Bradykinin and kallidin are cleaved from HMW or LMW kininogens by plasma or tissue kallikrein, respectively (Figure 24-2). Plasma kallikrein and tissue kallikrein are distinct enzymes that are activated by different mechanisms. Plasma prekallikrein is an inactive protein that complexes in a 1:1 ratio with its substrate, HMW kininogen. The ensuing proteolytic cascade is restrained by the protease inhibitors present in plasma (e.g., inhibitor of the activated first component of complement [C1-INH] and a2-macroglobulin). Under experimental conditions, the kallikrein-kinin system is activated by the binding of factor XII, also known as Hageman factor, to negatively charged surfaces. Factor XII, a protease that is common to both the kinin and the intrinsic coagulation cascades (see Chapter 54), undergoes autoactivation and, in turn, activates kallikrein. Importantly, kallikrein further activates factor XII, thereby exerting a positive feedback on the system.

Tissue kallikrein is synthesized as a preproprotein in the epithelial cells or secretory cells of a number of tissues, including salivary glands, pancreas, prostate, and distal nephron. Tissue kallikrein is also expressed in human neutrophils. It acts locally near its sites of origin. The synthesis of tissue prokallikrein is controlled by a number of factors, including aldosterone in the kidney and salivary gland and androgens in certain other glands. The activation of tissue prokallikrein to kallikrein requires proteolytic cleavage to remove a 7-amino acid propeptide.

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