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kinin [Gk] kīn(eîn) to move, set in motion. kallikrein [Gk ] kalli~ sweet and krein = kreos, flesh, named for the pancreatic extracts where it was first discovered[5][citation needed]
The system consists of a number of large proteins, some small polypeptides and a group of enzymes that activate and deactivate the compounds.[citation needed]
HMWK is produced by the liver together with prekallikrein (see below). It acts mainly as a cofactor on coagulation and inflammation, and has no intrinsic catalytic activity.
LMWK is produced locally by numerous tissues, and secreted together with tissue kallikrein.
Bradykinin (BK), which acts on the B2 receptor and slightly on B1, is produced when kallikrein releases it from HMWK. It is a nonapeptide (9 amino acids) with the amino acid sequence Arg–Pro–Pro–Gly–Phe–Ser–Pro–Phe–Arg.
Kallidin (KD) is released from LMWK by tissue kallikrein. It is a decapeptide. KD has the same amino acid sequence as Bradykinin with the addition of a Lysine at the N-terminus, thus is sometimes referred to as Lys-Bradykinin.
HMWK and LMWK are formed by alternative splicing of the same gene.[6]
Kallikreins (tissue and plasma kallikrein) are serine proteases that liberate kinins[7] (BK and KD) from the kininogens, which are plasma proteins that are converted into vasoactive peptides.[8]Prekallikrein is the precursor of plasma kallikrein. It can only activate kinins after being activated itself by factor XIIa or other stimuli.
Inhibition of ACE with ACE inhibitors leads to decreased conversion of angiotensin I to angiotensin II (a vasoconstrictor) but also to an increase in bradykinin due to decreased degradation. This explains why some patients taking ACE inhibitors develop a dry cough, and some react with angioedema, a dangerous swelling of the head and neck region.[citation needed]
Defects of the kinin-kallikrein system in diseases are not generally recognized. The system is the subject of much research due to its relationship to the inflammation and blood pressure systems. It is known that kinins are inflammatory mediators that cause dilation of blood vessels and increased vascular permeability. Kinins are small peptides produced from kininogen by kallikrein and are broken down by kininases. They act on phospholipase and increase arachidonic acid release and thus prostaglandin (PGE2) production.[citation needed]
C1-inhibitor is a serine protease inhibitor (serpin) protein. C1-INH is the most important physiological inhibitor of plasma kallikrein, fXIa and fXIIa. C1-INH also inhibits proteinases of the fibrinolytic, clotting, and kinin pathways. Deficiency of C1-INH permits plasma kallikrein activation, which leads to the production of the vasoactive peptide bradykinin.[citation needed]
The kinin–kallikrein system (KKS) is an enzymatic cascade comprising plasma proteins and tissue enzymes that generate vasoactive kinins, primarily bradykinin (BK) and lysyl-bradykinin (kallidin), from precursor kininogens, thereby regulating key physiological processes such as inflammation, blood pressure control, hemostasis, and renal function.[1][2] The system interacts with other pathways, including the renin-angiotensin-aldosterone system, coagulation cascade, and complement system, to maintain vascular homeostasis and respond to injury.[1]Central to the KKS are two main kininogen substrates—high-molecular-weight kininogen (HK) and low-molecular-weight kininogen (LK)—both synthesized in the liver from the KNG1 gene via alternative splicing, serving as precursors for kinin release.[2] The primary enzymes are serine proteases: plasma kallikrein, derived from prekallikrein (PK) activation, which cleaves HK to produce BK; and tissue kallikrein (KLK1), which predominantly liberates kallidin from LK in various tissues.[2] These kinins exert effects by binding to G-protein-coupled receptors, notably the constitutive B2 receptor (B2R) for vasodilation and the inducible B1 receptor (B1R) for inflammatory responses.[1] Kinins are rapidly degraded by enzymes like angiotensin-converting enzyme (ACE) to prevent excessive activity.[2]The KKS operates through two interconnected pathways: the plasma pathway, part of the contact activation system, where factor XII (FXII) autoactivates on negatively charged surfaces to convert PK to plasma kallikrein, which then releases BK from HK; and the tissue pathway, involving KLK1 acting locally in organs like the kidney and pancreas to generate kallidin from LK.[2] Regulation occurs via inhibitors such as C1-esterase inhibitor for the plasma arm and kallistatin for tissue kallikrein, ensuring balanced kinin production.[2] Dysregulation of these pathways can lead to conditions like hereditary angioedema due to C1-inhibitor deficiency or adverse effects from ACE inhibitors, highlighting the system's clinical relevance.[1]
