Kallikrein–kinin system in hepatic experimental models

Peptides 26 (2005) 1301–1307

Kallikrein–kinin system in hepatic experimental models Maria Kouyoumdjian a,∗ , M´arcia Regina Nagaoka a , Durval Rosa Borges b a

Department of Biochemistry, Universidade Federal de S˜ao Paulo, Rua Botucatu 862 (Ed JL Prado), 04023-900 S˜ao Paulo, SP, Brazil b Department of Medicine, Universidade Federal de S˜ ao Paulo, Rua Botucatu 862 (Ed JL Prado), 04023-900 S˜ao Paulo, Brazil Available online 26 April 2005

Abstract The purpose of this brief review is to describe some characteristics of the kallikrein–kinin system (KKS) in the liver. The liver synthesizes kininogens and prekallikrein and the synthesis of both proteins is increased in rats during the acute phase reaction. It is also the main organ to clear tissue as well as plasma kallikrein from the circulation in normal and pathological conditions. Bradykinin (BK), yielded by the kallikrein–kinin system, is a potent arterial hypotensive peptide, but in the liver it induces a portal hypertensive response. The portal hypertensive action of bradykinin is mediated by B2 receptors located on sinusoidal cells of the periportal region and is followed by its hydrolysis by angiotensin-converting enzyme, which is primarily present in the perivenous (centrolobular) region. © 2005 Elsevier Inc. All rights reserved. Keywords: Kallikrein; Galectin; Bradykinin; Bradykinin-receptor; Portal hypertension; ACE

1. Introduction In 1949, Rocha e Silva and collaborators [50] were interested in discovering whether the venom of Bothrops jararaca liberated histamine from dog liver. They perfused the liver through the portal vein with defibrinated blood and the perfusate was collected from the inferior cava vein and tested directly upon the guinea pig ileum. The researchers observed a contraction completely different from that produced by histamine. Furthermore, anti-histaminics and atropine did not have any effect upon this contraction. The contracting substance disappeared rapidly from the perfusate when it was left at room temperature, and when the venom was added directly to blood samples, the same effect upon the ileum was observed. It was obvious to them that the precursor of the substance was present in the blood and not in the liver. Rocha e Silva named this substance bradykinin (BK), from the Greek bradys for slow and kinesia for movement. The plasma and tissue kallikrein–kinin systems (KKS) are responsible for the liberation of the vasoactive and proinflammatory mediators bradykinin and Lys-BK (Fig. 1). Although the KKS is recognized as an important modulator in ∗

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vascular biology, blood pressure regulation and vascular inflammation, it has also been studied regarding its influence on thrombosis, fibrinolysis and angiogenesis [54]. The plasma and tissue systems may play different biochemical, immunological and pathophysiological functional roles in kinin release. The plasma system includes prekallikrein, high- (H) and low-molecular weight (L)-kininogen, kinins and kininases. Plasma prekallikrein is synthesized by the liver [9] and once activated, hydrolyzes H-kininogen at two sites releasing BK. Differently from plasma kallikrein, the tissue kallikreins release mainly Lys-BK preferentially from L-kininogen [60]. By the action of aminopeptidases Lys-BK is converted to BK [7]. Tissue kallikreins are found in their active form in various tissues and their fluids [16] including salivary gland, endocrine or endocrine-related tissues and in the nervous system, glandular and duct cells, as well as in neutrophils, and distal nephron; the vasculature is also an important site of kallikrein expression. They are implicated in the regulation of blood flow and in water and electrolyte balance [33,45] and used as tumor markers [62]. Many aspects of the kallikrein–kinin system have been studied in the isolated perfused rat liver [10]. The liver synthesizes kininogens [3] and plasma kallikrein [9], the latter as an inactive precursor, prekallikrein. The proteolytic activity of plasma kallikrein is regulated by plasma inhibitors

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Fig. 1. The kallikrein–kinin system: bradykinin generation. Abbreviations: B1 R, B1 receptor; B2 R, B2 receptor; BK, bradykinin.

and liver clearance [10]. Although BK is known as a potent vasodilator, in the liver it has a hypertensive effect. This BK effect on the liver, producing an increase in the portal vascular tone was first observed by Borges et al. [5].

