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Kinins and Their Receptors as Potential Therapeutic Targets —— A Tribute to Professor Domenico Regoli, A Key Figure in the Field of Kinins

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 40299

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Prof. Dr. Réjean Couture

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Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
Interests: inflammation; pain neuropathy; diabetes; ocular diseases; epilepsy; Alzheimer disease

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Dear Colleagues,

Kinins (bradykinin and kallidin) are important vasoactive peptides and CNS neuromediators that belong to the kallikrein-kinin system (KKS). These peptides exert their effects through the activation of two transmembrane G-protein-coupled receptors, denoted as B1 (B1R) and B2 (B2R). The B2R is activated by the parent molecules, while the B1R is activated by kinins deprived of the C-terminal Arg (des-Arg⁹-kinins) resulting from the enzymatic activity of kininase I (carboxypeptidase M/N).

Most physiological effects of kinins are mediated by the constitutive B2R, since B1R is virtually absent in healthy tissues. B2R contributes to the therapeutic effects of angiotensin-1-converting enzyme inhibitors (ACEI) and angiotensin AT1 receptor blockers. Benefits derive primarily from vasodilatory, antiproliferative, antihypertrophic, antifibrotic, antithrombic, and antioxidant properties. Uncontrolled production of kinins or the inhibition of their metabolism may lead to unwanted pro-inflammatory side effects. Thus, B2R antagonism is salutary in angioedema, septic shock, stroke, and Chagas vasculopathy.

B1R is induced and upregulated during tissue injury involving the cytokine pathway, oxidative stress, and the transcriptional nuclear factor NF-κB. The highly inducible character of B1R is often symptomatic of the occurrence of immune and inflammatory diseases.

B1R may play a compensatory role for the lack of B2R, and its upregulation during tissue damage may be a useful mechanism of host defense. The activation of both receptors may be beneficial, notably in neovascularisation, angiogenesis, heart ischemia, and diabetic nephropathy. At the same time, B1R is a potent activator of inducible nitric oxide and NADPH oxidase, which are associated with vascular inflammation, increased permeability, insulin resistance, endothelial dysfunction, and diabetic complications.

The dual beneficial and deleterious effects of kinin receptors, and particularly B1R, raise on the question of the therapeutic value of B1R/B2R agonists versus antagonists in various diseases. Hence, the Janus-face of kinin receptors needs to be seriously addressed in each pathological setting.

Authors are invited to submit original and review articles on preclinical and clinical findings contributing to the understanding of the current state of kinin receptors as potential therapeutic targets, to be published in this Special Issue of Pharmaceuticals. The proposed topics cover inflammation, chronic pain, diabetes and its complications (retinopathy, nephropathy, neuropathy, and vasculopathy), obesity, cancer, and neurological and neurodegenerative diseases.

I look forward to your valuable contribution.

Prof. Réjean Couture
Guest Editor

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Keywords

Bradykinin
Bradykinin type 1 receptor
Bradykinin type 2 receptor
Inflammation
Chronic pain
Diabetes mellitus
Obesity
Neurological diseases
Neurodegenerative diseases
Cancer.

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Research

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27 pages, 7950 KiB

Open AccessArticle

Contact System Activation in Plasma from Dengue Patients Might Harness Endothelial Virus Replication through the Signaling of Bradykinin Receptors

by Sharton V. A. Coelho, Naiara M. Rust, Lucas Vellasco, Michelle P. Papa, Aline S. G. Pereira, Matheus Ferreira da Silva Palazzo, Maria Aparecida Juliano, Simone M. Costa, Ada M. B. Alves, Marli T. Cordeiro, Ernesto T. A. Marques, Júlio Scharfstein and Luciana B. de Arruda

Pharmaceuticals 2021, 14(1), 56; https://doi.org/10.3390/ph14010056 - 12 Jan 2021