Overview
Definition and Scope
The kinin–kallikrein system (KKS) is an endogenous multiprotein proteolytic cascade comprising serine proteases known as kallikreins, which cleave kininogen substrates, including high- and low-molecular-weight kininogens, to liberate vasoactive kinins such as bradykinin and kallidin.[3] This system functions as a key regulatory pathway in mammalian physiology, generating peptide mediators that exert diverse effects through interactions with G-protein-coupled receptors.[4]The scope of the KKS encompasses two primary branches: the plasma branch, activated via contact with negatively charged surfaces in a process known as contact activation, and the tissue (or glandular) branch, which operates locally in organs such as the kidneys and salivary glands.[3] These branches interconnect with broader physiological processes, including the modulation of inflammation through increased vascular permeability and pain signaling, hemostasis via interactions with the coagulation cascade, and cardiovascular regulation by influencing blood pressure and vascular tone.[4]Evolutionarily, the KKS originated from gene duplications early in mammalian history, with the factor XI gene arising from duplication of the prekallikrein gene, enabling specialized roles in hemostasis alongside kinin generation.[5] Kinins serve as the central mediators of the system's bioactivity, bridging its biochemical cascade to physiological outcomes.[3]
Primary Functions
The kinin–kallikrein system plays essential roles in maintaining physiological homeostasis through the actions of kinins, which serve as key effector peptides. These functions encompass cardiovascular regulation, inflammatory responses, sensory perception, and hemostatic balance, contributing to overall tissue integrity and adaptive responses in healthy organisms.[6]A primary function of the system is the regulation of blood pressure, achieved via kinin-induced vasodilation and natriuresis. Kinins promote the relaxation of vascular smooth muscle, leading to decreased peripheral resistance and lowered arterial pressure. Additionally, they enhance renal sodium excretion, facilitating fluid balance and further supporting hypotensive effects.[4][7]The system also drives inflammatory processes by increasing vascular permeability and recruiting leukocytes to affected tissues. This heightened permeability allows plasma proteins and fluid to extravasate, forming an exudative environment that aids in immune cell infiltration and pathogen clearance. Such actions ensure efficient localized responses without systemic disruption in physiological contexts.[6][8]Furthermore, kinins contribute to nociception and smooth muscle contraction in specific tissues. They sensitize peripheral nerve endings, amplifying pain signals in response to stimuli, which serves as a protective mechanism. In the airways and uterus, kinins induce contraction of smooth muscle, regulating bronchial tone and uterine motility during normal physiological events.[9][7]The kinin–kallikrein system interacts with coagulation and fibrinolysis pathways, modulating clot formation and dissolution. Through cross-talk, it activates procoagulant factors while promoting the breakdown of fibrin deposits, thereby maintaining vascular patency and preventing inappropriate thrombosis.[6][4]
History
Early Discoveries
The initial observations of the kinin–kallikrein system's vasoactive properties date back to 1909, when French physiologists Jean Abelous and Émile Bardier conducted experiments demonstrating that intravenous injections of boiled human urine into dogs caused a pronounced and transient drop in blood pressure. This hypotensive response, which persisted even after urine was heated to denature proteins, indicated the presence of stable, low-molecular-weight factors capable of inducing vasodilation, laying the groundwork for recognizing endogenous vasoactive substances in biological fluids.[10][11]In the mid-1920s, German surgeon and physiologist Fritz Frey advanced these findings by isolating a hypotensive agent from extracts of dog and human pancreas, as well as from urine, during studies on glandular secretions. Frey's work revealed that this substance, which he termed kallikrein—derived from the Greek "kallikreas" meaning pancreas—triggered blood pressure reduction through mechanisms involving smooth muscle relaxation and increased vascular permeability. Collaborating with researchers like Heinrich Kraut and Eugen Werle, Frey's experiments established kallikrein as a proteolytic enzyme originating primarily from pancreatic tissue, though its presence in urine suggested broader distribution.