Kallikrein (KLK) was discovered by Kraut et al. In 1930 at a high concentration in the pancreas, named "Kallikrein". Over the past 30 years, with the development and application of molecular biology and cell biology technology, it has been discovered that the kallikrein-kinin system (KKS) as a complex endogenous multi-enzyme system is involved in regulating cardiovascular, the physiological functions of the kidney, nervous system, etc. are closely related to the occurrence of diseases such as heart disease, kidney disease, inflammation, cancer, etc.



The discovery

In 1909, Abelous et al. Reported for the first time that intravenous injection of human urine can cause a temporary drop in blood pressure in dogs, and it was found that hypotensive substances were present in the urine. In 1930 Kraut et al found a high concentration of this substance in the pancreas, named "Kallikrein", which is kallikrein (KLK). Over the past 30 years, with the development and application of molecular biology and cell biology technology, it has been discovered that the kallikrein-kinin system (KKS) as a complex endogenous multi-enzyme system is involved in regulating cardiovascular The physiological functions of the kidney, nervous system, etc. are closely related to the occurrence of diseases such as heart disease, kidney disease, inflammatory response, and cancer. Research on the cardiovascular system is progressing rapidly. Many clinical studies and basic experiments have confirmed that the occurrence of diseases such as diabetes, hypertension, heart failure, myocardial infarction, and left ventricular hypertrophy is related to the decrease in KKS activity. Therefore, in-depth study of the role of KKS provides another new way to study the pathogenesis and treatment of cardiovascular-related diseases.



The composition

KKS is one of the main antihypertensive systems in the body, consisting of kininogen, KLK, kininase and kinin. The kinin family includes bradykinin, lysyl bradykinin, methionyl? Lysyl bradykinin. Lysyl bradykinin and methionyl? Lysyl bradykinin can be degraded into bradykinin by aminopeptidase in plasma and urine.

KLK, also known as angiotensin, is the main rate-limiting enzyme of the kinin system. It is a group of serine proteases present in most tissues and body fluids, and is an endopeptidase. It specifically cleaves the substrate peptide at the carbon end, cleaves kininogen to release active kinin, and kinin plays a role in regulating the cardiovascular system and kidney function. KLK is divided into two categories: plasma KLK and tissue KLK, which are converted from prokinin releasing enzyme and KLK precursor (prokallikrein), respectively. They differ greatly in molecular weight, substrate, immunological properties, genetic structure, and the type of kinin released. Plasma KLK, also known as Fletcher factor, is specifically expressed in hepatocytes and is a high molecular weight glycoprotein that releases nonapeptide, BK, using HMWK as a substrate. Tissue KLK is a large gene family, mainly distributed in lung, kidney, blood vessel, brain, and adrenal tissues, and is a medium-sized glycoprotein. Among all known tissue kallikrein families, only pancreatic / kidney KLK can release active kinin from kininogen, which is the human KLK (hKLK1) protein encoded by the KLK1 gene. It mainly uses LMWK as a substrate to release decapeptide lysyl bradykinin, commonly known as kinin. Its body activity is stronger than BK, it can be cleaved by aminopeptidase into BK to continue to play a role

The half-life of kinin released in the gap between blood and tissue is very short, only a few seconds, and it is quickly hydrolyzed and inactivated by kininase. Kininase mainly includes kininase I, kininase II [namely angiotensin converting enzyme (ACE)], neutral endopeptidase 24,11 (NED24,11), carboxypeptidase and aminopeptidase.

 

Effect

Plasma-type KLK participates in the process of coagulation and fibrinolysis. It acts on HMWK to release BK to regulate vascular tone, inflammation and endogenous blood coagulation and fibrinolysis. Tissue KLK decomposes LMWK to produce kinin, participates in various physiological processes, and regulates physiological or pathological processes such as blood pressure regulation, electrolyte balance, and inflammatory response.



Kinin mainly plays an important biological role on neighboring cells through autocrine and paracrine pathways in the form of local hormones and two different types of BK receptors, namely B1 receptor and B2 receptor. Both B1 and B2 receptors are G protein-coupled receptors. The B1 receptor has a high affinity and sensitivity to kinins lacking the carboxyl terminus, such as de-arginine bradykinin and lysine de-arginine bradykinin.

It is generally believed that B1 receptors are absent in normal tissues, mainly expressed during bacterial lipopolysaccharide (endotoxin) and interleukin stimulation and inflammation, which may be related to inflammation and tissue damage. B1 receptor activation can stimulate smooth muscle cell proliferation and collagen formation. In addition to mediating inflammatory mediators, it also participates in the process of neovascularization.

B1 receptors are less prone to internalization and tolerance after receiving stimulants. At the same receptor density, B1 receptors are more dependent on basic signals. The B2 receptor is present in the normal body and has a high density. It is sensitive to BK and lysine bradykinin. It is generally believed that the B2 receptor mediates most of the cardiovascular effects, electrolyte metabolism and organ protection of kinin . BK binds to B2 receptors, stimulating the release of second messengers such as nitric oxide (NO) / cyclic adenosine monophosphate (cAMP) and prostacyclin I2 (PGI2) / cyclic guanosine monophosphate (cGMP), and renin-vascular tension The effect of the RAS system is antagonistic, thereby exerting a wide range of biological effects, expanding small arteries, increasing local blood flow, inhibiting renin secretion and increasing vasodilating prostaglandin synthase levels, increasing vascular permeability and making blood vessels Diastolic, promote blood pressure decline, regulate blood pressure and cardiovascular function.



o excessive secretion of mineralocorticoid steroids, the rest of the hypertension may be related to renal KKS dysfunction. The antihypertensive effect of BK is usually mediated by B2 receptors. Sharma et al. found that the B2 receptor antagonist B5630 can block the hypotensive effect of BK, in addition to inhibiting the hypotensive effect of angiotensin-converting enzyme inhibitor (ACEI) captopril, which can be inferred ACEI in addition to reducing the decomposition of BK and increasing the concentration in the blood, the antihypertensive effect can also prevent the desensitization of kinin B2 receptor and promote the up-regulation of receptor function.



Earlier studies have shown that oral porcine pancreatic KLK can significantly reduce the blood pressure of hypertensive patients. Its shortcoming is that the antihypertensive effect is short and requires repeated administration. Intravenous injection of purified tissue-type KLK in experimental animals can cause a rapid and short-term hypotensive effect [15], and the BK receptor inhibitor atebant (HOE140) can block this reaction. There have been several applications of tissues such as KLK gene therapy for hypertension, reversal of left ventricular hypertrophy (LVH), and alleviation of renal function damage. Various studies on hypertension models have shown that transgene therapy has a long-lasting antihypertensive effect and has good effects on cardiovascular and renal diseases


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