Detection and Quantitation of Cleaved and Uncleaved High Molecular Weight Kininogen in Plasma by Ligand Blotting with Radiolabeled Plasma Prekallikrein or Factor XI

Summary

A method for the quantitative assay of native single chain and kallikrein cleaved two-chain high molecular weight (HMW)-kininogen in plasma is described. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of whole plasma is followed by electrotransfer of the electropherogram to nitrocellulose membranes and detection of the blotted HMW-kininogen with its physiologic ligands, radiolabeled plasma prekallikrein or radiolabeled factor XI. Using unreduced SDS-PAGE cleaved two-chain HMW-kininogen (Mr ∼107,000 and 95,000), is elec-trophoretically separated from uncleaved single chain HMW-kininogen (Mr ∼150,000). Counting the radioactivity of the nitrocellulose pieces corresponding to cleaved HMW-kininogen permits its quantitative measurement by comparison with standards consisting of decreasing amounts of fully dextran sulfate activated normal human plasma. Single chain HMW-kininogen is similarly assayed using reduced SDS-PAGE and unactivated normal human plasma standards.

This technique is highly specific and sensitive to about 50 ng of either cleaved or uncleaved HMW-kininogen. Varying amounts of cleaved HMW-kininogen were found in a small series of plasmas from patients suffering from various inflammatory conditions. Higher levels of in vivo cleaved HMW-kininogen were observed during acute attacks of hereditary angioedema due to Cl-inhibitor deficiency. This technique may be useful for the assessment of the degree of in vitro or in vivo activation of the contact system.

Keywords

High molecular weight kininogen - Proteolytic cleavage - Ligand blotting - Contact activation system

