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PubMed1981

High-molecular-weight kininogen from horse plasma. Isolation, characterization and comparison with bovine high-Mr kininogen.

High-molecular-weight (high-Mr) kininogen was purified from horse plasma by chromatography on columns of DEAE-Sephadex A-50, CM-Sephadex C-50, p-chlorobenzylamine-Sepharose and Sephadex G-150. The yield was about 150 mg from 81 of fresh plasma. The purified material gave a single band on sodium dodecylsulfate/polyacrylamide gel electrophoresis and a single precipitin line on immunodiffusion and immunoelectrophoresis. The molecular weight of horse high-Mr kininogen was estimated to be 78000 by dodecylsulfate gel electrophoresis using the Ferguson plot. Its polypeptide content was determined to be 86% by amino acid analysis and there was a total of 581 amino acid residues/molecule of protein. The kininogen contained a total of 13.9% carbohydrates, consisting of hexoses (7.8%), glucosamine (1.9%), galactosamine (0.6%) and sialic acid (3.6%). On incubation of horse high-Mr kininogen with bovine and horse plasma kallikreins, several fragments which contained extremely high levels of histidine, were liberated, in addition to kinin. After the liberation of kinin and histidine-rich fragments, a protein free of kinin and its fragments was isolated. This protein consisted of two polypeptide chains, heavy chain and light chain, which are bridged by disulfide bonds. The molecular weight and amino acid composition of the heavy chain and the light chain from horse high-Mr kininogen were very similar to those of the heavy and light chains from bovine high-Mr kininogen, respectively. From these results, it was revealed that horse high-Mr kininogen is quite similar to bovine high-Mr kininogen in terms of their physicochemical and chemical properties, although they are immunologically distinguishable.

Amino Acids↗
PubMed1985

Rat high-molecular-weight kininogen: purification, production of antibodies and demonstration of lack of immunoreactive kininogen in a strain of brown Norway rats.

High-molecular-weight kininogen was purified to apparent homogeneity from Wistar rat plasma by a two-steps chromatographic procedure. 3 mg of kininogen were obtained from 205 ml of plasma. The purified high-Mr kininogen had a bradykinin content of 10.2 micrograms bradykinin equivalents/mg protein. Under denatured and reduced conditions it gave a single band on polyacrylamide gel electrophoresis corresponding to an apparent molecular mass of 110 kDa. Antibodies obtained against rat high-Mr kininogen gave a single precipitation line when tested against rat plasma in double immunodiffusion and in crossed immunoelectrophoresis. Although rat high-Mr kininogen possesses physicochemical properties (molecular mass, kinin content per molecule and amino acid composition) similar to human high-Mr kininogen, its antibodies do not cross-react with human, monkey or rabbit plasma, indicating major interspecies differences in the structure of the molecule. Immunoreactive kininogen of Wistar rats was identical to that of Brown Norway rats from a strain bred in Orleans, France (BN/Orl). However, plasma from a strain of Brown Norway rats bred in Leuven, Belgium (BN/Kat), reported to be deficient in a kinin precursor (Damas, J. and Adam, A. (1980) Experientia 36, 586-587), did not contain immunoreactive material discernible by double immunodiffusion or crossed immunoelectrophoresis.

Amino Acids↗
PubMed1978

Characterization of human high molecular weight kininogen. Procoagulant activity associated with the light chain of kinin-free high molecular weight kininogen.

Human high molecular weight (HMW) kininogen has been isolated and was found to be a single chain protein of approximately equal to 120,000 daltons. Upon digestion with plasma kallikrein bradykinin is generated, and SDS gel electrophoresis of the kinin-free protein reveals an apparent loss in size of 15,000 daltons. The kinin-free kininogen retains full activity as a coagulation factor and consists of two chains: a heavy chain of approximately equal to 66,000 daltons disulfide-linked to a light chain of 37,000 daltons. The heavy chain of HMW kininogen shares antigenic determinants with LMW kininogen and possesses no detectable coagulant activity. The isolated light chain is shown to be responsible for the coagulant activity of HMW kininogen and contains a unique antigenic determinant that distinguishes HMW kininogen from low molecular weight kininogen.

Blood Coagulation Factors↗
PubMed1992

Insights on monoclonal antibodies to kininogens' heavy chain which influence kininogens' binding to platelets.