2. Kallikrein liver receptors The enzymatic activity of tissue kallikrein is inhibited by aprotinin, which also inhibits other serine proteases. A serine proteinase inhibitor named kallistatin was described [64], but it inhibits tissue kallikrein slowly and incompletely. Plasma kallikrein activity is modulated by plasma inhibitors, including C1 inhibitor, ␣2 -macroglobulin, antithrombin III, ␣1 -antitrypsin and ␣2 -antiplasmin [53,59]. In addition to inhibition, plasma and tissue kallikrein concentration can be regulated by liver clearance with both enzymes being rapidly cleared from the circulation by the perfused liver [8]. 2.1. Tissue kallikrein receptors We showed that hepatic removal of the pig pancreatic and horse urinary tissue kallikreins from the circulation involves receptor-mediated endocytosis by C-type lectins, which were characterized as mannosyl- and galactosyl-specific, respectively [25]. Inflammatory stimulus induced by turpentine oil did not affect the clearance rate of pig pancreatic kallikrein [42]. Patients with liver cirrhosis show an increased blood level of tissue kallikrein [63], therefore, the hepatic clearance of circulating tissue kallikreins could eventually be an important mechanism to control their plasma level. 2.2. Plasma kallikrein receptors The liver synthesizes prekallikrein, and is unable to either activate or clear it from the circulation. The active form, plasma kallikrein, is mainly cleared by the liver [8] and there is evidence that the hepatic binding site of plasma kallikrein is on the heavy chain and latent on prekallikrein [4]. Hepato-

cytes are the main cells involved in plasma kallikrein endocytosis because the clearance is neither affected by the blockade of Kupffer cells with carbon particles [2] nor by the blockade of sinusoidal cells with a large excess of formaldehydetreated albumin [57]. The hepatic clearance of free plasma kallikrein by rat liver is mediated by a galectin in a calciumindependent way [2,43]. This uptake was significantly inhibited by methyl ␤-d-galactoside, but not by methyl ␣-dgalactoside, ␣-methyl mannoside, melibiose or thiodigalactoside [43]. The kallikrein–kinin system participates in fibrinolysis system activation through BK that stimulates the secretion of tissue-type plasminogen activator (t-PA) from endothelial cells [12]. Moreover, we verified that the binding of plasma kallikrein to liver cells was partially inhibited by a molar excess of tPA, but not by pig pancreatic kallikrein [43] or thrombin [28], suggesting that plasma kallikrein and t-PA share a common pathway for hepatic clearance. Since the inhibition by ␤galactosides was not complete, we proposed the participation of another recognition system, probably via protein domain for plasma kallikrein clearance [43]. Plasma kallikrein can also be cleared from circulation as a complex with natural inhibitors, C1 inhibitor or ␣2 macroglobulin [24], but the hepatic clearance rate of free plasma kallikrein is more effective as compared with its complex form [46]. In 1979, Damas reported a congenital strain of rats (Brown Norway; B/N may Pfd, from the Katholiek University, Leuven) with a deficiency in high- and low-molecular weight kininogens as well as low levels of prekallikrein. These rats showed no kinin release and less plasma kallikrein activity [17]. The disappearance of plasma kallikrein from the circulation was studied in these rats and we found that the clearance of the active enzyme was similar to that of Wistar rats. Therefore, the low level of prekallikrein in the circulation cannot be explained by accelerated clearance of the protein. We also observed that the lack of kininogens did not affect the fate of

