Bradykinin
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PROVIDER: S-EPMC2884574 | biostudies-literature | 2009 Nov
REPOSITORIES: biostudies-literature
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Project description:Bradykinin is a peptide implicated in inflammatory pain in both humans and rodents. In rodent sensory neurons, activation of B1 and B2 bradykinin receptors induces neuronal hyperexcitability. Recent evidence suggests that human and rodent dorsal root ganglia (DRG), which contain the cell bodies of sensory neurons, differ in the expression and function of key GPCRs and ion channels; whether BK receptor expression and function are conserved across species has not been studied in depth. In this study, we used human DRG tissue from organ donors to provide a detailed characterization of bradykinin receptor expression and bradykinin-induced changes in the excitability of human sensory neurons. We found that B2 and, to a lesser extent, B1 receptors are expressed by human DRG neurons and satellite glial cells. B2 receptors were enriched in the nociceptor subpopulation. Using patch-clamp electrophysiology, we found that acute bradykinin increases the excitability of human sensory neurons, while prolonged exposure to bradykinin decreases neuronal excitability in a subpopulation of human DRG neurons. Finally, our analyses suggest that donor’s history of chronic pain and age may be predictors of higher B1 receptor expression in human DRG neurons. Together, these results indicate that acute BK-induced hyperexcitability, first identified in rodents, is conserved in humans and provide further evidence supporting BK signaling as a potential therapeutic target for treating pain in humans.
| S-EPMC10081334 | biostudies-literature
Project description:Endometriosis (EM), a benign aseptic inflammatory disease, is associated with the presence of endometrial foci. Pain, one of its typical symptoms, has been reported as a constant stressor, but the etiology and pathogenesis of EM-associated pain are unclear. In the present study, eutopic and ectopic endometrium samples from women with EM (n=50) and normal endometrium samples from control subjects (n=20) were collected. Serum levels of prostaglandin E2 (PGE2), prostaglandin F2α (PGF2α) and bradykinin (BK) were measured using commercial ELISA kits. The expression of the BKB1 receptor (BKB1R) protein was evaluated by immunohistochemical staining and western blot assay. The mRNA expression of BKB1R was measured by reverse transcription-quantitative PCR. The results revealed that there was a substantial increase in the protein and mRNA expression of BKB1R, as well as the release of PGE2, PGF2α and BK in the blood, in the EM group compared with that in the control group. Moreover, PGE2, PGF2α and BK levels were significantly correlated with each other, as well as with the pain intensity of EM. The increased expression levels of BKB1R protein and mRNA were positively correlated with the pain degree of EM. Thus, these data indicated that BK and BKB1R were involved in the pathological onset of EM-associated pain and that they may play an important role in EM-related pain by inducing PGE2 and PGF2α. The data indicate a potential new therapeutic target for EM-related pain.
| S-EPMC8438668 | biostudies-literature
Project description:Stroke is a life-threatening disease with limited therapeutic options. Damage to the blood-brain barrier (BBB) is the key pathological feature of ischemic stroke. This study explored the role of the bradykinin (BK)/bradykinin 1 receptor (B1R) and its mechanism of action in the BBB. Human brain microvascular endothelial cells (BMECs) were used to test for cellular responses to BK by using the Cell Counting Kit-8 assay, 5-ethynyl-2'-deoxyuridine staining, enzyme-linked immunosorbent assay, flow cytometry, immunofluorescence, cellular permeability assays, and western blotting to evaluate cell viability, cytokine production, and reactive oxygen species (ROS) levels in vitro. A BBB induced by middle cerebral artery occlusion was used to evaluate BBB injuries, and the role played by BK/B1R in ischemic/reperfusion (I/R) was explored in a rat model. Results showed that BK reduced the viability of BMECs and increased the levels of proinflammatory cytokines (interleukin 6 [IL-6], IL-18, and monocyte chemoattractant protein-1) and ROS. Additionally, cellular permeability was increased by BK treatment, and the expression of tight junction proteins (claudin-5 and occludin) was decreased. Interestingly, Wnt3a expression was inhibited by BK and exogenous Wnt3a restored the effects of BK on BMECs. In an in vivo I/R rat model, knockdown of B1R significantly decreased infarct volume and inflammation in I/R rats. Our results suggest that BK might be a key inducer of BBB injury and B1R knockdown might provide a beneficial effect by upregulating Wnt3a.
| S-EPMC10078380 | biostudies-literature
Project description:Analysis of A549 cells treated with bradyikinin. In this dataset, we include the expression data obtained from A549 cells after treatment with bradykinin. We confirmed that A540 cells expressed bradykinin B2 receptor. Results provide insight into the effect of bradykin on MAP kinase pathway.