Purified domains of low molecular weight kininogen (LK) can be used directly to determine the epitopes of monoclonal antibodies (mAbs) that have been shown to influence kininogen function. LK, purified from plasma by carboxymethyl-papain-Sepharose 4B affinity chromatography and kaolin adsorption, was digested by trypsin and chymotrypsin. The domains of LK were then separated by gel filtration followed by carboxymethyl-papain-Sepharose 4B affinity chromatography. Using the purified domains of LK's heavy chain, the regions on kininogens' heavy chain which various monoclonal antibodies are directed to were determined by enzyme-linked immunosorbent assay and immunoblotting. MAb 2B5 which neutralized kininogens' ability to inhibit calpain cross-reacted with domains 2 and 3. MAb HKH8 which reacted with kininogens' domain 1 and 2 was found to inhibit 125I-HK binding to platelets. At two-fold molar excess, mAb HKH8 was a better inhibitor of 125I-HK binding to platelets than higher concentrations, where the antibody was shown to cause increased binding to platelets. Alternatively, HKH8 F(ab')2 completely inhibited 125I-HK binding to platelets even at high concentrations of antibody. These studies indicate that purified domains of kininogens' heavy chain can be used to rapidly localize epitopes for antibodies. Further, mAb HKH8 should be a valuable probe to understand the mechanisms of kininogens' binding to platelets.

Adsorption↗
PubMed1984

Demonstration of the third kininogen in high and low molecular weight kininogens-deficient Brown Norway Katholiek rat.

A gel filtration profile of the plasma of Brown Norway Katholiek (B/N-Ka) rat was compared with those of B/N-Kitasato (B/N-Ki) and Sprague-Dawley (SD) rats. In the chromatograms of B/N-Ki and SD rat plasmas, high-molecular weight (HMW) kininogen was eluted together with pre-kallikrein. In lower molecular weight fractions, there were two kininogens, one of which released kinin by urinary kallikrein, snake venom kininogenase (SVK) and trypsin, and the other released kinin only by trypsin. In the chromatogram of B/N-Ka rat plasma, there was no fraction which released kinin by plasma kallikrein, urinary kallikrein or SVK. However, the kinin-release only by trypsin was found in the lower molecular weight fraction, which corresponds to the third peak of kininogen in the chromatograms of B/N-Ki and SD rat plasmas. These results indicate that B/N-Ka rat plasma is deficient in HMW kininogen, and also deficient in the LMW kininogen susceptible to urinary kallikrein and SVK, but it contains the third kininogen responsive only to trypsin.

Animals↗
PubMed1993

Plasma kininogen deficiency: associated defective secretion of kininogens by primary cultures of hepatocytes from brown Norway Katholiek rats.

To clarify the mechanism of plasma kininogen deficiency of Brown Norway Katholiek strain (B/N-Katholiek) rats, we compared synthesis and secretion of kininogens by primary cultures of hepatocytes from B/N-Katholiek and B/N-Kitasato (normal strain) rats. Pulse-and-chase experiments using [35S]methionine demonstrated that kininogen antigens with molecular masses of 100 and 66 kDa, corresponding to high- and low-molecular-weight kininogens (HK and LK), respectively, were detected in the hepatocytes of both strains. These proteins were then processed to 108- and 71-kDa forms, respectively, and secreted by the normal hepatocytes, while the latter forms were hardly secreted in the culture media of the deficient hepatocytes. However in the deficient cells, 100- and 66-kDa forms were accumulated, but 108- and 71-kDa bands were faint. A subcellular fractionation study showed that a relatively higher amount of the kininogen antigens was present in the lysosomal fraction of B/N-Katholiek hepatocytes than in that of B/N-Kitasato hepatocytes. From these results we postulate the cause of the secretion defect of B/N-Katholiek liver to be as follows. (i) B/N-Katholiek liver could synthesize the mature secretable forms of HK and LK, but they are too rapidly transported to the lysosomes, or (ii) the mature forms in B/N-Katholiek hepatocytes might be synthesized much more slowly than those in the normal cells. T-Kininogen was normally synthesized and secreted by the hepatocytes of B/N-Katholiek, suggesting that the secretion defect could be limited to HK and LK, at a common site.

Animals↗
PubMed1994

Demonstration of derivation of rat urinary bradykinin from plasma low-molecular-weight kininogen: a study using kininogen-deficient rats.

