The cellular effects of KK are thought to reflect primarily the action of BK, a peptide hormone that produces proinflammatory and vasodilatory effects by activating two cell surface G protein-coupled receptors, the B1 and B2 bradykinin receptors, expressed on vascular endothelial and vascular smooth muscle cells (VSMCs) Vismodegib supplier (6). The KKS also interfaces with the renin-angiotensin system (RAS) (7). Plasma and tissue KK can convert prorenin to renin, the protease responsible for processing angiotensinogen to angiotensin I. Conversely, the angiotensin-converting enzyme, the protease responsible for processing angiotensin I to angiotensin II, also cleaves BK to produce its inactive fragment, BK (1,�C5). Thus, factors that enhance the generation of angiotensin II tend to dampen BK signaling.

Not surprisingly, given this reciprocal regulation, the KKS and RAS generally are thought to exert opposing effects in the regulation of vascular tone (8). Angiotensin II, acting via G protein-coupled AT1 and AT2 receptors, causes VSMC constriction and promotes hypertension, whereas under normal physiological conditions, BK stimulates vascular endothelial cells to produce nitric oxide (NO), leading to relaxation of the underlying VSMCs and vasodilation (9, 10). NO from endothelial cells also inhibits VSMC and renal mesangial cell proliferation (11, 12). However, in the setting of vascular injury and endothelial denudation, BK can act directly on VSMC to induce their contraction and activate multiple signaling pathways in a manner similar to vasoconstrictors like angiotensin II (13).

The protease-activated receptors (PARs) are a family of four G protein-coupled receptors that are activated upon enzymatic cleavage of their N termini by specific serine proteases (14, 15). Each receptor contains an internal ��tethered�� ligand buried within its N terminus that is exposed upon proteolysis. PARs are widely expressed, with PAR1, PAR3, and PAR4 present on platelets, endothelial cells, myocytes, and astrocytes, whereas PAR2 is also present on epithelium. PARs are activated or inhibited by a host of proteases from the coagulation cascade, inflammatory cells, and the digestive tract (15). PAR1, PAR3, and PAR4 are all activated by thrombin, whereas PAR2, which is present on intestinal epithelium, is activated by trypsin and tryptase.

Depending on their location, PARs regulate diverse processes, including hemostasis, inflammation, cell migration, and pain transmission (16,�C19). Although their physiologic roles have not been well studied, KK and KK-related proteases have been recently implicated as endogenous regulators of PARs in the central nervous system and prostate cancer (20,�C22). EGF receptors ErbB1�C4 comprise a family of classical receptor tyrosine kinases that control cell proliferation and survival via the Ras and phosphatidylinositol-3 kinase/Akt pathways Carfilzomib (23).