[12]Throughout the 1930s and 1940s, further investigations identified kinin-generating activity in additional exocrine secretions, notably saliva and urine, expanding the understanding of the system's physiological reach. Researchers, including Werle and colleagues, detected kallikrein-like enzymes in salivary glands of mammals, where they liberated hypotensive peptides from precursor proteins, contributing to local vasodilation and fluid secretion. Early bioassays for these peptides relied on measuring blood pressure decreases in anesthetized rabbits or cats following intravenous administration of saliva or urine extracts, providing quantitative evidence of their potency and stability. These assays highlighted the peptides' short half-life and role in inflammatory responses, though their exact chemical nature remained elusive.[13]By 1949, Brazilian physiologists Maurício Rocha e Silva, Waldemar Teixeira Beraldo, and Geraldo Rosenfeld achieved a significant milestone in characterizing early kinin extracts through incubating plasma with proteases from Bothrops jararacasnake venom. This approach yielded a potent, dialyzable hypotensive factor from a plasma globulin precursor, which they assayed for its ability to lower blood pressure in rabbits and contract isolated smooth muscle preparations like guinea pigileum and ratuterus. The extracts demonstrated rapid onset of action and synergy with other vasodilators, confirming the existence of intrinsically releasable peptides central to the system's activity.[14]
Etymology and Key Milestones
The term "kallikrein" originates from the Greek word "kallikreas," meaning pancreas, reflecting the enzyme's initial discovery in pancreatic extracts in the early 20th century.[15] The word "kinin" derives from the Greek "kinein," meaning "to move," due to the peptides' characteristic effects on smooth muscle contraction and motility.[16] "Bradykinin," the primary kinin in the system, combines "brady-" (Greek for "slow") with "kinin," highlighting its prolonged hypotensive and contractile actions compared to other kinins.[16]A pivotal milestone occurred in the 1950s when Brazilian pharmacologist Maurício Rocha e Silva and colleagues isolated bradykinin in 1949, identifying it as a hypotensive nonapeptide generated from plasma globulin by trypsin or snake venoms, such as those from Bothrops jararaca.[17] This discovery, detailed in their landmark paper, established bradykinin as a key vasoactive mediator and spurred research into kinin generation pathways.In the 1960s and 1970s, researchers elucidated the distinct plasma and tissue kallikrein-kinin pathways, with plasma prekallikrein—identified in 1965 by Hathaway et al. as the precursor to plasma kallikrein—emerging as central to contact activation and kinin release in coagulation and inflammation.[18] This period clarified how plasma kallikrein, activated via factor XII, liberates bradykinin from high-molecular-weight kininogen, contrasting with tissue kallikrein's role in local kinin production from low-molecular-weight kininogen.[19]From the 1980s to 2000s, molecular advances included the cloning and sequencing of kininogen genes by 1982, revealing their structure and alternative splicing to produce high- and low-molecular-weight forms.[19] Human tissue kallikrein genes were cloned in the late 1980s, uncovering a multigene family (KLK1-KLK15) on chromosome 19, which expanded understanding of kinin-generating diversity.[20] In the 1990s, bradykinin B2 and B1 receptor genes were cloned (B2 in 1992, B1 in 1994), enabling targeted therapeutics; by the 2010s, antagonists like icatibant gained prominence for hereditary angioedema treatment, underscoring receptor roles in inflammatory disorders.[21][22]Recent 2020s research has illuminated the evolutionary origins of the system, revealing that the prekallikrein gene duplicated to form the factor XI gene during early mammalian evolution, linking kinin formation to hemostasis and providing insights into species-specific variations in coagulation.[23] Further developments include investigations into the KKS's role in COVID-19 pathophysiology via the "bradykinin storm" hypothesis (2020-2021), implicating dysregulated kinin production in vascular leakage and inflammation, and approvals of additional plasma kallikrein inhibitors (e.g., sebetralstat in 2024) for hereditary angioedema management as of 2025.[24][25]
Components
Substrates and Precursors