• References

• 1 Jacobsen S, Kriz M. Some data on two purified kininogens from human plasma. Br J Pharmacol 1967; 29: 25-36
• 2 Habal FM, Movat HZ, Burrowes CE. Isolation of two functionally different kininogens from human plasma - separation from proteolytic inhibitors and interaction with plasma kallikrein. Biochem Pharmacol 1974; 23: 2291-2302
• 3 Thompson RE, Mandle R, Kaplan AP. Characterization of human high molecular weight kininogen. Procoagulant activity associated with the light chain of kinin-free high molecular weight kininogen. J Exp Med 1978; 147: 488-499
• 4 Iwanaga S, Kato H, Sugo T, Ikari N, Hashimoto N, Fujii S. In: Biological functions of proteinases. Holzer H, Tschesche H. (eds). pp 243-259 Berlin: Springer; 1979
• 5 Kato H, Han YN, Iwanaga S, Hashimoto N, Sugo T, Fujii S, Suzuki T. Mammalian plasma kininogens: Their structures and functions. In: Kininogenases Haberland GL, Rohen JW, Suzuki T. (eds). Vol.4 pp 63-72 Schattauer; Stuttgart: 1977
• 6 Kerbiriou DM, Bouma BN, Griffin JH. Immunochemical studies of human high molecular weight kininogen and of its complexes with plasma prekallikrein or kallikrein. J Biol Chem 1980; 255: 3952-3958
• 7 Nawa H, Kitamura N, Hirose T, Asai M, Inayama S, Nakanishi S. Primary structures of bovine liver low molecular weight kininogen precursors and their two mRNAs. Proc Natl Acad Sci (USA) 1983; 80: 90-94
• 8 Kitamura N, Takagaki Y, Furuto S, Tanaka T, Nawa H, Nakanishi S. A single gene for bovine high molecular weight and low molecular weight kininogens. Nature 1983; 305: 545-549
• 9 Lottspeich F, Kellermann J, Henschen A, Rauth G, Miiller-Esterl W. Human low-molecular-mass kininogen. Amino acid sequence of the light chain, homology with other protein sequences Eur J Biochem 1984; 142: 227-232
• 10 Lottspeich F, Kellermann J, Henschen A, Foertsch B, Miiller-Esterl W. The amino acid sequence of the light chain of human high- molecular-mass kininogen. Eur J Biochem 1985; 152: 307-314
• 11 Kellermann J, Lottspeich F, Henschen A, Miiller-Esterl W. Completion of the primary structure of human high-molecular-mass kininogen. The amino acid sequence of the entire heavy chain and evidence for its evolution by gene triplication Eur J Biochem 1986; 154: 471-478
• 12 Takagaki Y, Kitamura N, Nakanishi S. Cloning and sequence analysis of cDNAs for human high molecular weight and low molecular weight prekininogens. Primary structures of two human prekininogens J Biol Chem 1985; 260: 8601-9
• 13 Ohkubo I, Kurachi K, Takasawa T, Shiokawa H, Sasaki M. Isolation of a human cDNA for a2-thiol proteinase inhibitor and its identity with low molecular weight kininogen. Biochemistry 1984; 23: 5691-5697
• 14 Sueyoshi T, Enjyoji K, Shimada T, Kato H, Iwanaga S, Bando Y, Kominaini E, Katunuma N. A new function of kininogens as thiolproteinase inhibitors: Inhibition of papain and cathepsins B, H and L by bovine, rat and human plasma kininogens. FEBS letters 1985; 182: 193-195
• 15 Muller-Esterl W, Fritz H, Machleidt W, Ritonaja A, Brzin J, Kotnik M, Turk V, Kellermann J, Lottspeich F. Human plasma kininogens are identical with a-cysteine proteinase inhibitors. Evidence from immunological, emzymological and sequence data. FEBS letters 1985; 182: 310-314
• 16 Schmaier AH, Bradford H, Silver LD, Farber A, Scott CF, Schutsky D, Colman RW. High molecular weight kininogen is an inhibitor of platelet calpain. J Clin Invest 1986; 77: 1565-1573
• 17 Mandle RJ, Colman RW, Kaplan AP. Identification of prekallikrein and high molecular weight kininogen as a complex in human plasma. Proc Natl Acad Sci (USA) 1976; 73: 4179-4183
• 18 Thompson RE, Mandle R, Kaplan AP. Association of factor XI and high molecular weight kininogen in human plasma. J Clin Invest 1977; 60: 1376-1380
• 19 Wiggins RC, Bouma BN, Cochrane CG, Griffin JH. Role of high molecular weight kininogen in surface binding and activation of coagulation factor XI and prekallikrein. Proc Natl Acad Sci (USA) 1977; 74: 4636-4640
• 20 Griffin JH, Cochrane CG. Mechanisms for the involvement of high molecular weight kininogen in surface dependent reactions of Hage- man factor. Proc Natl Acad Sci (USA) 1976; 73: 2554-2558
