Development of diabetic cardiomyopathy and the kallikrein-kinin system – new insights from B1 and B2 receptor signaling

2008 ◽  
Vol 389 (6) ◽  
Author(s):  
Carsten Tschöpe ◽  
Dirk Westermann
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Calcium Handling ◽  
Kinin System ◽  
Cardiac Inflammation ◽  
B1 Receptor ◽  
Kinin Receptors ◽  
Patients With Diabetes ◽  
Underlying Mechanisms ◽  
Kallikrein Kinin System

Abstract Diabetic cardiomyopathy is a specific cardiomyopathy which develops in patients with diabetes mellitus in the absence of coronary atherosclerosis and hypertension. Despite the potential importance of this disease entity, the underlying mechanisms are only incompletely understood. Changes in calcium handling, disruption of the extracellular matrix regulation with accumulation of cardiac collagen, and furthermore cardiac inflammation may be an important mediator of this disease. This brief review focuses on the current aspects of the kallikrein-kinin system and its influence on the development of diabetic cardiomyopathy with particular regard to the kinin receptors B1 and B2, as their role in the development of this disease is still under discussion. Whether the role of the B1 receptor is similar to the well-described beneficial role of the B2 receptor or whether its function is opposed to the B2 receptor is controversial. Some recent findings suggest that the B1 receptor mediates cardiac inflammation and therefore may be detrimental for cardiac function in the setting of diabetic cardiomyopathy.

scholarly journals Kinins and Kinin Receptors in Cardiovascular and Renal Diseases

2021 ◽  
Vol 14 (3) ◽  
pp. 240
Author(s):  
Jean-Pierre Girolami ◽  
Nadine Bouby ◽  
Christine Richer-Giudicelli ◽  
Francois Alhenc-Gelas
Keyword(s):  
Experimental Studies ◽  
Physiological Role ◽  
Renal Diseases ◽  
Kinin System ◽  
Genetic Studies ◽  
Pharmacological Manipulation ◽  
Kininase Ii ◽  
Kinin Receptors ◽  
Kallikrein Kinin System

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.

scholarly journals Exendin-4 Protects against Hyperglycemia-Induced Cardiomyocyte Pyroptosis via the AMPK-TXNIP Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Hong Wei ◽  
Rui Bu ◽  
Qinghui Yang ◽  
Jing Jia ◽  
Tao Li ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
High Fat Diet ◽  
Rna Silencing ◽  
Diabetic Heart ◽  
Cardiac Inflammation ◽  
Caspase 1 ◽  
Signaling Mechanisms ◽  
Patients With Diabetes ◽  
Cardiac Condition

Diabetic cardiomyopathy is a common cardiac condition in patients with diabetes mellitus, which results in cardiac hypertrophy and subsequent heart failure. Chronic inflammation in the diabetic heart results in loss of cardiomyocytes and subsequentially cardiac dysfunction. Accumulated evidence implicated pyroptosis as a vital contributor to the hyperglycemia-induced cardiac inflammatory response. Exendin-4, a GLP analog, promotes survival of cardiomyocytes in cardiovascular diseases, including diabetic cardiomyopathy. However, the role of Exendin-4 in cardiac pyroptosis remains to be elucidated. Our study revealed that Exendin-4 treatment protected against heart remolding and dysfunction and attenuated cardiac inflammation in high-fat diet-fed rats. The activity of caspase-1 and production of pyroptotic cytokines were significantly inhibited by Exendin-4 treatment in the diabetic heart and in high glucose-treated cardiomyocytes as well. In an effort to understand the signaling mechanisms underlying the antipyroptotic property of Exendin-4, we found that blockade of AMPK, an oxidative stress sensor, activity diminished the antipyroptotic property of Exendin-4. Phosphorylation of AMPK resulted in degeneration of TXNIP that promoted the activation of the NLRP3 inflammasome. Exendin-4 treatment decreased the protein level of TXNIP. Moreover, RNA silencing of TXNIP mimicked the antipyroptotic actions of Exendin-4. These findings promoted us to propose a new signaling pathway mediating cardioprotective effect of Exendin-4 under hyperglycemic conditions: Exendin-4 → ROS↓ → pAMPK↑ → TXNIP↓ → caspase-1↓ → IL-1β and IL-18↓ → pyroptosis↓. In general, our study identified Exendin-4 as a pyroptotic inhibitor protecting against hyperglycemia-induced cardiomyocyte pyroptosis via the AMPK-TXNIP pathway.

scholarly journals In Vitro Modeling of Bradykinin-Mediated Angioedema States

2020 ◽  
Vol 13 (9) ◽  
pp. 201
Author(s):  
François Marceau ◽  
Hélène Bachelard ◽  
Xavier Charest-Morin ◽  
Jacques Hébert ◽  
Georges E. Rivard
Keyword(s):  
Analytical Techniques ◽  
Ace Inhibition ◽  
Factor Xii ◽  
Kinin System ◽  
Angiotensin I Converting Enzyme ◽  
B1 Receptor ◽  
Kallikrein Kinin System ◽  
Esterase Inhibitor

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.

scholarly journals The bradykinin system in stress and anxiety in humans and mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ari Rouhiainen ◽  
Natalia Kulesskaya ◽  
Marie Mennesson ◽  
Zuzanna Misiewicz ◽  
Tessa Sipilä ◽  
...  
Keyword(s):  
Anxiety Disorders ◽  
Stress Responses ◽  
Receptor Gene ◽  
Kinin System ◽  
Mediated Effects ◽  
B1 Receptor ◽  
Brown Adipose ◽  
Approach Avoidance ◽  
Kallikrein Kinin System

AbstractPharmacological 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.

