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Updates in Kallikrein-Kinin System—KININ2022 Conference
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Updates in Kallikrein-Kinin System—KININ2022 Conference

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Immunology".

Deadline for manuscript submissions: closed (25 August 2023) | Viewed by 6715

Special Issue Editors

Prof. Dr. Christian Drouet

E-Mail Website
Guest Editor
Institut Cochin, INSERM UMR1016, University Paris Cité, Paris, France
Interests: inflammation; kinin forming; kinin catabolism; serpins
Prof. Dr. Alvin Schmaier

E-Mail Website1 Website2
Guest Editor
Hematology and Oncology in Medicine and Pathology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA
Interests: hemostasis; thrombosis; vascular biology; kallikrein/kinin system (KKS); renin angiotensin system (RAS)
Dr. Arije Ghannam

E-Mail Website
Guest Editor
KininX SAS, Grenoble, France
Interests: inflammation-associated diseases; angioedema; kinin system

Special Issue Information

Dear Colleagues,

Kinins are short-lived peptides that cause pain, arteriolar dilation, increased vascular permeability and contractions in smooth muscle. They are generated from kininogens through proteolysis by kallikreins. Together, these proteins and peptides, as well as their regulators, constitute the components of the kallikrein–kinin system (KKS).

Kinin production is dependent upon serine proteases, namely, plasma and tissue kallikreins. A prekallikrein is the precursor of plasma kallikrein that liberates bradykinin after it is activated by factor XIIa or enzymes. The activation and activity of both plasma kallikrein and factor XIIa are under the control of inhibitor C1, a serine protease inhibitor (serpin) protein. A deficiency of inhibitor C1 presents as a disorder of hereditary angioedema, a condition where there is less regulation of the production of vasoactive peptide bradykinin.

Kinins are inactivated by metallo-peptidases, such as: (i) carboxypeptidases, alias kininase I, that are present in two forms, circulating carboxypeptidase N and membrane-bound carboxypeptidase M, which remove C-terminal arginine residues of kinins; (ii) angiotensin-I-converting enzyme, alias kininase II, inactivating a number of peptide mediators, including bradykinin; (iii) aminopeptidase P that inactivates desArg9-kinins; (iv) neutral endopeptidase, which also deactivates kinins.

Kinin receptors B2 (constitutive) and B1 (inducible) are G-protein-coupled receptors that mediate activation signals through multiple tissues, including endothelial cells.

Kinins are directly, or indirectly, involved in many inflammatory diseases. If defects of the KKS in diseases are not generally recognized, the gain-of-function of one of the KKS component has been recognized to participate in hereditary angioedema. The KKS has been the subject of much research due to its relationship to inflammation and blood pressure systems. Kinins are generally considered to be inflammatory mediators, the accumulation of which causes the dilation of blood vessels, increased vascular permeability and pain, due to acting on phospholipase, with a subsequent release of arachidonic acid and prostaglandin production.

Similar to the KININ2022 conference, this research topic aims to expand on current knowledge data, recent progress and future plans in the field of kinins and the KKS, along with their relationships to diseases.

Within this Special Issue, we hope to publish original research articles, reviews, systematic reviews, mini reviews, methods, policy and practice reviews, hypotheses and theories, perspectives, clinical trials, case reports and community case studies, classifications, data reports, policy briefs, brief research reports, study protocols and Opinion articles, all of which would cover:

  • Kallikrein–kinin system in biology;
  • Kinin receptors: pharmacology, signalling and regulation;
  • Animal models;
  • Kallikrein–kinin system in diseases;
  • Kallikrein–kinin system: drugs, inhibitors and antagonists.

We look forward to your participation. Thank you for your consideration.

Prof. Dr. Christian Drouet
Prof. Dr. Alvin Schmaier
Dr. Arije Ghannam
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • kallikrein-kinin system
  • kinin receptors
  • kinin catabolism
  • ACE inhibitors
  • Kinin biomarkers
  • kinin analysis
  • hereditary angioedema
  • C1 inhibitor and SERPING1 gene
  • bladder detrusor muscle
  • diabetic macular edema
  • retinal pathologies
  • host/parasite relationship

Published Papers (5 papers)

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Editorial

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5 pages, 218 KiB  
Editorial
Editorial: Kinin 2022 Meeting, Annecy, France
by Alvin H. Schmaier, Arije Ghannam and Christian Drouet
J. Clin. Med. 2023, 12(9), 3276; https://doi.org/10.3390/jcm12093276 - 04 May 2023
Viewed by 911
Abstract
The Kinin 2022 meeting took place at the Imperial Palace, Annecy, France, from 5–8 June 2022 [...] Full article
(This article belongs to the Special Issue Updates in Kallikrein-Kinin System—KININ2022 Conference)

