Tissue kallikreinkinin system components

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Tissue (glandular or renal) kallikrein (E.C. 3.4.21.35) belongs to a subgroup of serine proteinases and processes low molecular weight kininogen substrate to release vasoactive kinin peptides (1). The well-recognized function of tissue kallikrein is mediated by lysyl-bradykinin (Lys-BK or kallidin) and bradykinin (BK), which consist of 10 and 9 amino-acid peptides, respectively. Kinins are then degraded by enzymes such as kininases I and II and neutral endopeptidase (NEP) to produce a number of kinin metabolites or inactive fragments. Intact kinins bind to kinin B2 receptors, whereas kinin metabolites, such as Des-Arg9-BK or Des-Arg10-Lys-BK, bind to kinin B1 receptors. The physiological functions of the KKS are mediated by the constitutively expressed B2 receptor. Unlike the B2 receptor, the B1 receptor is expressed at low levels in the heart, vasculature, and kidney and is induced by trauma or inflammation (2). The binding of kinins to their respective receptors activates second messengers such as NO, cGMP, prostacyclin, and cAMP, which trigger a broad spectrum of biological effects including vasodilation, smooth muscle contraction and relaxation, inflammation, and pain (3,4). Figure 1 shows the inter-relationship of the tissue kallikrein-kinin system components.

The KKS can be regulated at different steps through system-specific inhibitors, kininases and antagonists, as well as through a kininase shared with the renin-angiotensin system (RAS). Expression of the tissue kallikrein gene is regulated by a number of hormones (5,6). The activity and metabolism of kallikrein are modulated post-translationally by

From: Contemporary Endocrinology: Hypertension and Hormone Mechanisms Edited by: R. M. Carey © Humana Press Inc., Totowa, NJ

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Pics Kinin System

Fig. 1. The interrelationship of the tissue kallikrein-kinin sysyem components.

Secondary Messengers (NO, cGMP, Prostacyclin, cAMP)

Fig. 1. The interrelationship of the tissue kallikrein-kinin sysyem components.

kallistatin, an endogenous and specific tissue kallikrein-binding protein and inhibitor (7-9). Kallistatin is a potent vasodilator, which induces blood pressure reduction in anesthesized rats and vasorelaxation in isolated aortic rings independent of its kallikrein inhibitory activity (10). The KKS can be blocked by tissue kallikrein inhibitors (kallistatin or aprotinin), icatibant (Hoe 140, a specific B2 receptor antagonist) or Des-Arg9-[Leu8] BK (a specific B1 receptor antagonist) (1,3). The KKS and RAS are linked by angiotensin-converting enzyme (ACE), a dipeptidase, which is the same enzyme as kininase II. ACE has dual functions: it not only converts angiotensin I to vasoconstrictor peptide angiotensin II (Ang II), but also degrades kinin to release a dipeptide fragment, Phe-Arg, from the carboxyl end of the kinin peptide, rendering kinin inactive. Therefore, the beneficial effects of ACE inhibition in hypertension, cardiovascular, and renal diseases may also be attributed to kinin accumulation, as icatibant can partially abolish these effects (11-13). Hypertension could result from either an excess of vasoconstrictor substances or a deficiency in vasodilator substances. Manipulation of the vasodilator KKS by a continuous supply of tissue kallikrein through gene transfer or protein infusion could potentially counter-balance the vasopressor effect of the RAS in blood pressure homeostasis and cardiovascular complications.

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