Bradykinin receptors

Endogenous kinins are important vasoactive peptides whose actions are mediated by G protein-coupled receptors (R), B2R (constitutive) and B1R (inducible). They are involved in vascular homeostasis, ischemic pre- and post-treatment, and cardiovascular disease and contribute to the therapeutic effects of angiotensin-1 converting enzyme inhibitors (ACEIs) and angiotensin AT1 receptor blockers.

The action of bradykinin receptors results primarily in vasodilator, antiproliferative, antihypertrophic, antifibrotic, antithrombotic, and antioxidant properties associated with the release of endothelial factors such as nitric oxide, prostacyclin, and tissue plasminogen activator.

Uncontrolled production of kinins or inhibition of their metabolism may lead to undesirable proinflammatory side effects. Therefore, B2R antagonism is beneficial in angioedema (effect of icatibant), septic shock, stroke, and Chagas vasculopathy.

B1R is virtually absent in healthy tissue, but this receptor is induced by the cytokine pathway and oxidative stress via the transcriptional nuclear factor NF-κB. Activation of both receptors is particularly observed in neovascularization, angiogenesis, cardiac ischemia, and diabetic nephropathy.

At the same time, B1R is a potent activator of inducible nitric oxide and NADPH oxidase, which have been associated with vascular inflammation, increased permeability, insulin resistance, endothelial dysfunction, and diabetic complications (Couture R et al. 2014).

B1 receptor: Bradykinin receptor B1 (B1) is a G protein-coupled receptor that in humans is encoded by the BDKRB1 gene. Its major ligand is bradykinin, a 9 amino acid peptide produced in pathophysiological conditions such as inflammation, trauma, burns, shock and allergy. The B1 receptor, like the B2 receptor, binds bradykinin and mediates responses to various pathophysiological conditions.Binding to the receptor causes an increase in cytosolic calcium ion concentration, ultimately leading to chronic and acute inflammatory responses.

B2 receptor: The B2 receptor is also a G protein-coupled receptor whose activation leads to stimulation of phospholipase C, increasing free intracellular calcium. In addition, the receptor stimulates mitogen-activated protein kinase pathways. It is ubiquitously and constitutively expressed in healthy tissues.

The B2 receptor forms a complex with angiotensin-converting enzyme (ACE), which is thought to play a role in interactions between the renin-angiotensin system (RAS) and the kinin-kallikrein system (KKS). The heptapeptide angiotensin also potentiates the action of bradykinin on B2 receptors.

BDKRB2 as an oncogene: Remarkably, bradykinin receptor B2 (BDKRB2) functions as an oncogene in several malignancies. For example, it is expressed at higher levels in gliomas, among others (Yang Y et al. 2021). Higher BDKRB2 expression indicates significantly shorter survival of glioma patients, suggesting that BDKRB2 is associated with a more aggressive phenotype of gliomas (Yang Y et al. 2021).

B1 and B2 receptor in sepsis: During sepsis, the endothelial barrier becomes insufficient, and leakage of plasma into the interstitial tissue occurs. Kinins released during sepsis cause vascular leakage and vasodilatation. They act through B1 (B1R) and B2 (B2R). B1R is inducible in the presence of proinflammatory cytokines, endotoxins, or after tissue injury. It acts at a later stage of sepsis and induces a sustained inflammatory response (Ruiz S et al 2020).

Icatibant is a second-generation B2 receptor antagonist with limited use in clinical trials for the treatment of pain and inflammation. Its skin indication, however, is "hereditary angioedema."

1. Couture R et al (2014) Kinin receptors in vascular biology and pathology. Curr Vasc Pharmacol 12:223-248.
2. Ruiz S et al (2020) Kinin B1 receptor: a potential therapeutic target in sepsis-induced vascular hyperpermeability. J Transl Med18:174.
3. Yang Y et al. (2021) BDKRB2 is a novel EMT-related biomarker and predicts poor survival in glioma. Aging (Albany NY) 13: 7499-7516.