KNG1

Kininogen-1 (KNG1), also known as high-molecular-weight kininogen (HMWK), functions as a multifunctional glycoprotein in plasma. It serves as a precursor for bradykinin, a vasoactive peptide mediating inflammation, vascular permeability, and blood pressure regulation. HMWK interacts with prekallikrein and coagulation factor XII (FXII) to initiate the contact activation system, linking coagulation, fibrinolysis, and innate immunity. Structurally, it contains domains for binding heparin, cell surfaces, and cysteine protease inhibition. Its cleavage by plasma kallikrein releases bradykinin, which activates G protein-coupled receptors (B1R/B2R), triggering nitric oxide and prostaglandin pathways.
Dysregulation of KNG1 is implicated in hereditary angioedema, thrombosis, and hypertension due to altered bradykinin metabolism. Reduced kininogen levels correlate with rheumatoid arthritis and sepsis progression. Pharmacologically, bradykinin receptor antagonists (e.g., icatibant) and kallikrein inhibitors (lanadelumab) target this pathway for angioedema treatment. Recent studies explore KNG1-derived peptides as biomarkers for endothelial dysfunction and therapeutic candidates for cardiovascular diseases. Ongoing trials investigate monoclonal antibodies against FXII to mitigate kinin-mediated pathologies while minimizing bleeding risks.