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plasma kallikrein; tissue accumulation of 125 I-kallikrein was similar to that observed in Wistar rats, except for the spleen [27]. In some pathological situations, such as inflammation [61], chronic ethanol intoxication [37], chronic liver disease [52] and induced diabetes [55], it was observed that the liver receptor-mediated endocytosis of some glycoproteins was reduced. We studied the hepatic clearance of plasma kallikrein in different experimental conditions. Since aggression to the liver may lead to a progressive process of inflammation, steatosis, fibrosis and cirrhosis, experimental models for each situation was chosen. Altered hepatic circulation as a result of injury and fibrosis is the basis of all functional failure and the most common liver diseases of human are caused either by cirrhosis or by parasites (schistosomiasis) [47]. 2.3. Inflammatory model The acute phase reaction induced either by turpentine oil or endogenous pyrogen preparation increased significantly plasma kallikrein clearance by the liver [34]. 2.4. Steatosis Chronic administration of ethanol to rats, which led to the development of steatosis without cirrhosis, did not affect hepatic clearance of plasma kallikrein, but decreased that of horse urinary kallikrein. This result suggests that ethanol and not steatosis may be responsible for the reduction in liver uptake of tissue kallikrein, which involves a C-type lectin [56]. 2.5. Zonal necrosis Parenchymal necrosis affecting zone 3 caused by acute acetaminophen treatment decreased the liver clearance rate of plasma kallikrein suggesting that its receptors may be localized mainly in the affected zone [57].

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2.6. Fibrosis In the classical experimental model of fibrosis, induced by porcine serum treatment [1], kallikrein clearance was not impaired (Fig. 2). On the contrary, in this model, the clearance of t-PA was decreased. Since t-PA binds to both hepatocytes and sinusoidal endothelial cells, it might explain the decrease in its clearance and not that of plasma kallikrein, which is cleared mainly by hepatocytes [41]. 2.7. Cirrhosis Rats treated with carbon tetrachloride may develop cirrhosis where hepatic clearance rate of plasma kallikrein was significantly slower than in the control group [58]. 2.8. Liver regeneration Plasma kallikrein clearance was also studied during the process of liver regeneration following partial hepatectomy. We observed that on day 1, there was a significant increase of plasma kallikrein clearance rate by the perfused rat liver remnant. Although there was an increased concentration of ␣2 -macroglobulin, an acute phase protein, the clearance of plasma kallikrein seems to be independent of the acute phase reaction since that protein was also elevated in the control rat group [11].

3. Hepatic bradykinin metabolism Bradykinin can cause all four signals of inflammation: swelling, heat, redness and pain, and therefore may be considered to be an important mediator of inflammation [51]. The action of released BK is very short, with a half-life in the circulation of less than 1 min [18]. Most of the actions of BK and Lys-BK are mediated through the B2 receptor and they may vary depending on the cell and tissue-type as well as on the B2 receptor subtypes and the specific G

Fig. 2. Possible receptor recognition systems for plasma kallikrein (PK) in the liver of normal, fibrotic and cirrhotic rats. PK has at least two pathways for hepatic clearance: one galectin-dependent and another probably mediated by a protein domain of the molecule. In experimental fibrosis model, the liver architecture is generally preserved, and an eventual sinusoidal capillarization was not intense enough to impair PK clearance. In advanced cirrhosis, there is a transition from the permeable perisinusoidal space to an impermeable membrane associated with complete endothelial defenestration, resulting in a barrier that prevents the transfer of oxygen, nutrients and important substances from the blood to the liver cells. In this model, the hepatic clearance rate of PK is impaired. ( , inhibition by galactosides). Abbreviations: PK, plasma kallikrein; ␤-gal, ␤-galactoside.