Role of kallikrein-kinin system in pathogenesis of bacterial cell wall-induced inflammation

1991 ◽  
Vol 260 (2) ◽  
pp. G213-G219 ◽  
Author(s):  
R. A. DeLa Cadena ◽  
K. J. Laskin ◽  
R. A. Pixley ◽  
R. B. Sartor ◽  
J. H. Schwab ◽  
...  
Keyword(s):  
Cell Wall ◽  
Acute Phase ◽  
Bacterial Cell ◽  
Chronic Phase ◽  
Bacterial Cell Wall ◽  
Kinin System ◽  
Kallikrein Kinin System ◽  
Bacterial Products

The plasma kallikrein-kinin system is activated in Gram-negative sepsis and typhoid fever, two diseases in which bacterial products have been shown to initiate inflammation. Because a single intraperitoneal injection of bacterial cell wall peptidoglycan-polysaccharide polymers from group A steptococci (PG-APS) into a Lewis rat produces a syndrome of relapsing polyarthritis and anemia, we investigated changes in the role of the kallikrein-kinin system in this model of inflammation. Coagulation studies after injection of PG-APS revealed an immediate and persistent decrease in prekallikrein levels. High-molecular-weight kininogen levels decreased significantly during the acute phase and correlated with the severity of arthritis. Factor XI levels were decreased only during the acute phase. Antithrombin III levels remained unchanged, indicating that neither decreased hepatic synthesis nor disseminated intravascular coagulation caused the decreased plasma contact factors. Plasma T-kininogen (an acute phase protein) was significantly elevated during the chronic phase. PG-APS failed to activate the contact system in vitro. Thus the kallikrein-kinin system plays an important role in this experimental model of inflammation, suggesting that activation of this system may play a role in the pathogenesis of inflammatory bowel disease and rheumatoid arthritis in which bacterial products might be etiologically important.

Expression and cellular localization of tissue kallikrein-kinin system in human adrenal gland

1996 ◽  
Vol 271 (3) ◽  
pp. F709-F716 ◽  
Author(s):  
D. Z. Wang ◽  
Q. Song ◽  
L. M. Chen ◽  
L. Chao ◽  
J. Chao
Keyword(s):  
Adrenal Gland ◽  
Cellular Localization ◽  
Zona Glomerulosa ◽  
Zona Fasciculata ◽  
Tissue Kallikrein ◽  
Kinin System ◽  
B1 Receptor ◽  
B2 Receptors ◽  
Kallikrein Kinin System

The tissue kallikrein-kinin system has been implicated in regulating blood pressure and electrolyte homeostasis. To understand the function of this system, we identified the expression and cellular localization of its components including tissue kallikrein, kallistatin, kininogen, and bradykinin B1 and B2 receptors in human adrenal gland. Reverse transcription-polymerase chain reaction followed by Southern blot analysis showed that these five components of this system were all expressed in human adrenal gland. In situ hybridization histochemistry with respective digoxigenin-labeled antisense riboprobes revealed localization of kallikrein transcript throughout the adrenal cortex and medulla except the zona glomerulosa, whereas kallistatin mRNA was only localized in the zona fasciculata. Low-molecular-weight kininogen and B2 receptor mRNAs were colocalized in the zona glomerulosa and zona fasciculata and also in the zona reticularis and chromaffin cells but to a lesser degree. The B1 receptor mRNA was stained in the zona fasciculata and medulla. These results show the expression and differential colocalization of the components of the tissue kallikrein-kinin system and reveal the potential action sites of this system in the adrenal gland.

The dual role of the contact system in bacterial infectious disease

2007 ◽  
Vol 98 (09) ◽  
pp. 497-502 ◽  
Author(s):  
Inga-Maria Frick ◽  
Lars Björck ◽  
Heiko Herwald
Keyword(s):  
Vascular Endothelium ◽  
Blood Cells ◽  
State Of The Art ◽  
Contact System ◽  
Intrinsic Pathway ◽  
Kinin System ◽  
Inflammatory Reactions ◽  
Bacterial Infectious Disease ◽  
Kallikrein Kinin System

SummaryHemostasis is a sensitive and tightly regulated process, involving the vascular endothelium and blood cells as well as factors of the coagulation and fibrinolytic cascades. Over the last four decades evidence has accumulated that during infection, inflammatory mediators from the microbe and/or host are capable to modulate the equilibrium between the procoagulant and anticoagulant status of the host. Dependent on the mode of activation, these changes can cause either local or systemic inflammatory reactions that may be beneficial or deleterious to the human host. The present review aims to present the state of the art with respect to the role of the contact system (also known as the intrinsic pathway of coagulation or the kallikrein/kinin system) in innate immunity and systemic inflammatory reactions.

scholarly journals Antihypertensive effect of MK-421 in rats. Role of the renal kallikrein-kinin system.

Hypertension ◽  
1984 ◽  
Vol 6 (2_pt_1) ◽  
pp. 229-235 ◽  
Author(s):  
M Yasujima ◽  
K Abe ◽  
M Tanno ◽  
Y Kasai ◽  
J Tajima ◽  
...  
Keyword(s):  
Antihypertensive Effect ◽  
Kinin System ◽  
Renal Kallikrein ◽  
Kallikrein Kinin System
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