• 21 Meier HL, Pierce JV, Colman RW, Kaplan AP. Activation and function of human Hageman factor. The role of high molecular weight kininogen and prekallikrein J Clin Invest 1977; 60: 18-31
• 22 Kerbiriou DM, Griffin JH. Human high molecular weight kininogen. Studies of structure - function relationships and of proteolysis of the molecule occurring during contact activation of plasma J Biol Chem 1979; 254: 12020-12027
• 23 Nakayasu T, Nagasawa S. Studies on human kininogens. I. Isolation, characterization, and cleavage by plasma kallikrein of high molecular weight (HMW)-kininogen J Biochem 1979; 85: 249-258
• 24 Mori K, Nagasawa S. Studies on human high molecular weight (HMW)-kininogen. II. Structural change of HMW-kininogen by the action of human plasma kallikrein J Biochem 1981; 89: 1465-1473
• 25 Tait JF, Fujikawa K. Identification of the binding site for plasma prekallikrein in human high molecular weight kininogen. A region of residues 185 to 224 of the kininogen light chain retains full binding activity J Biol Chem 1986; 261: 15396-15401
• 26 Berrettini M, Lammle B, White T, Heeb MJ, Schwarz HP, Zuraw B, Curd J, Griffin JH. Detection of in vitro and in vivo cleavage of high molecular weight kininogen in human plasma by immunoblotting with monoclonal antibodies. Blood 1986; 68: 455-462
• 27 ODonnell TF, Clowes GH A, Talamo RC, Colman RW. Kinin activation in the blood of patients with sepsis. Surg Gynecol Obstet 1976; 143: 539-45
• 28 Saameli K, Eskes TK A B. Bradykinin and cardiovascular system: Estimation of half-life. Am J Physiol 1962; 203: 261-265
• 29 Van Rosevelt RF. The bradykinin generation test. Clinical and pharmacological applications Thesis; University of Amsterdam: 1985
• 30 Lammle B, Berrettini M, Schwarz HP, Heeb MJ, Griffin JH. Quantitative immunoblotting assay of blood coagulation factor XII. Thromb Res 1986; 41: 747-759
• 31 Bouma BN, Vlooswijk RA A, Griffin JH. Immunologic studies of human coagulation factor XI and its complex with high molecular weight kininogen. Blood 1983; 62: 1123-131
• 32 Van der Graaf F, Tans G, Bouma BN, Griffin JH. Isolation and functional properties of the heavy and light chains of human plasma kallikrein. J Biol Chem 1982; 257 (14) 300-305
• 33 Bouma BN, Miles LA, Beretta G, Griffin JH. Human plasma prekallikrein. Studies of its activation by activated factor XII and of its inactivation by diisopropyl phospho-fluoridate Biochemistry 1980; 19: 1151-1160
• 34 Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent. J Biol Chem 1951; 193: 265-275
• 35 Me Conahey PJ, Dixon FJ. A method of trace iodination of proteins for immunologic studies. Int Arch Allergy 1966; 29: 185-189
• 36 Bolton AE, Hunter WM. The labelling of proteins to high specific radioactivities by conjugation to a ¹²⁵I-containing acylating agent. Application to the radioimmunoassay Biochem J 1973; 133: 529-539
• 37 Kluft C. Determination of prekallikrein in human plasma: optimal conditions for activating prekallikrein. J Lab Clin Med 1978; 91: 83-95
• 38 Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970; 227: 680-685
• 39 Johnson DA, Gautsch JW, Sportsman JR, Elder JH. Improved technique utilizing nonfat dry milk for analysis of proteins and nucleic acids transferred to nitrocellulose. Gene Anal Techn 1984; 1: 3-8
• 40 Lammle B, Berrettini M, Griffin JH. Immunoblotting studies of coagulation factor XII, plasma prekallikrein and high molecular weight kininogen. Sem Thromb Hemostas 1987; 13: 106-114
• 41 Colman RW. Patho-physiology of kallikrein system. Ann Clin Lab Sci 1980; 10: 220-226
• 42 Cochrane CG, Griffin JH. The biochemistry and pathophysiology of the contact system of plasma. Adv Immunol 1982; 33: 241-306
• 43 Colman RW. Surface-mediated defense reactions. The plasma contact activation system J Clin Invest 1984; 73: 1249-1253
• 44 Lammle B, Eichlisberger R, Marbet GA, Duckert F. Amidolytic activity in normal human plasma assessed with chromogenic substrates. Thromb Res 1979; 16: 245-254
• 45 Blomback M, Chmielewska J, Netre C, Akerblom O. Activation of blood coagulation, fibrinolytic and kallikrein systems during storage of plasma. Vox Sang 1984; 47: 335-342