The origin of urinary bradykinin was defined by use of plasma kininogen-deficient B/N-Katholiek rats, whose ureter urine contains very low amount of urinary kinin. The kinin level increased after the rats received an infusion of normal plasma. Furthermore, the bradykinin content in the ureter urine of these kininogen-deficient rats increased more by infusion of partially purified rat- low-molecular-weight kininogen than by that of high-molecular-weight kininogen. Urinary kallikrein activity of B/N-Katholiek rats was enzymatically identical with that of normal B/N-Kitasato rats. These results indicate that urinary bradykinin found in the ureter urine of normal rats is derived from plasma low-molecular-weight kininogen by cleavage by urinary kallikrein.

Animals↗
PubMed1989

Role of high molecular weight (HMW)-kininogen in inflammatory exudation: evidence with the studies of the HMW-kininogen deficient rat.

Role of the kallikrein-kinin system in inflammation has been studied in rat model of inflammation, such as paw edema and pleurisy. Previous works suggested involvement of HMW-kininogen and activation of plasma kallikrein system in the carrageenin-induced rat pleurisy at early phase. This study clearly demonstrates the involvement of HMW-kininogen in carrageenin-induced rat paw edema and carrageenin-induced rat pleurisy by using congenitally deficient rat strain in plasma HMW-kininogen. Conclusion is the followings: 1. Significantly less reactivity was noticed in the deficient strain, B/N-Ka, in comparison with normal strain, B/N-Ki, when carrageenin-paw edema or carrageenin- and kaolin-pleurisies were induced. 2. Pretreatment with captopril enhanced the paw swelling as well as pleural fluid accumulation in normal strain but no enhancement was observed in the deficient strain. These results indicate that HMW-kininogen is responsible to inflammatory exudation. 3. T-kinin may not be involved in these inflammations, since the deficient strain owns normal plasma level of T-kininogen.

Animals↗
PubMed1991

The kallikrein-kinin system in the rat hypothalamus. Immunohistochemical localization of high molecular weight kininogen and T kininogen in different neuronal systems.

High molecular weight kininogen (HKg) and T kininogen (TKg) were detected and localized by immunocytochemistry in adult rat hypothalamus. In addition, kininogens were measured by their direct radioimmunoassay (RIA) or by indirect estimation of kinins released after trypsin hydrolysis and high pressure liquid chromatography (HPLC) separation of bradykinin (BK) and T kinin. A specific HKg immunoreactivity demonstrated with antibodies directed against the light chain (LC) of HKg was colocated with SRIF in neurons of hypothalamic periventricular area (PVA) projecting to external zone (ZE) of median eminence (ME). Heavy chain (HC) immunoreactivity which could be related to HKg or to low molecular weight kininogen (LKg) was detected in some other systems: i) parvocellular neurons of suprachiasmatic (SCN) and arcuate nuclei containing SRIF, ii) magnocellular neurons (mostly oxytocinergic) of paraventricular (PVN) and supraoptic (SON) nuclei, iii) neurons of dorsomedian and lateral hypothalamic areas. TKg immunostaining was restricted to magnocellular neurons of PVN, SON, accessory nuclei (mostly vasopressinergic) and to parvocellular neurons of SCN (vasopressinergic). TKg projections are directed towards the internal zone (ZI) of ME, but very few immunoreactive terminals are detectable in neurohypophysis. TKg staining parallels with vasopressin during water deprivation, and is undetectable in homozygous Brattleboro rats. In some magnocellular neurons, TKg and HC (related to HKg or LKg) are coexpressed. TKg, was also detected in hypothalamus and cerebellum extracts by direct RIA, and BK and T kinin were identified after trypsin hydrolysis. HKg and LKg can act as precursor of BK which can play a physiological role as releasing factor, neuromodulator--neurotransmitter,--or modulator of local microcirculation in hypothalamus. The three kininogens are also potent thiolprotease inhibitors which could modulate both the maturation processes of peptidic hormones and their inactivation and catabolism.

Animals↗
PubMed1988

mRNA for kininogens and thiostatins (major acute phase alpha 1-proteins) in the liver of kininogen-deficient rats.

mRNAs for low and high molecular weight kininogens (1.6 and 3.0 kb in size, respectively) and for two thiostatins (1.6 kb in size) were found in the liver of kininogen-deficient Brown-Norway (BN/Mai Pfd) rats. The levels of mRNAs for thiostatins, but not those for low and high molecular weight kininogens (arising from a single kininogen gene), increased strongly during acute inflammation. The pattern of DNA restriction sites for the kininogen gene and the thiostatin genes in the mutant rat strain was identical to that in at least four other rat strains.

Animals↗
PubMed1976

Kininogen deficiency in Fitzgerald trait: role of high molecular weight kininogen in clotting and fibrinolysis.