2017-09-18 | GSE97175 | GEO
Project description:Background and purposeInhibition of bradykinin metabolizing enzymes (BMEs) can cause acute angioedema, as demonstrated in a recent clinical trial in patients administered the antihypertensive, omapatrilat. However, the relative contribution of specific BMEs to this effect is unclear and confounded by the lack of a predictive pre-clinical model of angioedema.Experimental approachRats were instrumented to record blood pressure and heart rate; inhibitors were infused for 35 min and bradykinin was infused during the last 5 min to elicit hypotension, as a functional marker of circulating bradykinin and relative angioedema risk.Key resultsIn the presence of omapatrilat bradykinin produced dose-dependent hypotension, an effect abolished by B(2) blockade. In the presence of lisinopril (ACE inhibitor), but not candoxatril (NEP inhibitor) or apstatin (APP inhibitor), bradykinin also elicited hypotension. Lisinopril-mediated hypotension was unchanged with concomitant blockade of NEP or NEP/DPPIV (candoxatril+A-899301). However, hypotension was enhanced upon concomitant blockade of APP and further intensified in the presence of NEP inhibition to values not different from omapatrilat alone.Conclusions and implicationsWe demonstrated that bradykinin is degraded in vivo with an enzyme rank-efficacy of ACE>APP>>NEP or DPPIV. These results suggest the effects of omapatrilat are mediated by inhibition of three BMEs, ACE/APP/NEP. However, dual inhibition of ACE/NEP or ACE/NEP/DPPIV elicits no increased risk of angioedema compared to ACE inhibition alone. Thus, novel BME inhibitors must display no activity against APP to avoid angioedema risk due to high prevalence of ACE inhibitor therapy in patients with diabetes and cardiovascular disease.
| S-EPMC2267285 | biostudies-literature
Project description:Ion mobility and mass spectrometry techniques are used to investigate the stabilities of different conformations of bradykinin (BK, Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9). At elevated solution temperatures, we observe a slow protonation reaction, i.e., [BK+2H]2++H+ → [BK+3H]3+, that is regulated by trans → cis isomerization of Arg1-Pro2, resulting in the Arg1- cis-Pro2- cis-Pro3-Gly4-Phe5-Ser6- cis-Pro7-Phe8-Arg9 (all- cis) configuration. Once formed, the all- cis [BK+3H]3+ spontaneously cleaves the bond between Pro2-Pro3 with perfect specificity, a bond that is biologically resistant to cleavage by any human enzyme. Temperature-dependent kinetics studies reveal details about the intrinsic peptide processing mechanism. We propose that nonenzymatic cleavage at Pro2-Pro3 occurs through multiple intermediates and is regulated by trans → cis isomerization of Arg1-Pro2. From this mechanism, we can extract transition state thermochemistry: Δ G‡ = 94.8 ± 0.2 kJ·mol-1, Δ H‡ = 79.8 ± 0.2 kJ·mol-1, and Δ S‡ = -50.4 ± 1.7 J·mol-1·K-1 for the trans → cis protonation event; and, Δ G‡ = 94.1 ± 9.2 kJ·mol-1, Δ H‡ = 107.3 ± 9.2 kJ·mol-1, and Δ S‡ = 44.4 ± 5.1 J·mol-1·K-1 for bond cleavage. Biological resistance to the most favored intrinsic processing pathway prevents formation of Pro3-Gly4-Phe5-Ser6- cis-Pro7-Phe8-Arg9 that is approximately an order of magnitude more antigenic than BK.
