments of the net and its simulations. The blockade of the renin-angiotensin (RAA) system revealed that the most significant effect on the emergence of essential hypertension has RAA activation. This blockade affects: (1) the formation of angiotensin II, (2) inflammatory process (by influencing C-reactive protein (CRP)), (3) the initiation of blood coagulation, (4) bradykinin generation via the kallikrein-kinin system, (5) activation of lymphocytes in hypertension, (6) the participation of TNF alpha in the activation of the acute phase response, and (7) activation of NADPH oxidase-a key enzyme of oxidative stress. On the other hand, we found that the blockade of the activation of the RAA system may not eliminate hypertension that can occur due to disturbances associated with the osmotically independent binding of Na in the interstitium. Moreover, we revealed that inflammation alone is not enough to trigger primary hypertension, but it can coexist with it. We believe that our research may contribute to a better understanding of the pathology of hypertension. It can help identify potential subprocesses, which blocking will allow better control of essential hypertension.
Assuntos
Hipertensão Essencial/fisiopatologia , Inflamação/fisiopatologia , Modelos Biológicos , Angiotensina II/fisiologia , Autoantígenos/imunologia , Coagulação Sanguínea , Bradicinina/biossíntese , Proteína C-Reativa/fisiologia , Endotélio Vascular/imunologia , Hipertensão Essencial/etiologia , Hipertensão Essencial/imunologia , Humanos , Inflamação/imunologia , Sistema Calicreína-Cinina/fisiologia , Ativação Linfocitária , NADPH Oxidases/fisiologia , Natriurese/fisiologia , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase Tipo III/fisiologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Pele/fisiopatologia , Sódio/metabolismo , Cloreto de Sódio na Dieta/farmacocinética , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
OBJECTIVE: The purpose of this study was to investigate the clinical evolution of patients treated with carbon-coated stent, as well as its patency and the inflammatory response triggered by this process through the quantification of serum elements of the kallikrein-kinin system (KKS). METHODS: This was a single-center prospective study with 27 patients with peripheral artery disease (PAD) who required percutaneous transluminal angioplasty and stenting of the iliacofemoropopliteal segment using carbon-coated stent grafts (carbostents). The blood concentrations of the total and kininogen fractions were evaluated using immunoenzymatic methods. Plasma kallikrein levels were assessed by the colorimetric method and tissue kallikrein levels were evaluated by the spectrophotometric method. The activity of kininase II was measured by -fluorometric analysis. RESULTS: Of the 27 patients who completed the 6 months of the study (11 iliac territory, 16 femoropopliteal territory), only one experienced restenosis (3.7%) (femoropopliteal segment) and no patient had occlusion (96.3% of patency). In 1 year, four patients were lost to follow-up and all 23 patients evaluated maintained stent patency, except for the patient who had restenosis throughout the first 6 months. We report complete (100%) member salvage in 12 months of follow-up. The activity levels of high- and low-molecular-weight kininogens decreased significantly over time (before vs. 24 h, p < 0.01; before vs. 6 months, p < 0.001, and before vs. 24 h, p < 0.01; before vs. 6 months, p < 0.001; 24 h vs. 6 months, p < 0.001, respectively). Patients also had signiï¬cantly lower levels of plasma and tissue kallikrein (before vs. 24 h, p < 0.001; before vs. 6 months, p < 0.001, and before vs. 24 h, p < 0.01; before vs. 6 months, p < 0.05, respectively). There was a significant increase in the enzymatic activity of kininase II at 24 h and after 6 months compared to the pre-treatment control (p < 0.001). CONCLUSION: Our early experience shows that the use of carbon-coated stents in PAD appears to be safe, with low rates of early restenosis (3.7% in the first 6 months and 5% in the 12 months of follow-up). We concluded that KKS was involved in the inflammatory response caused by the placement of carbon-coated stents.
Assuntos
Angioplastia/métodos , Sistema Calicreína-Cinina/fisiologia , Doença Arterial Periférica/terapia , Stents/efeitos adversos , Idoso , Carbono , Feminino , Humanos , Calicreínas/sangue , Cininogênio de Alto Peso Molecular/sangue , Masculino , Pessoa de Meia-Idade , Peptidil Dipeptidase A/metabolismo , Estudos ProspectivosRESUMO
Pharmacological research in mice and human genetic analyses suggest that the kallikrein-kinin system (KKS) may regulate anxiety. We examined the role of the KKS in anxiety and stress in both species. In human genetic association analysis, variants in genes for the bradykinin precursor (KNG1) and the bradykinin receptors (BDKRB1 and BDKRB2) were associated with anxiety disorders (p < 0.05). In mice, however, neither acute nor chronic stress affected B1 receptor gene or protein expression, and B1 receptor antagonists had no effect on anxiety tests measuring approach-avoidance conflict. We thus focused on the B2 receptor and found that mice injected with the B2 antagonist WIN 64338 had lowered levels of a physiological anxiety measure, the stress-induced hyperthermia (SIH), vs controls. In the brown adipose tissue, a major thermoregulator, WIN 64338 increased expression of the mitochondrial regulator Pgc1a and the bradykinin precursor gene Kng2 was upregulated after cold stress. Our data suggests that the bradykinin system modulates a variety of stress responses through B2 receptor-mediated effects, but systemic antagonists of the B2 receptor were not anxiolytic in mice. Genetic variants in the bradykinin receptor genes may predispose to anxiety disorders in humans by affecting their function.