Research

Jump to: Editorial

13 pages, 1131 KiB  
Article
Recessive SERPING1 Variant Leads to Kinin–Kallikrein System Control Failure in a Consanguineous Brazilian Family with Hereditary Angioedema
by Luana Sella Motta Maia, Bettina Burger, Arije Ghannam, Fernanda Leonel Nunes, Mariana Paes Leme Ferriani, Marina Mendonça Dias, Luisa Karla Arruda, Christian Drouet and Sven Cichon
J. Clin. Med. 2023, 12(23), 7299; https://doi.org/10.3390/jcm12237299 - 24 Nov 2023
Cited by 1 | Viewed by 799
Abstract
Background: Hereditary angioedema (HAE) is a severe and potentially life-threatening disease. The most common forms are caused by variants in SERPING1, resulting in C1-inhibitor (C1-INH) deficiency (HAE-C1-INH). C1-INH is a serine protease inhibitor (SERPIN) that regulates multiple proteases pathways, including the [...] Read more.
Background: Hereditary angioedema (HAE) is a severe and potentially life-threatening disease. The most common forms are caused by variants in SERPING1, resulting in C1-inhibitor (C1-INH) deficiency (HAE-C1-INH). C1-INH is a serine protease inhibitor (SERPIN) that regulates multiple proteases pathways, including the kallikrein–kinin system (KKS) and its complement. In HAE-C1-INH patients, C1-INH deficiencies affect KKS control, resulting in the development of kallikrein activity in plasma and the subsequent release of bradykinin (BK). While the overwhelming majority of disease-causing SERPING1 variants are dominant, very few recessive variants have been described. We present a large Brazilian HAE-C1-INH family with a recessive form of HAE-C1-INH. Methods: Blood samples of family members were investigated for protein levels of C1-INH, C4, C1q, and C1-INH function. The SERPING1 gene was sequenced. Results: In two severely affected sisters, we identified a homozygous missense variant in SERPING1 (NM_000062.3:c.964G>A;p.Val322Met). Fourteen family members were asymptomatic heterozygous carriers of the variant. Data regarding C1-INH function in the plasma showed that homozygous p.Val322Met strongly impacts C1-INH function to inhibit C1s and kallikrein (PKa). When heterozygously expressed, it affects the C1-INH control of C1s more than that of PKa. Conclusions: These studies of the variant’s effects on the structure–function relationship reinforce prior observations suggesting that C1-INH deficiency is a conformational disease. Full article
(This article belongs to the Special Issue Updates in Kallikrein-Kinin System—KININ2022 Conference)
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17 pages, 3965 KiB  
Article
Prevention of Inflammation, Neovascularization, and Retinal Dysfunction by Kinin B1 Receptor Antagonism in a Mouse Model of Age-Related Macular Degeneration
by Menakshi Bhat, Shima Shirzad, Abdel-Rahamane Kader Fofana, Fernand Gobeil, Jr., Réjean Couture and Elvire Vaucher
J. Clin. Med. 2023, 12(19), 6213; https://doi.org/10.3390/jcm12196213 - 26 Sep 2023
Viewed by 1062
Abstract
The kallikrein-kinin system (KKS) contributes to vascular inflammation and neovascularization in age-related macular degeneration (AMD), particularly via the kinin B1 receptor (B1R). The aim of the present study was to determine the protective effects of the topical administration of the [...] Read more.
The kallikrein-kinin system (KKS) contributes to vascular inflammation and neovascularization in age-related macular degeneration (AMD), particularly via the kinin B1 receptor (B1R). The aim of the present study was to determine the protective effects of the topical administration of the B1R antagonist (R-954) on inflammation, neovascularization, and retinal dysfunction in a murine model of neovascular AMD. Choroidal neovascularization (CNV) was induced in C57BL6 mice using an argon laser. A treatment with ocular drops of R-954 (100 μg/15 μL, twice daily in both eyes), or vehicle, was started immediately on day 0, for 7, 14, or 21 days. CNV, invasive microglia, and B1R immunoreactive glial cells, as well as electroretinography alterations, were observed within the retina and choroid of the CNV group but not in the control group. The staining of B1R was abolished by R-954 treatment as well as the proliferation of microglia. R-954 treatment prevented the CNV development (volume: 20 ± 2 vs. 152 ± 5 × 104 µm3 in R-954 vs. saline treatment). R-954 also significantly decreased photoreceptor and bipolar cell dysfunction (a-wave amplitude: −47 ± 20 vs. −34 ± 14 µV and b-wave amplitude: 101 ± 27 vs. 64 ± 17 µV in R-954 vs. saline treatment, day 7) as well as angiogenesis tufts in the retina. These results suggest that self-administration of R-954 by eye-drop treatment could be a promising therapy in AMD to preserve retinal health and vision. Full article
(This article belongs to the Special Issue Updates in Kallikrein-Kinin System—KININ2022 Conference)