| S-EPMC6503673 | biostudies-literature
Project description:Plasminogen activation is essential for fibrinolysis-the breakdown of fibrin polymers in blood clots. Besides this important function, plasminogen activation participates in a wide variety of inflammatory conditions. One of these conditions is hereditary angioedema (HAE), a rare disease with characteristic attacks of aggressive tissue swelling due to unregulated production and activity of the inflammatory mediator bradykinin. Plasmin was already implicated in this disease decades ago, but a series of recent discoveries have made it clear that plasmin actively contributes to this pathology. Collective evidence points toward an axis in which the plasminogen activation system and the contact system (which produces bradykinin) are mechanistically coupled. This is amongst others supported by findings in subtypes of HAE that are caused by gain-of-function mutations in the genes that respectively encode factor XII or plasminogen, as well as clinical experience with the antifibrinolytic agents in HAE. The concept of a link between plasminogen activation and the contact system helps us to explain the inflammatory side effects of fibrinolytic therapy, presenting as angioedema or tissue edema. Furthermore, these observations motivate the development and characterization of therapeutic agents that disconnect plasminogen activation from bradykinin production.
| S-EPMC6719523 | biostudies-literature
Project description:Inflammatory hyperalgesia represents a nociceptive phenotype that can become persistent in nature through dynamic protein modifications. However, a large gap in knowledge exists concerning how the integration of intracellular signaling molecules coordinates a persistent inflammatory phenotype. Herein, we demonstrate that Raf Kinase Anchoring Protein (RKIP) interrupts a vital canonical desensitization pathway to maintain bradykinin (BK) receptor activation in primary afferent neurons. Biochemical analyses of primary neuronal cultures indicate bradykinin-stimulated PKC phosphorylation of RKIP at Ser153. Furthermore, BK exposure increases G-protein Receptor Kinase 2 (GRK2) binding to RKIP, inhibiting pharmacological desensitization of the BK receptor. Additional studies found that molecular RKIP down-regulation increases BK receptor desensitization in real-time imaging of primary afferent neurons, identifying a key pathway integrator in the desensitization process that controls multiple GRK2-sensitive G-protein coupled receptors. Therefore, RKIP serves as an integral scaffolding protein that inhibits BK receptor desensitization.
| S-EPMC9283312 | biostudies-literature
Project description:Diabetic kidney disease is the major cause of end-stage kidney failure worldwide. Podocyte damage is one of the hallmarks of diabetic nephropathy, where the loss of the podocyte filtration barrier leads to proteinuria and progressive renal damage. Bradykinin (BK) is a vasoactive peptide that was shown to play an important role in the progression of renal damage. In this study, we aim to evaluate the changes in protein expression profiles of rat podocytes upon the treatment with BK by an advanced proteomics platform in conjunction with bioinformatics and pathway enrichment analysis. This analysis will help in discovering core effectors whose upstream and downstream protein profile can elucidate signaling mechanisms underlying BK’s modulation of the podocyte biology. Cultured immortalized rat podocytes were treated with BK at 10-7 M for 3 and 6 hours. Proteome profile was evaluated by LC-MS/MS analysis, and pathway enrichment analysis was performed on the resulting differential proteomic data. Proteomic analysis of podocytes treated by BK revealed 61 proteins that were differentially altered (up or downregulated) in response to BK treatment compared to unstimulated control podocytes. Pathway enrichment analysis suggested an inhibition of the cell death pathway and the involvement of elements of the cytoskeletal activity as well as activation of the inflammatory pathways. Of interest, one of the inflammatory proteins that were identified to be induced by BK treatment is Prostaglandin H Synthase-2 (PTGS-2, also known as COX-2). The upregulation of COX-2 by BK treatment was validated by western blot analysis. In addition, treatment of podocytes with BK significantly induced the production and release of PGE2 and this effect was inhibited by both COX-2 and MAPK inhibitors, demonstrating that the production of PGE2 by BK is mediated via a COX-2 and MAPK-dependent mechanisms. The findings of the present study provide a global understanding of the effector modulated proteome in response to BK treatment, and also reveal BK as an important modulator in the arachidonic acid metabolism pathway and a potential player in the progression of diabetic nephropathy.
2021-09-08 | PXD010015 | Pride
Project description:Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist.In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms.A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported.In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)
| S-EPMC4662377 | biostudies-literature