• 46 Towbin H, Staehelin T, Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci (USA) 1979; 76: 4350-4354
• 47 Gershoni JM, Palade GE. Protein blotting: principles and applications. Anal Biochem 1983; 131: 1-15
• 48 Towbin H, Gordon J. Immunoblotting and dot immunobinding - current status and outlook. J Immunol Meth 1984; 72: 313-340
• 49 Beisiegel U. Protein blotting. Electrophoresis 1986; 7: 1-18
• 50 Lammle B, Berrettini M, Griffin JH. Enhanced specificity of immunoblotting using radiolabeled antigen overlay: studies of blood coagulation factor XII and prekallikrein in plasma. Anal Biochem 1986; 156: 118-125
• 51 Schwarz HP, Heeb MJ, Lammle B, Berrettini M, Griffin JH. Quantitative immunoblotting of plasma and platelet protein S. Thromb Haemostas 1986; 56: 382-386
• 52 Heeb MJ, Schwarz HP, Nova CP, White T, Griffin JH. Quantitative immunoblotting of vitamin K dependent coagulation factors in plasma. Thromb Haemostas 1985; 54: 107 Abstr
• 53 Warn-Cramer BJ, Bajaj SP. Stoichiometry of binding of high molecular weight kininogen to factor Xl/XIa. Biochem Biophys Res Comm 1985; 133: 417-422
• 54 Aasen AO, Smith-Erichsen N, Amundsen E. Plasma kallikrein-kinin system in septicemia. Arch Surg 1983; 118: 343-346
• 55 Colman RW, Edelman R, Scott CF, Gilman RH. Plasma kallikrein activation and inhibition during typhoid fever. J Clin Invest 1978; 61: 287-296
• 56 Mason JW, Kleeberg U, Dolan P, Colman RW. Plasma kallikrein and Hageman factor in gram-negative bacteremia. Ann Intern Med 1970; 73: 545-551
• 57 Lammle B, Tran TH, Ritz R, Duckert F. Plasma prekallikrein, factor XII, antithrombin III, Cl-Inhibitor and a2-macroglobulin in critically ill patients with suspected disseminated intravascular coagulation. Am J Clin Pathol 1984; 82: 396-404
• 58 Landerman NS, Webster ME, Becker EL, Ratcliffe HE. Hereditary angioneurotic edema. II. Deficiency of inhibitor for serum globulin permeability factor and/or plasma kallikrein J Allergy 1962; 33: 330-341
• 59 Curd JG, Prograis LJ, Cochrane CG. Detection of active kallikrein in induced blister fluids of hereditary angioedema patients. J Exp Med 1980; 152: 742-747
• 60 Schapira M, Silver LD, Scott CF, Schmaier AH, Prograis LJ, Curd JG, Colman RW. Prekallikrein activation and high molecular weight kininogen consumption in hereditary angioedema. N Engl J Med 1983; 308: 1050-1053
• 61 Zuraw BL, Curd JG. Demonstration of modified inactive first component of complement (Cl) inhibitor in the plasmas of Cl- inhibitor-deficient patients. J Clin Invest 1986; 78: 567-575
• 62 Nilsson T, Back O. Elevated plasmin-a2-antiplasmin complex levels in hereditary angioedema: Evidence for the in vivo efficiency of the intrinsic fibrinolytic system. Thromb Res 1985; 40: 8171-8821
• 63 Lewin MF, Kaplan AP, Harpel PC. Studies of Cl-inactivator-plasma kallikrein complexes in purified systems and in plasma. Quantification by an enzyme-linked differential antibody immunosorbent assay. J Biol Chem 1983; 258: 6415-6421
• 64 Kaplan AP, Gruber B, Harpel PC. Assessment of Hageman factor activation in human plasma: Quantification of activated Hageman factor - Cl-inactivator complexes by an enzyme-linked differential antibody immunosorbent assay. Blood 1985; 66: 636-641
• 65 DeAgostini A, Schapira M, Wachtfogel YT, Colman RW, Carrel S. Human plasma kallikrein and Cl-inhibitor form a complex possessing an epitope that is not detectable on the parent molecules: demonstration using a monoclonal antibody. Proc Natl Acad Sci (USA) 1985; 82: 5190-5193
• 66 Schmaier AH, Smith PM, Purdon AD, White JG, Colman RW. High molecular weight kininogen: localization in the unstimulated and activated platelet and activation by a platelet calpain(s). Blood 1986; 67: 119-130
• 67 Wiggins RC. Kinin release from high molecular weight kininogen by the action of Hageman factor in the absence of kallikrein. J Biol Chem 1983; 258: 8963-8970
• 68 Kleniewski J, Donaldson VH, Wagner CJ. Some molecular and functional changes in high molecular weight kininogen induced by plasmin and trypsin. Thromb Res 1982; 25: 387-399