Cited by 5 | Viewed by 3239

Abstract

Since exacerbated inflammation and microvascular leakage are hallmarks of dengue virus (DENV) infection, here we interrogated whether systemic activation of the contact/kallikrein-kinin system (KKS) might hamper endothelial function. In vitro assays showed that dextran sulfate, a potent contact activator, failed to generate appreciable levels of activated plasma kallikrein (PKa) in the large majority of samples from a dengue cohort (n = 70), irrespective of severity of clinical symptoms. Impaired formation of PKa in dengue-plasmas correlated with the presence of cleaved Factor XII and high molecular weight kininogen (HK), suggesting that the prothrombogenic contact system is frequently triggered during the course of infection. Using two pathogenic arboviruses, DENV or Zika virus (ZIKV), we then asked whether exogenous BK could influence the outcome of infection of human brain microvascular endothelial cells (HBMECs). Unlike the unresponsive phenotype of Zika-infected HBMECs, we found that BK, acting via B2R, vigorously stimulated DENV-2 replication by reverting nitric oxide-driven apoptosis of endothelial cells. Using the mouse model of cerebral dengue infection, we next demonstrated that B2R targeting by icatibant decreased viral load in brain tissues. In summary, our study suggests that contact/KKS activation followed by BK-induced enhancement of DENV replication in the endothelium may underlie microvascular pathology in dengue. Full article

(This article belongs to the Special Issue Kinins and Their Receptors as Potential Therapeutic Targets —— A Tribute to Professor Domenico Regoli, A Key Figure in the Field of Kinins)

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16 pages, 2607 KiB

Open AccessArticle

Kinin B2 Receptor Activation Prevents the Evolution of Alzheimer’s Disease Pathological Characteristics in a Transgenic Mouse Model

by Marielza Andrade Nunes, Mariana Toricelli, Natalia Mendes Schöwe, Helena Nascimento Malerba, Karis Ester Dong-Creste, Daniela Moura Azevedo Tuma Farah, Katia De Angelis, Maria Claudia Irigoyen, Fernand Gobeil, Tânia Araujo Viel and Hudson Sousa Buck

Pharmaceuticals 2020, 13(10), 288; https://doi.org/10.3390/ph13100288 - 01 Oct 2020

Cited by 5 | Viewed by 2845

Abstract

Background: Alzheimer’s disease is mainly characterized by remarkable neurodegeneration in brain areas related to memory formation. This progressive neurodegeneration causes cognitive impairment, changes in behavior, functional disability, and even death. Our group has demonstrated changes in the kallikrein–kinin system (KKS) in Alzheimer’s disease (AD) experimental models, but there is a lack of evidence about the role of the KKS in Alzheimer’s disease. Aim: In order to answer this question, we evaluated the potential of the kinin B2 receptors (BKB2R) to modify AD characteristics, particularly memory impairment, neurodegeneration, and Aβ peptide deposition. Methods: To assess the effects of B2, we used transgenic Alzheimer’s disease mice treated with B2 receptor (B2R) agonists and antagonists, and performed behavioral and biochemical tests. In addition, we performed organotypic hippocampal culture of wild-type (WT) and transgenic (TG) animals, where the density of cytokines, neurotrophin BDNF, activated astrocyte marker S100B, and cell death were analyzed after treatments. Results: Treatment with the B2R agonist preserved the spatial memory of transgenic mice and decreased amyloid plaque deposition. In organotypic hippocampal culture, treatment with B2R agonist decreased cell death, neuroinflammation, and S100B levels, and increased BDNF release. Conclusions: Our results indicate that the kallikrein–kinin system plays a beneficial role in Alzheimer’s disease through B2R activation. The use of B2R agonists could, therefore, be a possible therapeutic option for patients diagnosed with Alzheimer’s disease. Full article

(This article belongs to the Special Issue Kinins and Their Receptors as Potential Therapeutic Targets —— A Tribute to Professor Domenico Regoli, A Key Figure in the Field of Kinins)

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20 pages, 3080 KiB

Open AccessArticle

Pharmacological Modulation of Blood–Brain Barrier Permeability by Kinin Analogs in Normal and Pathologic Conditions

by Dina Sikpa, Lisa Whittingstall, Martin Savard, Réjean Lebel, Jérôme Côté, Stephen McManus, Sylvain Chemtob, David Fortin, Martin Lepage and Fernand Gobeil

Pharmaceuticals 2020, 13(10), 279; https://doi.org/10.3390/ph13100279 - 29 Sep 2020