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protein-coupled second messenger system [31]. Upon activation, B2 receptors initiate an array of intracellular and intercellular response. Early post-binding events include an increase in cytosolic calcium, activation of G protein, guanylate cyclase and phospholipases C, D and A2 [48]. BK and Lys-BK have a short half-life in the circulation, with rapid hydrolysis by several peptidases, called kininases [16], as well as by B2 receptor-bound internalization [40]. 3.1. BK hydrolysis Angiotensin I-converting enzyme (ACE; kininase II; EC 4.4.15.1) is the main kininase, which removes sequentially two carboxy-terminal dipeptide from BK or Lys-BK, hydrolyzing the vasoactive peptides. It is a widely distributed membrane-bound zinc peptidase and located on endothelial cells. Kininase I enzymes (carboxypeptidases N and M) remove the Arg C-terminal from BK, Lys-BK and other vasoactive peptides such as angiotensin and endothelins. Carboxypeptidase N (EC 3.4.17.3) is synthesized in the liver and secreted in plasma, while carboxypeptidase M is a widely distributed membrane-bound peptidase. These kininase I enzymes are of particular importance because the removal of the Arg C-terminal from native kinins transforms them into desArg9 -BK and Lys-des-Arg9 -BK, which are also bioactive, but act through a distinct receptor. There are other physiologically relevant kininases responsible for kinin metabolism such as neutral endopeptidase 24.11 (NEP, neprylysin, EC 3.4.24.11) and aminopeptidase P (APP, EC 3.4.11.9) [16]. BK inactivation is also modulated by the liver [49,5]. The liver contains several kininases and in “in vitro” assays with rat liver homogenate, the metaloendopeptidase (EC 3.4.24.15) predominates over the angiotensin-converting enzyme and prolyl-endopeptidase [38]. The hepatic EC 3.4.24.15 cleaves BK at the Phe5 -Ser6 bond releasing two peptides [26]; the ArgProProGlyPhe (BK 1–5) fragment has a protective effect from the deleterious effects of lipopolysaccharides in rats [39]. The hepatic distribution of EC 3.4.24.15 [20] and ACE is similar and predominates in the perivenous region, that is surrounding the centrolobular vein (zone 3) [21]. Although we suggested that EC 3.4.24.15 might be the main liver kininase, it cannot be considered important at least in the extracellular metabolism of BK. In addition, we suggest that ACE is the main kininase involved in BK degradation by the liver [21]. 3.2. Hepatic bradykinin-receptors Besides inactivation, kinins can be removed from the circulation by specific receptor-mediated endocytosis [40]. Studies about the action of BK on the vascular bed demonstrated that it acts on two types of receptors, B1 (inducible) and B2 (constitutive) [31]. Both receptors mediate action on vascular tone and initially their differentiation was based on a comparison of the potency of agonists and inhibitors in several vascular preparations. In normal tissue, the major phar-