High-molecular-weight kininogen (HMWK) is a single-chain glycoprotein synthesized primarily in hepatocytes through alternative splicing of the KNG1 gene transcript on chromosome 3, resulting in a 626-amino-acid polypeptide with a molecular mass of approximately 120 kDa after post-translational modifications such as glycosylation.[26] It circulates in plasma at concentrations around 70 µg/mL and serves as the primary precursor for bradykinin, a nonapeptide embedded within its domain 4 (D4) sequence.[26] Structurally, HMWK comprises six distinct domains (D1–D6), where D1–D3 form the heavy chain involved in general protein interactions, D4 harbors the bradykinin moiety, and D5–D6 constitute the light chain; notably, D5 contains histidine-rich motifs that facilitate binding to factor XII, while D6 includes stretches for prekallikrein association, enabling cofactor roles in coagulation.[26]Low-molecular-weight kininogen (LMWK), also derived from the KNG1 gene via alternative splicing that excludes exons encoding the D5–D6 light chain domains of HMWK, is a shorter glycoprotein of about 409 amino acids and 68–70 kDa, produced in the liver and present in plasma as well as various secretions.[27] This form lacks the coagulation cofactor domains but retains the bradykinin/kallidin-releasing sequence in its central region, serving as a precursor primarily for kallidin (Lys-bradykinin), a decapeptide.[28] LMWK is characterized by its potent inhibitory activity against cysteine proteases, mediated by structural homology in its heavy chain domains that bind and suppress thiol-dependent enzymes like papain and cathepsins, contributing to its role beyond kinin generation.[28][27]Prekallikrein (PK), the zymogen precursor to plasma kallikrein, is a single-chain glycoprotein of 619 amino acids and approximately 88 kDa, encoded by the KLKB1 gene located on the long arm of chromosome 4 (4q35).[29] It is biosynthesized in the liver, where it undergoes N-linked glycosylation before secretion into the bloodstream at concentrations of 20–50 µg/mL, remaining inactive until proteolytic activation.[30] Structurally, PK features four apple domains (A1–A4) in its heavy chain for protein interactions, a catalytic serine protease domain in the light chain, and an activation site at Arg371-Ile372, positioning it as a key reservoir for enzymatic activity in the plasma kinin system.[30]Tissue-specific precursors, known as pro-kallikreins, are zymogen forms of kallikrein-related peptidases expressed in glandular tissues, where they are synthesized as pre-pro-enzymes and activated locally.[31] A prominent example in the kinin-kallikrein system is pro-tissue kallikrein (KLK1), encoded by the KLK1 gene on chromosome 19q13.3-q13.4, a 293-amino-acid preproenzyme (262 mature after signal and pro-peptide cleavage) of approximately 33-39 kDa depending on glycosylation, produced in tissues such as kidney, pancreas, and salivary glands.[32][31] These pro-kallikreins, including KLK1, are secreted and activated by cleavage of the pro-peptide, enabling localized kinin release distinct from plasma counterparts. Kinins such as bradykinin and kallidin are released from kininogens like HMWK and LMWK by activated kallikreins derived from these precursors.[26]
Kinins
Kinins are a family of small bioactive peptides central to the kinin-kallikrein system, primarily consisting of bradykinin (BK) and lys-bradykinin (kallidin, KD), which are generated from kininogen precursors.[33][34] These peptides exhibit vasodilatory properties and contribute to various physiological responses, with BK recognized as a highly potent vasodilator.[35]Bradykinin is a nonapeptide with the amino acid sequence Arg¹-Pro²-Pro³-Gly⁴-Phe⁵-Ser⁶-Pro⁷-Phe⁸-Arg⁹.[33] Lys-bradykinin, or kallidin, is a decapeptide featuring an N-terminal lysine residue added to the bradykinin sequence, resulting in Lys¹-Arg²-Pro³-Pro⁴-Gly⁵-Phe⁶-Ser⁷-Pro⁸-Phe⁹-Arg¹⁰; it is rapidly converted to bradykinin by aminopeptidases in circulation.[34][36]Key variants include des-Arg⁹-bradykinin and des-Arg¹⁰-kallidin, formed by cleavage of the C-terminal arginine by carboxypeptidases, with the latter showing preferential distribution in peripheral tissues where tissue-specific processing occurs.[37][38]Kinins are highly unstable in biological fluids, undergoing rapid degradation by kininases such as angiotensin-converting enzyme (ACE, also known as kininase II), which cleaves bradykinin to inactive metabolites like bradykinin-(1-7) and bradykinin-(1-5).[39] The plasma half-life of bradykinin is approximately 34 seconds, reflecting its susceptibility to enzymatic breakdown and limiting its duration of action.[39]
Pathways and Mechanisms
Plasma System Activation