Cited by 9 | Viewed by 3633

Abstract

The blood–brain barrier (BBB) is a major obstacle to the development of effective diagnostics and therapeutics for brain cancers and other central nervous system diseases. Peptide agonist analogs of kinin B1 and B2 receptors, acting as BBB permeabilizers, have been utilized to overcome this barrier. The purpose of the study was to provide new insights for the potential utility of kinin analogs as brain drug delivery adjuvants. In vivo imaging studies were conducted in various animal models (primary/secondary brain cancers, late radiation-induced brain injury) to quantify BBB permeability in response to kinin agonist administrations. Results showed that kinin B1 (B1R) and B2 receptors (B2R) agonists increase the BBB penetration of chemotherapeutic doxorubicin to glioma sites, with additive effects when applied in combination. B2R agonist also enabled extravasation of high-molecular-weight fluorescent dextrans (155 kDa and 2 MDa) in brains of normal mice. Moreover, a systemic single dose of B2R agonist did not increase the incidence of metastatic brain tumors originating from circulating breast cancer cells. Lastly, B2R agonist promoted the selective delivery of co-injected diagnostic MRI agent Magnevist in irradiated brain areas, depicting increased vascular B2R expression. Altogether, our findings suggest additional evidence for using kinin analogs to facilitate specific access of drugs to the brain. Full article

(This article belongs to the Special Issue Kinins and Their Receptors as Potential Therapeutic Targets —— A Tribute to Professor Domenico Regoli, A Key Figure in the Field of Kinins)

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9 pages, 4650 KiB

Open AccessCommunication

Molecular Features of Non-Selective Small Molecule Antagonists of the Bradykinin Receptors

by Bahareh Rasaeifar, Patricia Gomez-Gutierrez and Juan J. Perez

Pharmaceuticals 2020, 13(9), 259; https://doi.org/10.3390/ph13090259 - 21 Sep 2020

Cited by 11 | Viewed by 3620

Abstract

Angiotensin converting enzyme 2 (ACE2) downregulation is a key negative factor for the severity of lung edema and acute lung failure observed in patients infected with SARS-CoV-2. ACE2 downregulation affects the levels of diverse peptide mediators of the renin-agiotensin-aldestosterone and kallikrein-kinin systems, compromising vascular hemostasis. Increasing evidence suggests that the inflammatory response observed in covid-19 patients is initiated by the action of kinins on the bradykinin receptors. Accordingly, the use of bradykinin antagonists should be considered as a strategy for therapeutic intervention against covid-19 illness progression. Presently, icatibant is the only bradykinin antagonist drug approved. In the present report, we investigated the molecular features characterizing non-selective antagonists targeting the bradykinin receptors and carried out a in silico screening of approved drugs, aimed at the identification of compounds with a non-selective bradykinin antagonist profile that can be evaluated for drug repurposing. The study permitted to identify eight compounds as prospective non-selective antagonists of the bradykinin receptors, including raloxifene; sildenafil; cefepime; cefpirome; imatinib; ponatinib; abemaciclib and entrectinib. Full article

(This article belongs to the Special Issue Kinins and Their Receptors as Potential Therapeutic Targets —— A Tribute to Professor Domenico Regoli, A Key Figure in the Field of Kinins)

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20 pages, 4110 KiB

Open AccessFeature PaperArticle

Differential Expression of Kinin Receptors in Human Wet and Dry Age-Related Macular Degeneration Retinae

by Rahmeh Othman, Simon Berbari, Elvire Vaucher and Réjean Couture

Pharmaceuticals 2020, 13(6), 130; https://doi.org/10.3390/ph13060130 - 24 Jun 2020

Cited by 5 | Viewed by 2875

Abstract

Kinins are vasoactive peptides and mediators of inflammation, which signal through two G protein-coupled receptors, B1 and B2 receptors (B1R, B2R). Recent pre-clinical findings suggest a primary role for B1R in a rat model of wet age-related macular degeneration (AMD). The aim of the present study was to investigate whether kinin receptors are differentially expressed in human wet and dry AMD retinae. The cellular distribution of B1R and B2R was examined by immunofluorescence and in situ hybridization in post-mortem human AMD retinae. The association of B1R with inflammatory proteins (inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor A (VEGFA)), fibrosis markers and glial cells was also studied. While B2R mRNA and protein expression was not affected by AMD, a significant increase of B1R mRNA and immunoreactivity was measured in wet AMD retinae when compared to control and dry AMD retinae. B1R was expressed by Müller cells, astrocytes, microglia and endothelial/vascular smooth muscle cells, and colocalized with iNOS and fibrosis markers, but not with VEGFA. In conclusion, the induction and upregulation of the pro-inflammatory and pro-fibrotic kinin B1R in human wet AMD retinae support previous pre-clinical studies and provide a clinical proof-of-concept that B1R represents an attractive therapeutic target worth exploring in this retinal disease. Full article

