The Kallikrein–Kinin system

Pre-dating Hippocrates, more than 4000 years ago, human urine was already a fascinating research medium, climaxing in the renaissance. An oft-repeated story in the literature is that of a woman wishing to avoid a pregnancy diagnosis by blending her urine with that of a cow. Very much to her distress, the leche announced that both she and her cow were pregnant (Armstrong 2007)! It was in 1909 that Abelous and Bardier discovered in human urine a blood pressure-lowering substance (Abelous & Bardier 1909). In 1920, Pribram and Herrnheiser analysed the nondialysable fraction of human urine and injected it into a rabbit, which resulted in a marked fall in blood pressure (Pribram & Herrnheiser 1920). Six years later, Frey confirmed the effect of a hypotensive substance recovered from urine (Frey 1926). Frey and his co-worker Kraut believed the vasodilator substance extracted from urine was of pancreatic origin and named it kallikrein, derived from the Greek word for pancreas (Kraut & Werle 1930). Kallikreins are a heterogeneous group of serine proteases, which occur in the plasma as well as in several tissues, such as pancreas, kidney, intestine and salivary glands (Schachter 1979). A century of research later, we know that kallikreins are the initating element of the kallikrein–kinin system (KKS), cleaving the protein substrate kininogen to liberate kinins, among which the muscle-contracting nonapeptide bradykinin is known best (Bader 2009). Kinin acts mainly via two membrane receptors, the bradykinin receptor B1R and bradykinin receptor B2R, and this set of molecules (Kallikrien, substrate Kininogen, kinins and receptors) comprises the KKS, which seemed at first – based on the origin of its discovery – to be particularly relevant for renal function. Webster, Gilmore and Gill established the natriuretic/diuretic capabilities of kinins (Webster & Gilmore 1964, Gill et al. 1965). Bradykinin administration can increase renal blood flow without significantly changing glomerular filtration. Kinins reduce vascular resistance and stimulate water and electrolyte (sodium) excretion as a function of increased renal blood flow (Stein et al. 1972). Urine volume increases with a strong increase in fluid disposal to the distal nephron (Nasjletti & Malik 1981). (Terragno et al. 1972) and (McGiff et al. 1972), discovered that bradykinin stimulates prostaglandin release which led to the proposal that the kallikrein–kinin and arachidonate-prostaglandin systems are related (Fig. 1). Nowadays, an enormous amount of data has been published about the KKS, an important but still poorly understood and underestimated player in many different aspects (Leeb-Lundberg et al. 2005). A repertory of transgenic animals shed light onto the diverse functions of the KKS (Pesquero & Bader 2006). Besides its role in renal physiology, the KKS is relevant for cardiovascular function, such as blood pressure regulation (vasodilation), and has been implicated the pathogenesis of hypertension (Marceau & Regoli 2004, Regoli et al. 2012). Furthermore, the KKS is a central regulator of inflammatory processes and is in turn regulated by components of the innate immune response (Kaplan & Ghebrehiwet 2010). Various articles from Acta Physiologica (Oxford) have aided our understanding of the KKS' major sites of action, that is haemostasis, complement activation, vascular tone and inflammation (Fig. 2). The KKS can be activated on surface of endothelial cells along with the coagulation cascade involving the binding to gC1qR, cytokeratin 1 and the urokinase plasminogen activated receptor (u-PAR; Sainz et al. 2007). The intrinsic clotting cascade is an innate protection mechanism but may have adverse effects in pathology, such as in thrombosis (Lominadze et al. 2010). Coagulation is initiated by the contact of plasma with a negatively charged surface that results in autoactivation of factor XII (Hageman factor) to generate factor XIIa. The activated Factor XII is cleaved by kallikrein or plasmin to yield Factor XII fragment (Factor XIIf), increasing the clotting cascade by a positive feedback mechanism (Moreau et al. 2005). The intrinsic coagulation/kinin-forming cascade may be altered depending on genetical background or sex (Santos et al. 2010). The clotting cascade involves activation of several factors and results in generation of