Assuntos
Transtornos de Ansiedade/metabolismo , Bradicinina/metabolismo , Sistema Calicreína-Cinina/fisiologia , Estresse Psicológico/metabolismo , Adulto , Animais , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/patologia , Antagonistas de Receptor B1 da Bradicinina/administração & dosagem , Antagonistas de Receptor B2 da Bradicinina/administração & dosagem , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Sistema Calicreína-Cinina/efeitos dos fármacos , Cininogênios/genética , Cininogênios/metabolismo , Masculino , Camundongos , Naftalenos/administração & dosagem , Compostos Organofosforados/administração & dosagem , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Polimorfismo de Nucleotídeo Único , Receptor B1 da Bradicinina/genética , Receptor B1 da Bradicinina/metabolismo , Receptor B2 da Bradicinina/genética , Receptor B2 da Bradicinina/metabolismo , Especificidade da Espécie , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/patologia , Regulação para CimaRESUMO
Temporal lobe epilepsy (TLE) is a chronic disease, characterized by severe and refractory seizures, triggered in the hippocampus and/or amygdala, disrupting the blood-brain barrier. This disruption can sustain, or aggravate, the epileptic condition. The aim of this study was to evaluate the activation of the kallikrein-kinin system in patients with TLE, as it relates to the maintenance of blood-brain barrier. Human hippocampal sclerotic tissues removed after surgery for seizure control, plasma, and serum were used in the following assays: immunostaining for white blood cells in the TLE hippocampus, C-reactive protein in serum, quantification of plasma kallikrein (PKal) and cathepsin B (CatB) activity in serum and plasma, quantification of C1-inhibitor, analysis of high-molecular-weight kininogen (H-kininogen) fragments, and activation of plasma prekallikrein for comparison with healthy controls. Infiltration of white blood cells in the sclerotic hippocampus and a significant increase in the neutrophil/lymphocyte ratio in the blood of TLE patients were observed. High levels of C-reactive protein (TLE = 1.4 ± 0.3 µg/mL), PKal (TLE = 5.4 ± 0.4 U/mL), and CatB (TLE = 4.9 ± 0.4 U/mL) were also evident in the serum of TLE patients comparing to controls. A strong linear correlation was observed between active CatB and PKal in the serum of TLE patients (r = 0.88). High levels of cleaved H-kininogen and free PKal, and low levels of C1-inhibitor (TLE = 188 ± 12 µg/mL) were observed in the serum of TLE patients. Our data demonstrated that the plasma kallikrein-kinin system is activated in patients with TLE. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.
Assuntos
Catepsina B/sangue , Epilepsia do Lobo Temporal/metabolismo , Inflamação/metabolismo , Sistema Calicreína-Cinina/fisiologia , Calicreínas/sangue , Adulto , Feminino , Hipocampo/metabolismo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Aberrant lipoprotein metabolism has been implicated in experimental pulmonary hypertension, but the relevance to patients with pulmonary arterial hypertension (PAH) is inconclusive. OBJECTIVE: To investigate the relationship between circulating lipoprotein subclasses and survival in patients with PAH. METHODS: Using nuclear magnetic resonance spectroscopy, 105 discrete lipoproteins were measured in plasma samples from two cohorts of patients with idiopathic or heritable PAH. Data from 1124 plasma proteins were used to identify proteins linked to lipoprotein subclasses. The physical presence of proteins was confirmed in plasma lipoprotein subfractions separated by ultracentrifugation. RESULTS: Plasma levels of three lipoproteins from the small high-density lipoprotein (HDL) subclass, termed HDL-4, were inversely related to survival in both the discovery (n=127) and validation (n=77) cohorts, independent of exercise capacity, comorbidities, treatment, N-terminal probrain natriuretic peptide, C reactive protein and the principal lipoprotein classes. The small HDL subclass rich in apolipoprotein A-2 content (HDL-4-Apo A-2) exhibited the most significant association with survival. None of the other lipoprotein classes, including principal lipoprotein classes HDL and low-density lipoprotein cholesterol, were prognostic. Three out of nine proteins identified to associate with HDL-4-Apo A-2 are involved in the regulation of fibrinolysis, namely, the plasmin regulator, alpha-2-antiplasmin, and two major components of the kallikrein-kinin pathway (coagulation factor XI and prekallikrein), and their physical presence in the HDL-4 subfraction was confirmed. CONCLUSION: Reduced plasma levels of small HDL particles transporting fibrinolytic proteins are associated with poor outcomes in patients with idiopathic and heritable PAH.