macological effects of BK and Lys-BK are mediated by B2 receptors. In contrast, B1 receptors are not found in normal tissue, but are induced in a variety of cells following an inflammatory injury, and respond more efficiently to Lys-desArg9 -BK and des-Arg9 -BK than to BK itself. Antagonists of B1 and B2 are des-Arg9 [Leu8 ]-bradykinin and HOE, respectively [23]. Analysis by RT-PCR and Southern blot have shown the expression of the human B1 gene in almost all tissues (salivary glands, pancreas, thyroid, spleen, brain, pituitary gland, liver, lung, etc.) [14], although it does not imply concurrent synthesis of the receptor protein. In rats, a very low level of B1 receptor mRNA was detected in the normal liver and it did not increase after LPS administration [44]. Its expression is up-regulated, “in vitro” and “in vivo”, following the release of various inflammatory stimuli in situations of trauma, stress or injury, or administration of lipopolysaccharides or cytokines [31]. When activated by agonists, B2 receptors undergo desensitization, internalization and recycling to the cell surface; conversely B1 receptors are not internalized or desensitized following agonist stimulation [32]. Studying BK metabolism, we showed, in 1976, that BK produces hypertensive effects on the hepatic microcirculation, although the peptide was known as a potent arterial vasodilator. When BK is added either to the isolated liver perfusion medium or introduced directly in the portal vein cannula as a bolus injection, it causes an increase in portal pressure [5,30]. This hepatic hypertensive response to BK is mediated by the B2 receptor and modulated by the L-Argnitric oxide pathway [30]. The effect of BK was also studied in a recirculating bivascular liver perfusion performed in the anterograde mode (entry via the portal vein and hepatic artery; exit via the hepatic vein) and BK was injected “in bolus” into the hepatic artery or portal vein. We observed that BK induced a double hypertensive response by acting on the B2 receptor through a distinct pathway. The arterial hypertensive response was calcium-independent and mediated by eicosanoids, since it was practically abolished by naproxen [21]. We also demonstrated that BK had an effect on all sinusoidal cells (quiescent hepatic stellate, hepatic endothelial and Kupffer cells), but not on hepatocytes as observed by microphysiometer analysis [21]. Hepatic stellate and endothelial cells contain contractile filaments, tubules and proteins, and are involved in the modulation of intrahepatic vascular tonus [35], therefore, BK may participate in this modulation. The sequence of events following “in bolus” BK injection in the rat liver perfusion medium is illustrated in Fig. 3. 3.3. Experimental models and BK B2 receptors The severity of liver disease is related to deposits of collagen, leading to fibrosis. As fibrosis increases, a point is reached at which blood flow is hindered by distortion of the usual flow of blood and the portal pressure must increase to preserve flow [22]. During liver injury, stellate cells undergo a process called “activation” characterized by cell enlargement,

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Fig. 3. Bradykinin (BK): action and degradation by the perfused rat liver. BK produces both portal and arterial hypertensive responses by a distinct pathway. In the portal vein (PV), the effect is modulated by B2 receptors (B2 R) present in sinusoidal endothelial cell (SEC) and stellate hepatic cell (SHC). In the hepatic artery (HA), the effect might be on the sphincter. BK is inactivated by angiotensin-converting enzyme (ACE). (*) Blocked by HOE-140; (**) not tested for B1 agonists/antagonist.

local proliferation, enhanced fibrogenesis and expression of smooth muscle ␣-actin. The latter may be responsible for the contractile behavior of activated stellate cells, implying that these cells may be important in vasoregulation during liver injury [19]. There is evidence of a participation of BK in the pathogenesis of vasodilatation and ascites formation in cirrhotic patients. Plasma ratio of hydrolyzed to total H-kininogen is greater in cirrhotic patients with great ascites volume than in normal persons [15]. The portal hypertensive response induced by BK is preserved in inflamed or cirrhotic rat livers [29]. In experimental fibrosis, the activation of stellate cells did not alter the portal hypertensive response to BK indicating that the effect on these cells does not depend on previous activation. In addition, during liver regeneration, after a 70% liver resection, the portal hypertensive response to BK is present although it is lower on days 1 and 2 as compared to day 0 [6]. The increasing effect on hepatic portal pressure caused by BK does not persist and it vanishes within 2 min due to rapid

inactivation during the first passage through the organ [5]. BK added to the perfusion fluid disappears completely within 5 min of perfusion with a half-life of 1.5 ± 0.2 min. The addition of the B2 receptor antagonist, HOE-140, to the perfusion fluid abolished the hypertensive action of BK, but not its hydrolysis. On the other hand, captopril (ACE inhibitor) but not JA-2 (EC 3.4.24.15 inhibitor) increases BK half-life more than three times without affecting the hypertensive action of BK [21]. 3.4. Experimental models and BK B1 receptors Des-Arg9 -BK or Lys-des-Arg9 -BK does not promote a hepatic hypertensive response in both normal and LPStreated rats. In relation to BK, LPS treatment did not affect the hypertensive response. Previous addition of HOE-140 to the perfusion medium abolished BK action suggesting that its hepatic effect, even after inflammatory stimuli, is mediated by B2 receptors only. The synthetic agonist Sar-[D-Phe8 ]des-Arg9 -BK, more resistant to the enzymatic action of peptidase, was also tested in liver perfusion experiments and