Plasma from an asymptomatic person with defects in blood coagulation, release of kinin, and evolution of fibrinolytic activity upon contact with a foreign surface was deficient in kininogen. The coagulation defect was identified as "Fitzgerald trait." A preparation of high molecular weight kininogen repaired the defects in clotting, kinin release and fibrinolysis, but a preparation of low molecular weight kininogen did not. Therefore, Fitzgerald factor appears to be a high molecular weight kininogen. The site of action of the kininogen appears to be after that of activated Hageman factor and kallikrein in the generation of clot-promoting activity through activation of plasma thromboplastin antecedent (PTA).

Adult↗
PubMed2003

Characterization of molecular defects of Fitzgerald trait and another novel high-molecular-weight kininogen-deficient patient: insights into structural requirements for kininogen expression.

A 6-year-old male with vertebral-basilar artery thrombosis was recognized to have high-molecular-weight kininogen (HK) deficiency. The propositus had no HK procoagulant activity and antigen (< 1%). Using monoclonal antibodies (Mabs) to kininogen domain 3, the propositus, family members, and Fitzgerald plasma were determined to have detectable low-molecular-weight kininogen. Mabs to HK domains 5 and 6 do not detect HK antigen in the propositus' plasma. The propositus has a single base pair (bp) deletion in cDNA position 1492 of exon 10 affecting amino acid 480 of the mature protein and resulting in a frameshift and a premature stop codon at position 1597 (amino acid 532). Unexpectedly, Mabs to the heavy chain and domain 5 of HK detect a 92-kDa form of HK in Fitzgerald plasma, the first HK-deficient plasma. The 92-kDa Fitzgerald HK has amino acid residues through 502, corresponding to domains 1 through 5, but lacks epitopes of domain 6 (positions 543 to 595). Fitzgerald DNA has a normal exon 10, but a 17-bp mutation in intron 9. These combined results indicate that mutations in the kininogen gene may differentially affect biosynthesis, processing, and/or secretion of HK.

Child↗
PubMed1987

Porcine high molecular weight kininogen: its purification and properties as a thiol proteinase inhibitor as compared to human high molecular weight kininogen.

1. High mol. wt kininogen (HMW kininogen) was purified to a homogeneous state from porcine plasma. 2. The protein exhibited a strong inhibitory activity for thiol proteinases such as ficin, papain and calpain I, whereas it did not inhibit serine proteinases, trypsin and chymotrypsin. 3. The mol. wt, isoelectric point, amino acid and carbohydrate compositions, stabilities to temperature and pH, kinetic constants, and immunological properties of the porcine HMW kininogen were determined and compared with those of human HMW kininogen.

Amino Acids↗
PubMed1986

Identification of the binding site for plasma prekallikrein in human high molecular weight kininogen. A region from residues 185 to 224 of the kininogen light chain retains full binding activity.

We studied the ability of fragments of the light chain of human high molecular weight kininogen to bind to plasma prekallikrein. In a competitive fluorescence polarization assay, kallikrein-cleaved light chain (light chain-2; residues 49-255), a cyanogen bromide fragment (residues 185-242), and a tryptic peptide (T-7; residues 185-224) had binding affinities of approximately 20 nM, equivalent to the value for the intact light chain (residues 1-255) of high-molecular-weight kininogen. In contrast, fragments consisting of residues 49-184 and 243-255 showed no binding activity (Kd much greater than 1,000 nM). Direct titrations of fluorescein-labeled derivatives of light chain-2 and peptide T-7 with prekallikrein confirmed that T-7 retained full binding activity for prekallikrein (Kd = 12 +/- 2 nM for labeled light chain-2; Kd = 7 +/- 1 nM for labeled T-7). These results localize the binding site of high molecular weight kininogen for prekallikrein within a region of 40 amino acids (residues 185-224) that resides in the near carboxyl terminus of the light chain of kininogen.

Binding Sites↗
PubMed1985

A new function of kininogens as thiol-proteinase inhibitors: inhibition of papain and cathepsins B, H and L by bovine, rat and human plasma kininogens.

The amidolytic activities of papain and rat liver cathepsins B, H and L were strongly inhibited by high (HMM) and low (LMM) molecular mass kininogens from bovine, human and rat plasmas, and their Ki values were estimated to be in the order of 10(-10) - 10(-11)M for papain and 10(-8) - 10(-9)M for cathepsins. The derivatives of bovine kininogens, HMM kinin-free protein, HMM kinin- and fragment 1 X 2-free protein, and LMM kinin-free protein also showed strong inhibitory activity toward these thiol-proteinases. These results suggest that a reactive site which interacts with thiol-proteinases is contained in the heavy chain portion in kininogens.

