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The plasma kallikrein-kinin system counterbalances the renin-angiotensin system
Alvin H. Schmaier
University of Michigan, Departments of Internal Medicine and Pathology, 5301 Medical Science Research Building III, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109-0640, USA.
Phone: (734) 647-3124; Fax: (734) 647-5669; E-mail: aschmaie@umich.edu.
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Published April 15, 2002 - More info
J Clin Invest. 2002;109(8):1007–1009. https://doi.org/10.1172/JCI15490.
© 2002 The American Society for Clinical Investigation
The plasma kallikrein-kinin system (KKS), first recognized over 40 years ago, was originally believed to contribute to physiologic hemostasis. At the time, factor XII (Hageman factor, FXII) and the related proteins prekallikrein (PK) and high molecular–weight kininogen (HK) were known to be essential for efficient surface-activated blood coagulation, as measured in the activated partial thromboplastin time (APTT) test. Indeed, in this test, autoactivation of FXII in glass tubes promotes thrombin formation.
According to the then-current “contact activation” hypothesis, FXII activation on a negatively charged surface was thought to initiate hemostasis in a similar manner by a cascade of proteolytic reactions that culminate in thrombin formation. This model was undermined by the failure to identify such a physiologically relevant surface, coupled with evidence that individuals deficient in FXII, PK, or HK are free of bleeding disorders. In addition, the recognition that factor XI, whose deficiency is associated with bleeding, can be activated by thrombin provided a bypass mechanism that obviated a need for FXII to activate factor XI.
Only over the last 6 years have alternative explanations for the physiologic role of the KKS and its assembly and activation begun to emerge. Rather than assembling on a negatively charged surface such as that used in the APTT test, the proteins of the plasma KKS are now known to bind a multiprotein receptor complex in the intravascular compartment. As shown in Figure 1, HK, the critical regulator of plasma KKS assembly and activation, binds an endothelial cell surface receptor complex containing cytokeratin 1 (CK1), urokinase plasminogen activator receptor (uPAR), and gC1qR (1–6). Recent studies with cultured human umbilical vein endothelial cells indicate that FXII can also bind to this receptor (7), but that this interaction is highly regulated. Plasma concentrations of HK completely block FXII binding to the multiprotein receptor complex. Further, FXII binding requires a 30-fold higher free Zn2+ concentration than does HK, which can only be achieved in a milieu of activating platelets or other cells (7). Thus, under physiologic conditions, HK binds to this endothelial cell complex but FXII is prevented from doing so.
Figure 1Assembly and activation of the plasma KKS on endothelial cells. Plasma PK circulates in complex with HK. The HK•PK complex binds to a multiprotein receptor complex that consists of cytokeratin 1 (CK1), urokinase plasminogen activator receptor (uPAR) and gC1qR. The proteins of the HK•PK receptor complex co-localize on endothelial cell membranes. When HK•PK binds to endothelial cells, PK is rapidly converted to kallikrein (K) by the enzyme prolylcarboxypeptidase (PRCP), which is constitutively active on endothelial cell membranes. The resulting kallikrein autodigests its receptor, HK, to liberate bradykinin (BK), which can liberate tissue plasminogen activator (tPA), nitric oxide (NO), and prostacyclin (PGI2) from endothelial cells. Kallikrein also activates FXII, which binds to the same multiprotein receptor complex as HK in its absence. In this revised hypothesis for assembly and activation of the proteins of the plasma KKS, FXII is activated by kallikrein after PK activation. ScuPA, single chain urokinase plasminogen activator.
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Mechanisms of KKS activation
This interaction of HK with its endothelial cell–surface receptor is key to the regulated activation of PK, which circulates in the plasma in a complex with HK. Work with cultured endothelial cells suggests a novel mechanism by which HK-bound PK is rapidly converted to kallikrein in a process that is independent of FXII (8, 9). On cultured endothelial cells and cell matrices, FXII activation occurs subsequent to PK activation (9, 10). Activated forms of FXII thus do not initiate PK activation, although they can feed back to increase the rate and extent of its activation. Activation of PK — unlike that of a structurally related zymogen, factor XI — can therefore proceed even in the absence of factor XIIa (11). As shown in Figure 1, endothelial cell–associated active kallikrein then cleaves HK to liberate bradykinin. The assembly of the HK•PK complex on endothelial cells is thus predicted to lead to constitutive production of bradykinin, which can then activate the bradykinin B2 receptor. Activation of this receptor regulates vascular tone by stimulating NO formation in endothelial cells (12).
This mechanism for bradykinin production depends on the activity of an endothelial cell–borne PK activator, whose identity was unknown until quite recently. We have now reported that the serine protease prolylcarboxypeptidase (PRCP, lysosomal carboxypeptidase, angiotensinase C) represents one such enzyme (13). Its Km for PK (7 nM) is consistent with a physiologic role as a specific PK activator (13), and it is found on endothelial cell membranes and in the endothelial cell–endomembrane system that communicates between the cell’s lysosomal and membrane compartments. Previous investigations by Erdös and colleagues identified angiotensin II (Km = 0.2 mM) and bradykinin (Km = 1 mM) as substrates of the same processing enzyme (14). PRCP can activate the biologically inert angiotensin I or the vasoconstrictor angiotensin II to form angiotensin II1–7, a biologically active peptide that induces vasodilation by stimulating NO formation (15, 16) (Figure 2). The finding that PRCP also activates PK indicates that it can produce two biologically active peptides, bradykinin and angiotensin II1–7, each of which can reduce blood pressure, counterbalancing the vasoconstrictive effects of angiotensin II.
Figure 2The interaction between the plasma KKS and RAS. Plasma kallikrein converts prorenin to renin, and renin has the ability to convert angiotensinogen to angiotensin I. Angiotensin-converting enzyme (ACE) converts inactive angiotensin I to the vasoconstrictor angiotensin II. Angiotensin II stimulates plasminogen activator inhibitor 1 (PAI1) release from endothelial cells. At the same time ACE degrades bradykinin into bradykinin(1–7) (not shown) or bradykinin(1–5), a peptide with thrombin inhibitory activity. PRCP is the enzyme that degrades angiotensin II or angiotensin I to the vasodilating peptide, angiotensin II(1–7). Angiotensin II(1–7) stimulates NO and PGI2 formation, which potentiates the effects of bradykinin. PRCP also has the ability to convert PK to kallikrein. Formed kallikrein digests kininogens to liberate bradykinin, leaving a kinin-free kininogen (HKa) that has anti-proliferative and anti-angiogenic properties. Thus, PRCP, the same enzyme that degrades the vasoconstrictor angiotensin II, leads to the increased formation of the vasodilators bradykinin and angiotensin II(1–7). Finally, the resulting bradykinin stimulates tPA, NO, and PGI2 formation, thus counterbalancing the prothrombotic effect of angiotensin II.
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