The plasma kinin-kallikrein system in the bloodstream is primarily activated via the contact activation pathway, which begins with the autoactivation of factor XII (also known as Hageman factor), a zymogen circulating in plasma as an inactive precursor. This process is triggered when factor XII binds to and undergoes conformational change on negatively charged surfaces, such as artificial materials like glass or kaolin, or biological entities including bacterial cell walls and polyphosphates released from activated platelets.[40][6] The autoactivation efficiency is notably low in isolation but is markedly enhanced—up to 100-fold—by the presence of high-molecular-weight kininogen (HMWK) and prekallikrein, which facilitate the conversion of factor XII to its enzymatically active form, factor XIIa.[6]Factor XIIa then initiates the amplification cascade by cleaving prekallikrein, a zymogen bound to HMWK in plasma, to produce plasma kallikrein. This activation step occurs with high affinity, reflecting the physiological relevance of surface-bound interactions in vivo. Plasma kallikrein reciprocally activates additional factor XII through heteroactivation, establishing a positive feedback loop that sustains the pathway. Furthermore, plasma kallikrein proteolytically cleaves HMWK in a sequential manner, releasing bradykinin—a nonapeptide kinin that promotes vasodilation and inflammation—as the primary bioactive product, while generating cleaved HMWK (also known as kininogen-1 light chain).[41][6][40]The pathway incorporates additional amplification via factor XI, which is activated by factor XIIa to factor XIa; this step not only enhances contact activation but also integrates the kinin-kallikrein system with the intrinsic coagulation cascade. Activated factor XIa, in turn, promotes the activation of factor IX, leading to the generation of factor Xa and ultimately thrombin, thereby linking kinin formation to thrombus stabilization without requiring tissue factor.[6][41] This cross-talk underscores the system's role in bridging inflammation and hemostasis in plasma environments.[40]
Tissue System Activation
The tissue kallikrein-kinin system operates through localized activation in glandular and parenchymal tissues, distinct from the circulating plasma pathway. Tissue kallikreins, such as KLK1 (also known as tissue kallikrein), are serine proteases primarily expressed in organs including the pancreas, salivary glands, kidneys, and prostate. These enzymes are secreted as inactive pro-forms and activated extracellularly by trypsin-like proteases, initiating the release of kinins in a tissue-specific manner.[38][42]Upon activation, tissue kallikreins cleave low-molecular-weight kininogen (LMWK) or, to a lesser extent, high-molecular-weight kininogen (HMWK) in extracellular spaces, predominantly generating kallidin (lysyl-bradykinin) rather than bradykinin. This process occurs independently of plasma contact factors like factor XII, relying instead on local proteolytic environments triggered by tissue injury, inflammation, or hormonal signals. Kallidin formation supports localized vasodilatory and inflammatory responses without systemic dissemination.[38][43][3]In organ-specific contexts, KLK1 in the salivary glands contributes to hypotensive effects by promoting vasodilation in perivascular tissues, aiding in saliva production and local blood flow regulation. In the kidneys, activated KLK1 drives natriuresis through kinin-mediated enhancement of sodium excretion, renal blood flow, and glomerular filtration, while also counteracting oxidative stress and supporting electrolyte homeostasis. For instance, KLK1 infusion in experimental models increases urinary sodium output via bradykinin B2 receptor activation and nitric oxide production. In the pancreas, KLK1 participates in exocrine function and inflammatory modulation. Similarly, in the prostate, KLK3 (prostate-specific antigen, PSA) exemplifies tissue-specific expression, contributing to seminal fluid processing and tissue remodeling.[38][35][3][44]Tissue kallikrein expression and activation are regulated by hormones, including androgens that upregulate KLK3 in the prostate and estrogens that induce KLK1 in glandular tissues, ensuring organ-specific responsiveness to physiological demands. This hormonal control underscores the system's role in maintaining local homeostasis, such as androgen-driven prostate function and estrogen-modulated salivary responses.[38][20]
Regulation
Enzymes Involved
The kinin–kallikrein system relies on several serine proteases as its core enzymes, which catalyze the release and processing of kinins through specific peptide bond hydrolysis. These enzymes share a conserved catalytic triad consisting of histidine 57 (His57), aspartic acid 102 (Asp102), and serine 195 (Ser195), enabling nucleophilic attack by the serine hydroxyl group on the carbonyl carbon of peptide bonds, facilitated by the histidine-aspartate charge relay system.[28]Plasma kallikrein, encoded by the KLKB1 gene located on chromosome 4q34–35, is synthesized in the liver as an inactive zymogen called prekallikrein, which circulates in plasma bound to high-molecular-weight kininogen.[29] Upon activation, the mature enzyme exhibits trypsin-like specificity, preferentially cleaving peptide bonds after arginine residues, such as the Arg-Ser bond in kininogens to liberate kinins.