(This article belongs to the Special Issue Kinins and Their Receptors as Potential Therapeutic Targets —— A Tribute to Professor Domenico Regoli, A Key Figure in the Field of Kinins)

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Review

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13 pages, 547 KiB

Open AccessReview

Kinins and Kinin Receptors in Cardiovascular and Renal Diseases

by Jean-Pierre Girolami, Nadine Bouby, Christine Richer-Giudicelli and Francois Alhenc-Gelas

Pharmaceuticals 2021, 14(3), 240; https://doi.org/10.3390/ph14030240 - 08 Mar 2021

Cited by 14 | Viewed by 2184

Abstract

This review addresses the physiological role of the kallikrein–kinin system in arteries, heart and kidney and the consequences of kallikrein and kinin actions in diseases affecting these organs, especially ischemic and diabetic diseases. Emphasis is put on pharmacological and genetic studies targeting kallikrein; ACE/kininase II; and the two kinin receptors, B1 (B1R) and B2 (B2R), distinguished through the work of Domenico Regoli and his collaborators. Potential therapeutic interest and limitations of the pharmacological manipulation of B1R or B2R activity in cardiovascular and renal diseases are discussed. This discussion addresses either the activation or inhibition of these receptors, based on recent clinical and experimental studies. Full article

(This article belongs to the Special Issue Kinins and Their Receptors as Potential Therapeutic Targets —— A Tribute to Professor Domenico Regoli, A Key Figure in the Field of Kinins)

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25 pages, 2013 KiB

Open AccessFeature PaperReview

Role of Kinins in Hypertension and Heart Failure

by Suhail Hamid, Imane A. Rhaleb, Kamal M. Kassem and Nour-Eddine Rhaleb

Pharmaceuticals 2020, 13(11), 347; https://doi.org/10.3390/ph13110347 - 28 Oct 2020

Cited by 24 | Viewed by 4884

Abstract

The kallikrein–kinin system (KKS) is proposed to act as a counter regulatory system against the vasopressor hormonal systems such as the renin-angiotensin system (RAS), aldosterone, and catecholamines. Evidence exists that supports the idea that the KKS is not only critical to blood pressure but may also oppose target organ damage. Kinins are generated from kininogens by tissue and plasma kallikreins. The putative role of kinins in the pathogenesis of hypertension is discussed based on human mutation cases on the KKS or rats with spontaneous mutation in the kininogen gene sequence and mouse models in which the gene expressing only one of the components of the KKS has been deleted or over-expressed. Some of the effects of kinins are mediated via activation of the B₂ and/or B₁ receptor and downstream signaling such as eicosanoids, nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF) and/or tissue plasminogen activator (T-PA). The role of kinins in blood pressure regulation at normal or under hypertension conditions remains debatable due to contradictory reports from various laboratories. Nevertheless, published reports are consistent on the protective and mediating roles of kinins against ischemia and cardiac preconditioning; reports also demonstrate the roles of kinins in the cardiovascular protective effects of the angiotensin-converting enzyme (ACE) and angiotensin type 1 receptor blockers (ARBs). Full article

(This article belongs to the Special Issue Kinins and Their Receptors as Potential Therapeutic Targets —— A Tribute to Professor Domenico Regoli, A Key Figure in the Field of Kinins)

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28 pages, 3758 KiB

Open AccessReview

Kinins and Their Receptors in Infectious Diseases

by Ana Paula A. Dagnino, Maria M. Campos and Rodrigo B. M. Silva

Pharmaceuticals 2020, 13(9), 215; https://doi.org/10.3390/ph13090215 - 27 Aug 2020