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22 pages, 5450 KiB  
Article
Genetic Ablation and Pharmacological Blockade of Bradykinin B1 Receptor Unveiled a Detrimental Role for the Kinin System in Chagas Disease Cardiomyopathy
by Ana Carolina Oliveira, Amanda Roberta Revoredo Vicentino, Daniele Andrade, Isabela Resende Pereira, Leonardo Saboia-Vahia, Otacílio da Cruz Moreira, Carla Eponina Carvalho-Pinto, Julia Barbalho da Mota, Leonardo Maciel, Glaucia Vilar-Pereira, João B. Pesquero, Joseli Lannes-Vieira, Pierre Sirois, Antônio Carlos Campos de Carvalho and Julio Scharfstein
J. Clin. Med. 2023, 12(8), 2888; https://doi.org/10.3390/jcm12082888 - 15 Apr 2023
Cited by 2 | Viewed by 1609
Abstract
Chagas disease, the parasitic infection caused by Trypanosoma cruzi, afflicts about 6 million people in Latin America. Here, we investigated the hypothesis that T. cruzi may fuel heart parasitism by activating B1R, a G protein-coupled (brady) kinin receptor whose expression is upregulated [...] Read more.
Chagas disease, the parasitic infection caused by Trypanosoma cruzi, afflicts about 6 million people in Latin America. Here, we investigated the hypothesis that T. cruzi may fuel heart parasitism by activating B1R, a G protein-coupled (brady) kinin receptor whose expression is upregulated in inflamed tissues. Studies in WT and B1R−/− mice showed that T. cruzi DNA levels (15 days post infection—dpi) were sharply reduced in the transgenic heart. FACS analysis revealed that frequencies of proinflammatory neutrophils and monocytes were diminished in B1R−/− hearts whereas CK-MB activity (60 dpi) was exclusively detected in B1R+/+ sera. Since chronic myocarditis and heart fibrosis (90 dpi) were markedly attenuated in the transgenic mice, we sought to determine whether a pharmacological blockade of the des-Arg9-bradykinin (DABK)/B1R pathway might alleviate chagasic cardiomyopathy. Using C57BL/6 mice acutely infected by a myotropic T. cruzi strain (Colombian), we found that daily treatment (15–60 dpi) with R-954 (B1R antagonist) reduced heart parasitism and blunted cardiac injury. Extending R-954 treatment to the chronic phase (120–160 dpi), we verified that B1R targeting (i) decreased mortality indexes, (ii) mitigated chronic myocarditis, and (iii) ameliorated heart conduction disturbances. Collectively, our study suggests that a pharmacological blockade of the proinflammatory KKS/DABK/B1R pathway is cardioprotective in acute and chronic Chagas disease. Full article
(This article belongs to the Special Issue Updates in Kallikrein-Kinin System—KININ2022 Conference)
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15 pages, 2325 KiB  
Article
Peptides Derived from a Plant Protease Inhibitor of the Coagulation Contact System Decrease Arterial Thrombus Formation in a Murine Model, without Impairing Hemostatic Parameters
by Daniel Alexandre De Souza, Bruno Ramos Salu, Ruben Siedlarczyk Nogueira, José Carlos Sá de Carvalho Neto, Francisco Humberto de Abreu Maffei and Maria Luiza Vilela Oliva
J. Clin. Med. 2023, 12(5), 1810; https://doi.org/10.3390/jcm12051810 - 23 Feb 2023
Cited by 3 | Viewed by 1320
Abstract
Several plant protein inhibitors with anticoagulant properties have been studied and characterized, including the Delonix regia trypsin inhibitor (DrTI). This protein inhibits serine proteases (trypsin) and enzymes directly involved in coagulation, such as plasma kallikrein, factor XIIa, and factor XIa. In this study, [...] Read more.
Several plant protein inhibitors with anticoagulant properties have been studied and characterized, including the Delonix regia trypsin inhibitor (DrTI). This protein inhibits serine proteases (trypsin) and enzymes directly involved in coagulation, such as plasma kallikrein, factor XIIa, and factor XIa. In this study, we evaluated the effects of two new synthetic peptides derived from the primary sequence of DrTI in coagulation and thrombosis models to understand the mechanisms involved in the pathophysiology of thrombus formation as well as in the development of new antithrombotic therapies. Both peptides acted on in vitro hemostasis-related parameters, showing promising results, prolonging the Partially Activated Thromboplastin Time (aPTT) and inhibited platelet aggregation induced by adenosine diphosphate (ADP) and arachidonic acid. In murine models, for arterial thrombosis induced by photochemical injury, and platelet-endothelial interactions monitored by intravital microscopy, both peptides at doses of 0.5 mg/kg significantly extended the time of artery occlusion and modified the platelet adhesion and aggregation pattern with no changes in bleeding time, demonstrating the high biotechnological potential of both molecules. Full article
(This article belongs to the Special Issue Updates in Kallikrein-Kinin System—KININ2022 Conference)
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