Kinin-kallikrein system
Encyclopedia
The kinin-kallikrein system or simply kinin system is a poorly understood system of blood
protein
s that plays a role in inflammation
, blood pressure
control, coagulation
and pain
. Its important mediators bradykinin
and kallidin
are vasodilators and act on many cell types.
(high in kinins) led to hypotension
(low blood pressure). The researchers Emil Karl Frey, Heinrich Kraut and Eugen Werle discovered high-molecular weight kininogen
in urine around 1930.
Etymology: 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
(HMWK) and low-molecular weight kininogen (LMWK) are precursors of the polypeptides. They have no activity of themselves.
HMWK and LMWK are formed by alternative splicing of the same gene.
s 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 of ACEi's develop a dry cough
, and some react with angioedema
, a dangerous swelling of the head and neck region.
There are hypotheses that many of the ACE-inhibitors' beneficial effects are due to their influence on the kinin-kallikrein system. This includes their effects in arterial hypertension, in ventricular remodeling
(after myocardial infarction) and possibly diabetic nephropathy
.
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.
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s that plays a role in inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
, blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
control, coagulation
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
and pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
. Its important mediators bradykinin
Bradykinin
Bradykinin is a peptide that causes blood vessels to dilate , and therefore causes blood pressure to lower. A class of drugs called ACE inhibitors, which are used to lower blood pressure, increase bradykinin further lowering blood pressure...
and kallidin
Kallidin
Kallidin is a bioactive kinin formed in response to injury from kininogen precursors through the action of kallikreins.Kallidin is a decapeptide that can be converted to bradykinin by the aminopeptidase enzyme....
are vasodilators and act on many cell types.
History
The system was discovered in 1909 (Abelous & Bardier) when researchers discovered that injection with urineUrine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
(high in kinins) led to hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
(low blood pressure). The researchers Emil Karl Frey, Heinrich Kraut and Eugen Werle discovered high-molecular weight kininogen
High-molecular weight kininogen
High-molecular-weight kininogen , also known as the Williams-Fitzgerald-Flaujeac factor or the Fitzgerald factor or the HMWK-kallikrein factor, is a protein from the blood coagulation system as well as the kinin-kallikrein system. It is a protein that adsorbs to the surface of biomaterials that...
in urine around 1930.
Etymology: 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
Members
The system consists of a number of large proteins, some small polypeptides and a group of enzymes that activate and deactivate the compounds.Proteins
High-molecular weight kininogenHigh-molecular weight kininogen
High-molecular-weight kininogen , also known as the Williams-Fitzgerald-Flaujeac factor or the Fitzgerald factor or the HMWK-kallikrein factor, is a protein from the blood coagulation system as well as the kinin-kallikrein system. It is a protein that adsorbs to the surface of biomaterials that...
(HMWK) and low-molecular weight kininogen (LMWK) are precursors of the polypeptides. They have no activity of themselves.
- HMWK is produced by the liverLiverThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
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.
Polypeptides
- BradykininBradykininBradykinin is a peptide that causes blood vessels to dilate , and therefore causes blood pressure to lower. A class of drugs called ACE inhibitors, which are used to lower blood pressure, increase bradykinin further lowering blood pressure...
(BK), which acts on the B2 receptor and slightly on B1, is produced when kallikrein releases it from HMWK. It is a nonapeptide with the amino acidAmino acidAmino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg. - KallidinKallidinKallidin is a bioactive kinin formed in response to injury from kininogen precursors through the action of kallikreins.Kallidin is a decapeptide that can be converted to bradykinin by the aminopeptidase enzyme....
(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.
Enzymes
- KallikreinKallikreinKallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein has no known homologue, while tissue kallikrein-related peptidases encode a family of fifteen closely related serine proteases...
s (tissue and plasma kallikrein) are serine proteaseSerine proteaseSerine proteases are enzymes that cleave peptide bonds in proteins, in which serine serves as the nucleophilic amino acid at the active site.They are found ubiquitously in both eukaryotes and prokaryotes...
s that liberate kinins (BK and KD) from the kininogens, which are plasma proteins that are converted into vasoactive peptides. PrekallikreinPrekallikreinPrekallikrein , also known as Fletcher factor, is a 85,000 Mr serine protease that complexes with High-molecular-weight kininogen. PK is the precursor of plasma kallikrein, which is a serine protease that activates kinins. PK is cleaved to produce kallikrein by activated Factor XII . -...
is the precursor of plasma kallikrein. It can only activate kinins after being activated itself by factor XIIFactor XIICoagulation factor XII also known as Hageman factor is a plasma protein. It is the zymogen form of factor XIIa, an enzyme of the serine protease class. In humans, factor XII is encoded by the F12 gene.- Function :...
a or other stimuli. - CarboxypeptidaseCarboxypeptidaseA carboxypeptidase is a protease enzyme that hydrolyzes the peptide bond of an amino acid residue at the carboxy-terminal end...
s are present in two forms: N circulates and M is membrane-bound. They remove arginine residues at the carboxy-terminus of BK and KD. - Angiotensin converting enzyme (ACE), also termed kininase II, inactivates a number of peptide mediators, including bradykininBradykininBradykinin is a peptide that causes blood vessels to dilate , and therefore causes blood pressure to lower. A class of drugs called ACE inhibitors, which are used to lower blood pressure, increase bradykinin further lowering blood pressure...
. It is better known for activating angiotensinAngiotensinAngiotensin, a peptide hormone, causes blood vessels to constrict, and drives blood pressure up. It is part of the renin-angiotensin system, which is a major target for drugs that lower blood pressure. Angiotensin also stimulates the release of aldosterone, another hormone, from the adrenal cortex...
. - Neutral endopeptidaseNeprilysinNeprilysin, also known as membrane metallo-endopeptidase, neutral endopeptidase , CD10, and common acute lymphoblastic leukemia antigen , is a zinc-dependent metalloprotease enzyme that degrades a number of small secreted peptides, most notably the amyloid beta peptide whose abnormal misfolding and...
also deactivates kinins and other mediators.
Pharmacology
Inhibition of ACE with ACE inhibitorACE inhibitor
ACE inhibitors or angiotensin-converting enzyme inhibitors are a group of drugs used primarily for the treatment of hypertension and congestive heart failure...
s 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 of ACEi's develop a dry cough
Cough
A cough is a sudden and often repetitively occurring reflex which helps to clear the large breathing passages from secretions, irritants, foreign particles and microbes...
, and some react with angioedema
Angioedema
Angioedema or Quincke's edema is the rapid swelling of the dermis, subcutaneous tissue, mucosa and submucosal tissues. It is very similar to urticaria, but urticaria, commonly known as hives, occurs in the upper dermis...
, a dangerous swelling of the head and neck region.
There are hypotheses that many of the ACE-inhibitors' beneficial effects are due to their influence on the kinin-kallikrein system. This includes their effects in arterial hypertension, in ventricular remodeling
Ventricular remodeling
Ventricular remodeling refers to the changes in size, shape, and function of the heart after injury to the ventricles. The injury is typically due to acute myocardial infarction , but may be from a number of causes that result in increased pressure or volume overload on the heart...
(after myocardial infarction) and possibly diabetic nephropathy
Diabetic nephropathy
Diabetic nephropathy , also known as Kimmelstiel-Wilson syndrome, or nodular diabetic glomerulosclerosis and intercapillary glomerulonephritis, is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli. It is characterized by nephrotic syndrome and diffuse...
.
Role in disease
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 inflammationInflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
and blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
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
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
release and thus prostaglandin (PGE2) production.