[28] Its structure features a heavy chain (including four apple domains for substrate binding) non-covalently linked to a light chain containing the catalytic domain, with the active site pocket accommodating basic residues via an aspartate residue at position 189.[45]Tissue kallikreins form a family of 15 homologous serine proteases encoded by the KLK1–KLK15 genes, clustered in tandem on chromosome 19q13.4, with KLK1 serving as the classical kininogenase responsible for kinin release in extravascular tissues.[46] These enzymes primarily display trypsin-like specificity, hydrolyzing bonds after basic amino acids (arginine or lysine); KLK1 specifically cleaves the atypical Met-Lys and Arg-Ser bonds in kininogens to generate lys-bradykinin from low- or high-molecular-weight kininogens.[28][31] Structurally, they possess a single-chain zymogen form activated by cleavage to expose the N-terminus, which inserts into a activation pocket to align the catalytic triad, with variable substrate-binding loops conferring specificity across family members.[47]Accessory enzymes support kinin processing, including Factor XIIa, a serine protease that cleaves prekallikrein at the Arg371-Ile372 bond to generate active plasma kallikrein, utilizing its own catalytic triad for this reciprocal activation step.[48][49] Aminopeptidases, such as aminopeptidase P, further modify kinins by exopeptidase activity, removing N-terminal lysine from lys-bradykinin to yield bradykinin, with a zinc-dependent active site facilitating sequential amino acid cleavage at neutral pH.[50]
Inhibitors and Modulators
The kinin–kallikrein system is primarily regulated by serpins and other protease inhibitors that prevent excessive activation and kinin production. C1-esterase inhibitor (C1-INH), a serine protease inhibitor (serpin), serves as the main regulator of the plasma pathway by inhibiting plasma kallikrein, factor XIIa, and factor XIa, thereby limiting the generation of bradykinin and other kinins.[51] C1-INH achieves this through stoichiometric binding and irreversible inhibition of these enzymes, maintaining homeostasis in the contact activation cascade.[52]Alpha-2-macroglobulin acts as a broad-spectrum protease trap in plasma, capturing and inactivating free kallikreins by forming stable complexes that sterically hinder substrate access to the enzyme's active site.[6] This mechanism supplements C1-INH by scavenging excess kallikrein activity, particularly during high proteolytic loads, and contributes to the overall control of the system's amplification.[53]Angiotensin-converting enzyme (ACE), also known as kininase II, modulates the system by degrading kinins such as bradykinin through cleavage of their C-terminal dipeptides, thereby terminating their vasoactive effects and linking the kinin–kallikrein system to the renin-angiotensin pathway.[54] This enzymatic degradation provides a key post-activation control, reducing kinin bioavailability in circulation.[55]Other serpins, including antithrombin III, exert minor inhibitory effects on plasma kallikrein, particularly in the presence of glycosaminoglycans like heparin that enhance their activity, though their role is secondary to C1-INH.[6] In glandular and mucosal tissues, secretory leukocyte protease inhibitor (SLPI) functions as a local modulator by inhibiting tissue kallikreins and related serine proteases, protecting epithelial barriers from uncontrolled proteolysis.[56]
Receptors and Signaling
Kinin Receptor Types
The kinin–kallikrein system exerts its effects primarily through two subtypes of G-protein-coupled receptors, B1 and B2, which are activated by kinins such as bradykinin (BK) and kallidin (KD). These receptors belong to the rhodopsin-like family of seven-transmembrane domain proteins and are encoded by the BDKRB1 and BDKRB2 genes, respectively, both located on human chromosome 14q32.2.[57]B2 receptors are constitutively expressed under normal physiological conditions and exhibit high affinity for intact kinins, including BK and KD. They are widely distributed in various tissues, particularly the endothelium and smooth muscle cells of blood vessels, where they mediate baseline vascular responses.[57][58]In contrast, B1 receptors are typically expressed at low levels in healthy tissues but are rapidly inducible and upregulated at sites of inflammation or injury, often within hours of stimulus exposure. These receptors show preferential high affinity for the des-arginine metabolites of kinins, particularly des-Arg10-kallidin (KD ≈ 0.1 nM in human) over des-Arg9-BK (Ki ≈ 0.1–2 μM in human), with minimal response to intact BK or KD. Affinities vary by species; for example, rodent B1 receptors display more comparable affinities for des-Arg9-BK and Lys-des-Arg9-BK. B1 receptors are prominently expressed in inflamed tissues, sensory neurons, and certain central nervous system regions during pathological states.[57][58][59]
