Towards understanding the kallikrein-kinin system: insights from measurement of kinin peptides

Abstract

The kallikrein-kinin system is complex, with several bioactive peptides that are formed in many different compartments. Kinin peptides are implicated in many physiological and pathological processes including the regulation of blood pressure and sodium homeostasis, inflammatory processes, and the cardioprotective effects of preconditioning. We established a methodology for the measurement of individual kinin peptides in order to study the function of the kallikreinkinin system. The levels of kinin peptides in tissues were higher than in blood, confirming the primary tissue localization of the kallikreinkinin system. Moreover, the separate measurement of bradykinin and kallidin peptides in man demonstrated the differential regulation of the plasma and tissue kallikrein-kinin systems, respectively. Kinin peptide levels were increased in the heart of rats with myocardial infarction, in tissues of diabetic and spontaneously hypertensive rats, and in urine of patients with interstitial cystitis, suggesting a role for kinin peptides in the pathogenesis of these conditions. By contrast, blood levels of kallidin, but not bradykinin, peptides were suppressed in patients with severe cardiac failure, suggesting that the activity of the tissue kallikrein-kinin system may be suppressed in this condition. Both angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitors increased bradykinin peptide levels. ACE and NEP inhibitors had different effects on kinin peptide levels in blood, urine, and tissues, which may be accounted for by the differential contributions of ACE and NEP to kinin peptide metabolism in the multiple compartments in which kinin peptide generation occurs. Measurement of the levels of individual kinin peptides has given important information about the operation of the kallikrein-kinin system and its role in physiology and disease states.

Interactions Between Angiotensin-(1-7), Kinins, and Angiotensin II in Kidney and Blood Vessels

“…21 The major effects of the renal KKS, diuresis and natriuresis, involves BK-B 2 receptors and are caused by an increase in renal blood flow and by inhibition of sodium and water reabsorption in the distal nephron. 21,22 Indeed, this system is believed to play a pivotal role in the regulation of fluid and electrolyte balance, mostly through its renal actions. 22 The interactions between the RAS and KKS at the renal level are only starting to be appreciated.…”

“…An evidence for a possible interaction between the 2 systems is the simultaneous presence of KKS and RAS components and receptors along the nephron. 21,22 Transgenic animals with various alterations of the KKS and RAS have been recently produced. 17,21,23,24 This approach has substantially increased the understanding of the physiological role of these peptidergic systems and the interaction between them.…”

“…21,22 Transgenic animals with various alterations of the KKS and RAS have been recently produced. 17,21,23,24 This approach has substantially increased the understanding of the physiological role of these peptidergic systems and the interaction between them. 23 Using AT 1 receptor-deficient mice, Tsuchida et al 24 showed that the BK-B 2 receptor system has a potent antihypertrophic effect on the renal vasculature in vivo.…”

“…On the other hand, a number of studies have suggested that AT 2 receptors may interact with the KKS. 17,21,25 Siragy et al 25 postulated that Ang II tonically stimulates renal kinin peptide production by an AT 2 receptor-dependent mechanism. However, studies performed by Campbell and coworkers 21 do not support the hypothesis that the AT 2 receptor regulates kinin peptide production.…”

“…20,21 Furthermore, it is well known that renal KKS can produce local concentrations of BK much higher than those present in blood. 21 The major effects of the renal KKS, diuresis and natriuresis, involves BK-B 2 receptors and are caused by an increase in renal blood flow and by inhibition of sodium and water reabsorption in the distal nephron. 21,22 Indeed, this system is believed to play a pivotal role in the regulation of fluid and electrolyte balance, mostly through its renal actions.…”