Table 1 Kallikrein clearance and portal hypertensive response to bradykinin in experimental models Substance

Receptor

Experimental model

Liver response

Reference

Pancreatic kallikrein Urinary kallikrein

Mannosyl-specific lectin Galactosyl-specific lectin

Inflammation Ethanol-induced steatosis

Normal uptake Reduced uptake

[34,54] [34,74]

Plasma kallikrein

Galectin

Normal Ethanol-induced steatosis Inflammation Toxic hepatitis Fibrosis Cirrhosis Liver regeneration, day 1 Liver regeneration, days 2–7

Normal uptake Increased uptake Reduced uptake Normal uptake Reduced uptake Increased uptake Normal uptake

[10,13] [54,74] [54,55] [76] [54,56] [76] [16] [16]

Normal Inflammation Fibrosis Cirrhosis Liver regeneration, days 1–2 Liver regeneration, days 3–7

Normal PHRa Normal PHR Normal PHR Reduced PHR Normal PHR

[28,41] [42] [14] [42] [14] [14]

Bradykinin

a PHR,

B2

portal hypertensive response.

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we observed no hypertensive response in any of the groups (manuscript in preparation). These results suggest that in the liver, even though induction of B1 receptor may occur, it is not operative [6]. Campos and Calixto [13] demonstrated the presence of B1 receptors in rings of rat portal vein. In this model, the contraction induced by des-Arg9 -BK increases progressively from initial low levels as a function of “in vitro” incubation time. There is evidence that tissue injury produced by “in vitro” long incubation time of rat portal vein leads to the activation of p38 MAPK and JNK as well as the transcriptional factor NF-␬B which, in turn, has a critical role in modulating functional and molecular up-regulation of B1 receptors [36]. 4. Conclusions Table 1 summarizes all the liver receptors for kallikreins and bradykinin in normal and experimental models studied up to now. The liver is the main organ to clear porcine pancreatic, horse urinary and rat plasma kallikreins by different receptors, which are independently modulated in some pathological situations. In the liver, BK produces a portal hypertensive response mediated by B2 receptor on sinusoidal endothelial cell (SEC) and stellate hepatic cell (SHC) or a calcium-independent arterial hypertensive response mediated by eicosanoids. Finally, BK can be degraded by ACE, mainly in the perivenous area. The study of modulation of the kallikrein–kinin system by the liver is important to better understand its possible participation in inflammation and liver diseases. Acknowledgements Financial support provided by FAPESP (02/05260-6), CNPq (300499/2003) and FADA/UNIFESP. References [1] Bhunchet E, Wake K. The portal lobule in rat liver fibrosis: a reevaluation of the liver unit. Hepatology 1998;27:481–7. [2] Borges DR, Gordon AH, Guimar˜aes JA, Prado JL. Rat plasma kallikrein clearance by perfused rat liver. Braz J Med Biol Res 1985;18:187–94. [3] Borges DR, Gordon AH. Kininogen and kininogenase synthesis by the liver of normal and injured rats. J Pharm Pharmacol 1976;28:44–8. [4] Borges DR, Kouyoumdjian M. The recognition site for hepatic clearance of plasma kallikrein is on its heavy chain and is latent on prokallikrein. J Hepatol 1992;16:115–21. [5] Borges DR, Limaos EA, Prado JL, Camargo AC. Catabolism of vasoactive polypeptides by perfused rat liver. Naunyn Schmiedebergs Arch Pharmacol 1976;295:33–40. [6] Borges DR, Nagaoka MR, Teixeira FO, Minary P, Kouyoumdjian M. Chemical aggression or inflammatory and regenerative stimuli do not induce bradykinin B1 receptor expression in the liver. Liver Int 2004;24:33.

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