Intracellular Pathways
The bradykinin B2 receptor (B2R) primarily couples to heterotrimeric Gq/11 proteins upon ligand binding, activating phospholipase C-β (PLC-β) at the plasma membrane.[60] This enzyme hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).[60] IP3 diffuses to the endoplasmic reticulum, where it binds IP3 receptors to mobilize intracellular calcium stores, elevating cytosolic Ca²⁺ concentrations.[61] The resulting Ca²⁺ transient activates calmodulin-dependent endothelial nitric oxide synthase (eNOS) in endothelial cells, stimulating nitric oxide (NO) production and subsequent smooth muscle relaxation for vasodilation.[62]In contrast, the bradykinin B1 receptor (B1R) couples to Gi/o proteins, inhibiting adenylyl cyclase and reducing cyclic AMP levels while activating mitogen-activated protein kinase (MAPK) cascades such as ERK1/2.[63] This Gi/o-mediated signaling promotes inflammatory cytokine production, leukocyte recruitment, and cellular proliferation in various tissues.[64]Cross-talk between pathways enhances kinin effects; for instance, B2R activation in endothelium boosts eNOS via Ca²⁺-calmodulin, amplifying NO-mediated vasodilation, while also stimulating phospholipase A2 (PLA2) to liberate arachidonic acid from membrane phospholipids.[62] Arachidonic acid serves as a substrate for cyclooxygenase enzymes, yielding prostanoids like prostaglandin E2 (PGE2) that contribute to inflammation and further vascular permeability.[65]To prevent sustained signaling, both B1R and B2R undergo desensitization following prolonged agonist exposure, involving phosphorylation by G protein-coupled receptor kinases (GRKs) on serine/threonine residues in the C-terminal tail and intracellular loops. Phosphorylated receptors recruit β-arrestins, which uncouple G proteins, inhibit further activation, and facilitate clathrin-mediated endocytosis and lysosomal internalization, thereby attenuating responses.[66]
Clinical Aspects
Involvement in Pathophysiology
The kinin–kallikrein system (KKS) plays a central role in hereditary angioedema (HAE), particularly in types I and II, where deficiency or dysfunction of C1 esterase inhibitor (C1-INH) leads to uncontrolled activation of the plasma contact system, resulting in excessive bradykinin production.[67]Bradykinin, generated through sequential cleavage by factor XIIa and kallikrein, binds to B2 receptors on endothelial cells, inducing vascular permeability and episodic subcutaneous or submucosal swelling without urticaria or pruritus.[68] This dysregulation occurs because C1-INH normally inhibits plasma kallikrein and factor XIIa, preventing spontaneous bradykinin release; in HAE patients, low C1-INH levels (less than 50% of normal in type I) or impaired function (in type II) allow unchecked kinin formation, often triggered by stress, trauma, or estrogen.[67] Attacks typically affect the face, extremities, gastrointestinal tract, or larynx, with laryngeal involvement posing life-threatening risks due to airway obstruction.[68]In sepsis and septic shock, hyperactivation of the KKS contributes to hemodynamic instability through excessive bradykinin-mediated vasodilation and increased vascular permeability.[69] Endothelial damage from bacterial endotoxins or cytokines triggers factor XII activation on damaged surfaces, leading to kallikrein formation and bradykinin release, which exacerbates hypotension by promoting nitric oxide production and smooth muscle relaxation in arterioles.[6] This also induces capillary leak syndrome, where bradykinin increases endothelial gaps via B2 receptor signaling, resulting in fluid extravasation, tissue edema, and multi-organ hypoperfusion.[69] Studies in animal models of bacteremia demonstrate that KKS inhibition reduces these effects, highlighting its amplification of inflammatory cascades in severe infections like those caused by Gram-negative bacteria.[6]The KKS has also been implicated in the pathophysiology of severe COVID-19, where dysregulation leads to excessive bradykinin production, contributing to vascular permeability, lung edema, and inflammation.[70] In SARS-CoV-2 infection, interactions with the renin-angiotensin system (RAS) and complement pathways amplify KKS activation, potentially worsening outcomes in critically ill patients.[71]Dysregulation of the KKS contributes to hypertension by altering vascular tone through impaired kinin activity and interactions with the renin-angiotensin system (RAS).[28] Kinins such as bradykinin normally promote vasodilation by stimulating endothelial nitric oxide synthase, counterbalancing angiotensin II-induced vasoconstriction; however, decreased KKS activity in hypertensive states diminishes this protective effect, leading to elevated blood pressure.