cross-linked fibrin. The activation occurs continuously at a finite rate but is held in check by plasma inhibitors. However, properties of fibrin generation/degradation are critical in certain pathophysiological processes, for example haemorrhagic stroke (Edvinsson & Povlsen 2011). Intrinsic factors such as coagulation or environmental factors activate the complement pathway (Morabito et al. 2011), which is cross-activated with the plasma bradykinin cascade. The C1 inhibitor (C1-INH) is not only the inhibitor of activated C1r and C1s (Blankesteijn et al. 2001), but it is the key control protein of the plasma bradykinin-forming cascade. C1-INH inhibits the ability of Factor XIIa to activate prekallikrein and thereby prevents activation of high-molecular-weight kininogen (HK) by kallikrein (Kaplan & Ghebrehiwet 2010). Deficiency in C1-INH permits plasma kallikrein activation, which leads to the production of the vasoactive peptide bradykinin, a mediator of increased endothelial permeability, resulting in hereditary angioedema (Schreiber et al. 1976). Plasma-derived kallikreins release bradykinin from a high-molecular-weight form of kininogen (HMW-Kininogen), which has an extremely short half-life. Bradykinin is the basic vasoactive peptide of the KKS involved in the regulation of blood pressure as well as flow (Bagher & Segal 2011). Bradykinin signals via B2R, a constitutively expressed receptor in the cardiovascular system. Autocrine and paracrine activation stimulate the release of NO and prostaglandins (vascular smooth muscle relaxation) (Holzer 2011). Reduced bradykinin generation results in hypertension, which may be associated with genetic defects or pregnancy (Aljabri et al. 2011). KKS components have a certain therapeutic potential in hypertension (Marketou & Vardas 2012). The KKS and RAS are connected by the angiotensin-converting enzyme (ACE), which degrades bradykinin and generates angiotensin II from angiotensin I (Wang et al. 2010). Angiotensin II has a vasoconstrictive action, causes target organ lesions, promotes atheromatosis and arteriole remodelling, and increases catecholamine release and sympathetic nervous system activity (Wong et al. 1983, Fandriks 2011), having made the renin-angiotensin system a main therapeutic target in hypertension (Vlasova et al. 2010). However, ACE inhibition causes bradykinin stabilization, which is responsible for ACE inhibitors' cardioprotective effects (Silvestre et al. 2001, Dahl et al. 2011). Tissue-derived kallikreins release the decapeptide lysyl-bradykinin from the low-molecular-weight form of Kininogen (LMW-Kininogen), which signals via the B1R. The B1R, in contrast to B2R, is weakly expressed in physiological conditions but is induced in inflammation in a variety of tissues (Duchene & Ahluwalia 2009). Whereas the B2R undergoes rapid desensitization, the B1R does not, but activates the transcription factor NF-κB, aggravating the inflammatory response (Duchene et al. 2009). Several studies have confirmed the major role of the B1R in inflammatory cell recruitment, as leucocyte recruitment is blocked in B1R−/− mice or by B1R antagonists. However, the B1R is implicated in a wide range of other biological phenomena such as sepsis (Hirsch et al. 1974), pain (Raja et al. 1992), and multiple sclerosis (Schulze-Topphoff et al. 2009). Hence, hundred years of research have probably revealed only a small fraction of the KKS' capability. Recent finding in the cardiovascular field showed that B1R may have therapeutic potential for renal diseases and atherosclerosis (Merino et al. 2009). Bradykinin receptors B1R and B2R are involved in endothelial cell proliferation and a strong inductor of sprouting angiogenesis (Emanueli et al. 2002, Krankel & Madeddu 2009). Furthermore, B1R regulate collateral artery growth (arteriogenesis) by modulating events on circulating leucocytes (Hillmeister et al. 2011). This discovery may be of significant importance, because arteriogenesis is the most effective endogenous rescue mechanism against vascular occlusive disease (Persson & Buschmann 2011, Styp-Rekowska et al. 2011). Therapeutic stimulation of arteriogenesis is a promising concept to prevent cardiovascular ischaemia (Kanlop et al. 2011, Duelsner et al. 2012). The KKS may have yet unnoticed clinical relevance – a treasure we need to appreciate. There is no conflict of interest to declare.