Assuntos
Hipertensão Pulmonar/sangue , Lipoproteínas HDL/sangue , Adulto , Idoso , Biomarcadores/sangue , Estudos de Coortes , Feminino , Fibrinólise/fisiologia , Hemodinâmica/fisiologia , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/fisiopatologia , Sistema Calicreína-Cinina/fisiologia , Estimativa de Kaplan-Meier , Lipoproteínas/sangue , Espectroscopia de Ressonância Magnética/métodos , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Prognóstico , ProteomaRESUMO
Neutrophil recruitment and plasma exudation are key elements in the immune response to injury or infection. Activated neutrophils stimulate opening of the endothelial barrier; however, the underlying mechanisms have remained largely unknown. In this study, we identified a pivotal role of the proinflammatory kallikrein-kinin system and consequent formation of bradykinin in neutrophil-evoked vascular leak. In mouse and hamster models of acute inflammation, inhibitors of bradykinin generation, and signaling markedly reduced plasma exudation in response to chemoattractant activation of neutrophils. The neutrophil-driven leak was likewise suppressed in mice deficient in either the bradykinin B2 receptor or factor XII (initiator of the kallikrein-kinin system). In human endothelial cell monolayers, material secreted from activated neutrophils induced cytoskeletal rearrangement, leading to paracellular gap formation in a bradykinin-dependent manner. As a mechanistic basis, we found that a neutrophil-derived heparin-binding protein (HBP/azurocidin) displaced the bradykinin precursor high-molecular-weight kininogen from endothelial cells, thereby enabling proteolytic processing of kininogen into bradykinin by neutrophil and plasma proteases. These data provide novel insight into the signaling pathway by which neutrophils open up the endothelial barrier and identify the kallikrein-kinin system as a target for therapeutic interventions in acute inflammatory reactions.-Kenne, E., Rasmuson, J., Renné, T., Vieira, M. L., Müller-Esterl, W., Herwald, H., Lindbom, L. Neutrophils engage the kallikrein-kinin system to open up the endothelial barrier in acute inflammation.
Assuntos
Permeabilidade da Membrana Celular , Endotélio Vascular/fisiologia , Inflamação/patologia , Sistema Calicreína-Cinina/fisiologia , Neutrófilos/metabolismo , Edema Pulmonar/patologia , Animais , Bradicinina/metabolismo , Endotélio Vascular/citologia , Fator XII/metabolismo , Feminino , Humanos , Inflamação/metabolismo , Cininogênio de Alto Peso Molecular/metabolismo , Masculino , Mesocricetus , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos , Edema Pulmonar/etiologia , Edema Pulmonar/metabolismoRESUMO
Kidney injury is a frequent outcome in patients with disseminated Candida albicans fungal infections. IL-17 receptor (IL-17R) signaling is critical for renal protection against disseminated candidiasis, but the identity and function of IL-17-responsive cells in mediating renal defense remains an active area of debate. Using BM chimeras, we found that IL-17R signaling is required only in nonhematopoietic cells for immunity to systemic C. albicans infection. Since renal tubular epithelial cells (RTEC) are highly responsive to IL-17 in vitro, we hypothesized that RTEC might be the dominant target of IL-17 activity in the infected kidney. We generated mice with a conditional deletion of IL-17 receptor A (Il17ra) in RTEC (Il17raΔRTEC). Strikingly, Il17raΔRTEC mice showed enhanced kidney damage and early mortality following systemic infection, very similar to Il17ra-/- animals. Increased susceptibility to candidiasis in Il17raΔRTEC mice was associated with diminished activation of the renal protective Kallikrein-kinin system (KKS), resulting in reduced apoptosis of kidney-resident cells during hyphal invasion. Moreover, protection was restored by treatment with bradykinin, the major end-product of KKS activation, which was mediated dominantly via bradykinin receptor b1. These data show that IL-17R signaling in RTEC is necessary and likely sufficient for IL-17-mediated renal defense against fatal systemic C. albicans infection.