[28] In the context of diabetic complications, KKS overactivation drives inflammation and vascular damage, particularly in nephropathy and retinopathy.[72] Elevated plasma kallikrein in diabetic conditions cleaves high-molecular-weight kininogen to release bradykinin, which activates B1 and B2 receptors to promote renal inflammation, macrophage infiltration, and fibrosis via pro-inflammatory cytokines like TNF-α.[73] In diabetic retinopathy, KKS activation independently of VEGF increases retinal vascular permeability and leukostasis, contributing to macular edema through bradykinin-induced endothelial barrier disruption.[74]In cancer, particularly prostate cancer, tissue kallikreins such as prostate-specific antigen (PSA, or KLK3) and KLK2 facilitate tumor progression by proteolytic remodeling of the extracellular matrix and promoting invasive growth.[75] PSA, overexpressed in prostate tumors, cleaves insulin-like growth factor-binding proteins, enhancing bioavailability of growth factors that stimulate cell proliferation and survival.[75] Kinins generated by the KKS further support oncogenesis by inducing angiogenesis; bradykinin activates B1 and B2 receptors on endothelial cells, upregulating VEGF expression and matrix metalloproteinases, which promote neovascularization essential for tumor expansion and metastasis.[76] This pro-angiogenic role is evident in various cancers, where KKS components correlate with advanced disease stages and poor prognosis.[76]
Therapeutic Targeting
The kinin–kallikrein system is a primary target for therapies addressing hereditary angioedema (HAE), a condition characterized by bradykinin-mediated angioedema attacks due to C1-inhibitor (C1-INH) deficiency or dysfunction.[77] Direct modulation of system components, such as bradykinin receptors, kallikrein, and C1-INH, forms the basis of approved treatments that interrupt excessive bradykinin production or action.[78]Bradykinin B2 receptor antagonists, such as icatibant, provide on-demand relief for acute HAE attacks by competitively blocking bradykinin binding to its primary receptor, thereby reducing vascular permeability and swelling.[79] Administered subcutaneously, icatibant has demonstrated rapid symptom resolution in clinical trials, with onset within 2 hours and efficacy in treating abdominal, cutaneous, and laryngeal attacks.[77]C1-INH replacement therapies restore the natural inhibitor of the contact activation pathway, preventing kallikrein-mediated bradykinin generation. Berinert, a plasma-derived C1-INH concentrate, is used for acute HAE treatment via intravenous infusion, achieving attack resolution in over 90% of cases within 4 hours.[79] For prophylaxis in HAE type I, Cinryze is administered intravenously every 3–7 days, reducing attack frequency by up to 87% in randomized trials.[80]Kallikrein inhibitors target the enzyme directly to halt bradykinin formation upstream. Ecallantide, a recombinant protein administered subcutaneously, inhibits plasma kallikrein and has shown significant reduction in HAE attack severity and duration, with treatment success in 68% of patients compared to 41% with placebo.[77] Lanadelumab, a monoclonal antibody that binds and inhibits kallikrein, is used prophylactically via subcutaneous injection every 2–4 weeks, decreasing monthly attack rates by 87% in phase 3 studies for patients aged 2 years and older.[81]Angiotensin-converting enzyme (ACE) inhibitors, such as enalapril, indirectly modulate the kinin–kallikrein system by reducing bradykinin degradation, leading to elevated bradykinin levels that contribute to their vasodilatory effects in treating heart failure and hypertension.[82] However, this accumulation often causes a persistent dry cough in 5–20% of patients due to bradykinin-induced airway sensitivity, prompting discontinuation in some cases.[83]Emerging strategies include kallikrein gene therapy, which aims to regulate blood pressure by delivering the human tissue kallikrein gene via viral vectors to enhance kinin production and counteract hypertension. Preclinical studies in hypertensive rat models have shown sustained blood pressure reduction through increased urinary kinin and cyclic GMP levels following intramuscular or vascular gene delivery.[84] Although still investigational, this approach holds potential for long-term modulation of the system in cardiovascular diseases.[85] Additional emerging targets include plasma kallikrein inhibitors in clinical trials for diabetic macular edema as of 2025.[25] For HAE, new approvals in 2025 include garadacimab (a monoclonal antibody inhibiting factor XIIa), donidalorsen (an siRNA targeting prekallikrein), and sebetralstat (an oral plasma kallikrein inhibitor).[86]