Cited by 19 | Viewed by 6926

Abstract

Kinins and their receptors have been implicated in a series of pathological alterations, representing attractive pharmacological targets for several diseases. The present review article aims to discuss the role of the kinin system in infectious diseases. Literature data provides compelling evidence about the participation of kinins in infections caused by diverse agents, including viral, bacterial, fungal, protozoan, and helminth-related ills. It is tempting to propose that modulation of kinin actions and production might be an adjuvant strategy for management of infection-related complications. Full article

(This article belongs to the Special Issue Kinins and Their Receptors as Potential Therapeutic Targets —— A Tribute to Professor Domenico Regoli, A Key Figure in the Field of Kinins)

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14 pages, 2232 KiB

Open AccessReview

In Vitro Modeling of Bradykinin-Mediated Angioedema States

by François Marceau, Hélène Bachelard, Xavier Charest-Morin, Jacques Hébert and Georges E. Rivard

Pharmaceuticals 2020, 13(9), 201; https://doi.org/10.3390/ph13090201 - 19 Aug 2020

Cited by 4 | Viewed by 3935

Abstract

Kinins (peptides related to bradykinin, BK) are formed from circulating substrates, the kininogens, by the action of two proteases, the kallikreins. The only clinical application of a BK receptor ligand, the B₂ receptor antagonist icatibant, is the treatment of the rare hereditary angioedema (HAE) caused by the deficiency of C1-esterase inhibitor (C1-INH). Less common forms of HAE (genetic variants of factor XII, plasminogen, kininogen) are presumably mediated by increased BK formation. Acquired forms of BK-mediated angioedema, such as that associated with angiotensin-I converting enzyme (ACE) inhibition, are also known. Antibody-based analytical techniques are briefly reviewed, and support that kinins are extremely short-lived, prominently cleared by ACE. Despite evidence of continuous activation of the kallikrein–kinin system in HAE, patients are not symptomatic most of the time and their blood or plasma obtained during remission does not generate excessive immunoreactive BK (iBK), suggesting effective homeostatic mechanisms. HAE-C1-INH and HAE-FXII plasmas are both hyperresponsive to fibrinolysis activation. On another hand, we suggested a role for the alternate tissue kallikrein–kinin system in patients with a plasminogen mutation. The role of the BK B₁ receptor is still uncertain in angioedema states. iBK profiles under in vitro stimulation provide fresh insight into the physiopathology of angioedema. Full article

(This article belongs to the Special Issue Kinins and Their Receptors as Potential Therapeutic Targets —— A Tribute to Professor Domenico Regoli, A Key Figure in the Field of Kinins)

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20 pages, 3813 KiB

Open AccessReview

A Systematic Review of Molecular Imaging Agents Targeting Bradykinin B1 and B2 Receptors

by Joseph Lau, Julie Rousseau, Daniel Kwon, François Bénard and Kuo-Shyan Lin

Pharmaceuticals 2020, 13(8), 199; https://doi.org/10.3390/ph13080199 - 17 Aug 2020

Cited by 27 | Viewed by 5133

Abstract

Kinins, bradykinin and kallidin are vasoactive peptides that signal through the bradykinin B1 and B2 receptors (B1R and B2R). B2R is constitutively expressed in healthy tissues and mediates responses such as vasodilation, fluid balance and retention, smooth muscle contraction, and algesia, while B1R is absent in normal tissues and is induced by tissue trauma or inflammation. B2R is activated by kinins, while B1R is activated by kinins that lack the C-terminal arginine residue. Perturbations of the kinin system have been implicated in inflammation, chronic pain, vasculopathy, neuropathy, obesity, diabetes, and cancer. In general, excess activation and signaling of the kinin system lead to a pro-inflammatory state. Depending on the disease context, agonism or antagonism of the bradykinin receptors have been considered as therapeutic options. In this review, we summarize molecular imaging agents targeting these G protein-coupled receptors, including optical and radioactive probes that have been used to interrogate B1R/B2R expression at the cellular and anatomical levels, respectively. Several of these preclinical agents, described herein, have the potential to guide therapeutic interventions for these receptors. Full article

(This article belongs to the Special Issue Kinins and Their Receptors as Potential Therapeutic Targets —— A Tribute to Professor Domenico Regoli, A Key Figure in the Field of Kinins)

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