Animals↗
PubMed1989

[Concentration of kininogens and low molecular kininogen antigen in plasma of pregnant rabbits and newborn progeny in health and following intravenous infusion of purified thrombin].

High levels of trypsin-releasing kinin and low molecular plasma kininogen antigen were detected in plasma of pregnant female rabbits. Respective values in plasma of their new born progeny was 2.7 times lower than that in maternal plasma. Intravenous infusion of the highly purified bovine thrombin administered to pregnant female rabbits markedly decreased plasma fibrinogen platelet count and increased fibrinogen/fibrin degradation products in blood serum. A marked decrease of trypsin-releasing kinin plasma levels accompanied these changes. No changes in the kininogen antigen levels were seen during the same experiments. Thrombin infusions administered to pregnant female rabbits did not produce measurable changes in trypsin-releasing kinin levels and plasma low molecular kininogen antigen in the progeny obtained for the investigations with the aid of cesarean section.

Animals↗
PubMed1998

Evidence for the presence of a kininogen-like species in a case of total deficiency of low and high molecular weight kininogens.

Low and high molecular weight kininogens (LK and HK), containing 409 and 626 amino acids with masses of approximately 65 and 120 kDa after glycosylation, respectively, are coded by a single gene mapped to the human chromosome 3 by alternative splicing of the transcribed mRNA. The NH2-termini Glu1-Thr383 region, identical in LK and HK, contains bradykinin (BK) moieties Arg363-Arg371. LK, HK and their kinin products Lys-BK and BK are involved in several biologic processes. They are evolutionarily conserved and only 7 patients, all apparently normal, have been reported to lack them. In one of these patients (Williams' trait), a codon mutation (Arg178-->stop) has been blamed for the absence of LK and HK. However, using Western blots with 2 monoclonal anti-HK antibodies, one that recognizes the region common to LK and HK and the other that recognizes only HK, 1 detected approximately 110-kDa bands in the plasma of this LK/HK-deficient patient vs approximately 120-kDa bands in normal human and ape plasmas. With polyclonal anti-Lys-BK antibody, which strongly detects BK cleaved at its COOH-terminus in purified HK, 1 detected approximately 110-kDa bands in the normal and the deficient plasmas. Western blots with a monoclonal anti-prekallikrein (PK) antibody showed that surface activation of PK and distribution of PK activation products, both dependent on HK, were similar in these plasmas. These findings suggest that a mutant gene yielded a kininogen-like species possibly involving aberrant mRNA splicing-structurally different from normal HK, but apparently with the capacity to carry out seemingly vital HK functions.

Antibodies, Monoclonal↗
PubMed1993

The kinin released from high molecular weight-kininogen is responsible for inflammatory exudation in rats: detection of kinin-free-kininogen in the exudate by immunoblot analysis.

Kinin release and its involvement in inflammatory exudation were assessed by immuno-blot analysis of the kinin-precursor protein, high molecular weight kininogen (HK). HK consists of heavy (H) chain, bradykinin and light (L) chain. After bradykinin was released by plasma kallikrein, HK remains two-chain-kinin-free form;, i.e., H-chain and L-chain link each other through a disulfide bond. By Western blot analysis using antibody recognizing the light chain of HK, a band of 110-kD mass, which corresponds to intact HK, was detected in plasma after SDS-PAGE under reducing conditions, while a 46-kD band, corresponding to the light chain of HK, but no 110-kD band, was found in the exudate of rats with carrageenin-induced pleurisy at 3 hr as well as at 16 h. This result indicates that in the exudate most all of the HK molecules had released kinin to form kinin-free-HK, whereas the HK in the plasma remained intact. On the contrary, low molecular weight kininogen (LK) in the exudate was mostly in its intact form. These results indicate that plasma kallikrein could be activated in the exudate to release kinin from HK, as it reacts exclusively with HK and not with LK, and they are also mostly consistent with the features of the kinin release from the exudate and the plasma. That is, no kinin was detected in the exudate when the latter was incubated with plasma kallikrein, whereas salivary kallikrein did release kinin, indicating that kinin had already been released from HK, but not from LK in the exudate. Immunoblot analysis of HK in the pleural exudate also demonstrated no kinin involvement in phorbol myristate acetate- or zymosan-induced pleurisy, since no light chain band, but an intact HK band, was found in the exudates from these pleurisies.

Animals↗