Kinin Receptors in Vascular Biology and Pathology

Abstract

Endogenous kinins are important vasoactive peptides whose effects are mediated by two G-Protein-coupled receptors (R), named B2R (constitutive) and B1R (inducible). They are involved in vascular homeostasis, ischemic pre- and post- conditioning, but also in cardiovascular diseases. They contribute 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, which are associated with the release of endothelial factors such as nitric oxide, prostacyclin and tissue plasminogen activator. 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 virtually absent in healthy tissues, yet this receptor is induced by the cytokine pathway and the oxidative stress via the transcriptional nuclear factor NF-κB. The B1R may play a compensatory role for the lack of B2R, and its up-regulation during tissue damage may be a useful mechanism of host defense. 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 an unsettled issue on the therapeutic value of B1R/B2R agonists versus antagonists in cardiovascular diseases. Hence, the Janus-face of kinin receptors needs to be seriously addressed in the upcoming clinical trials for each pathological setting.

Novel Innate Immune Genes Regulating the Macrophage Response to Gram Positive Bacteria

“…Both bradykinin receptors were identified in the TNF-a response to LTA in our mapping study. Bdkrb1 gene inhibition led to decreased and Bdkrb2 gene inhibition to increased cytokine production in response to LTA stimulation in cultured macrophages, consistent with the complementary roles of these two receptors (Couture et al 2014). Our study is the first to demonstrate a role for kinin receptors in the response to Gram positive bacterial stimulation.…”

“…Bradykinin receptor genes encode two G-protein-coupled receptors, inducible BDKRB1, and constitutive BDKRB2, that respond to endogenous kinin ligands as well as cytokines via the NF-kB pathway in the case of inducible BDKRB1 (Couture et al 2014). Both bradykinin receptors were identified in the TNF-a response to LTA in our mapping study.…”

“…Bradykinin 1 receptor (Bdkrb1) has a well-established role in the regulation of inflammation, particularly in the brain (Albert-Weissenberger et al 2014), cardiovascular system (Couture et al 2014), and the lung (Yang et al 2014). Bradykinin receptor genes encode two G-protein-coupled receptors, inducible BDKRB1, and constitutive BDKRB2, that respond to endogenous kinin ligands as well as cytokines via the NF-kB pathway in the case of inducible BDKRB1 (Couture et al 2014).…”

A primary role for kinin B1 receptor in inflammation, organ damage, and lethal thrombosis in a rat model of septic shock in diabetes

“…5,6 Diabetes mellitus and septic shock increase the production of reactive oxygen species (ROS) and pro-inflammatory cytokines, involving particularly the kallikrein-kinin system. 7 Kinin B1 receptor (B1R), an important component of this system, is upregulated by endotoxins and may represent a therapeutic target in sepsis, yet its contribution in the acute phase of lipopolysaccharide (LPS)-induced endotoxin shock remains controversial. [8][9][10][11][12] Hypotension, renal failure, and mortality were increased by LPS in B1R knockout mice as a possible consequence of supra activation of kinin B2 receptor (B2R).…”

2D-LC–MS/MS to Measure Cleaved High-Molecular-Weight Kininogen in Human Plasma as A Biomarker for C1-Inh-Hae

“…The 56 kDa light chain in cHMWK (denoted 56 kDa cHMWK) can be further cleaved by plasma kallikrein at the N-terminal por-2D-LC-MS/MS to measure cleaved highmolecular-weight kininogen in human plasma as a biomarker for C1-INH-HAE Guodong (Figure 1) [9][10][11][12]. The bradykinin released from HMWK acts as a key mediator of pain, inflammation, edema and angiogenesis [13]. Dysregulated plasma kallikrein proteolysis of HMWK can result in accumulation of bradykinin, which induces vasopermeability resulting in the edematous attacks associated with C1-INH-HAE [12,[14][15][16][17].…”