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Abstract

Targeting the renin–angiotensin system (RAS) constitutes a major advance in the treatment of cardiovascular diseases. Evidence indicates that angiotensin-converting enzyme inhibitors and angiotensin AT1 receptor blockers act on both the RAS and the kallikrein–kinin system (KKS). In addition to the interaction between the RAS and KKS at the level of angiotensin-converting enzyme catalyzing both angiotensin II generation and bradykinin degradation, the RAS and KKS also interact at other levels: 1) prolylcarboxypeptidase, an angiotensin II inactivating enzyme and a prekallikrein activator; 2) kallikrein, a kinin-generating and prorenin-activating enzyme; 3) angiotensin-(1-7) exerts kininlike effects and potentiates the effects of bradykinin; and 4) the angiotensin AT1 receptor forms heterodimers with the bradykinin B2 receptor. Moreover, angiotensin II enhances B1 and B2 receptor expression via transcriptional mechanisms. These cross-talks explain why both the RAS and KKS are up-regulated in some circumstances, whereas in other circumstances both systems change in the opposite manner, expressed as an activated RAS and a depressed KKS. As the cross-talks between the RAS and the KKS play an important role in response to different stimuli, taking these cross-talks between the two systems into account may help in the development of drugs targeting the two systems.

Keywords

Angiotensin AT1 receptor blocker angiotensin-converting enzyme inhibitor AT1/B2 heterodimers cardiovascular disease the kallikrein–kinin system the renin–angiotensin system transcriptional regulation

Introduction

The renin–angiotensin system (RAS) is a ubiquitous hormone system. Classically, plasma renin secreted by the kidneys catabolizes the conversion of angiotensinogen released by the liver to angiotensin I, which is subsequently converted to angiotensin II by the angiotensin I-converting enzyme (ACE) localized in the vascular endothelium of different organs, adventitial layers of the aorta and pulmonary artery, cardiac valve leaflets and epithelial cells of the renal proximal tubules.^1–3 In addition, angiotensins are generated not only in the plasma but also locally in tissues from precursors and substrates either locally expressed or imported from the circulation.^4,5 The RAS is complicated by the existence of two types of ACE (ACE and ACE2) and two types of receptors (AT₁ and AT₂). Most of the known cardiovascular effects induced by angiotensin II (e.g. vasoconstriction, water and salt retention, aldosterone synthesis and release, growth and remodeling) are mediated via AT₁ receptors.⁶ Experiments in cells and vessels, as well as in vivo studies in rats and mice, including studies in transgenic animals, have shown that AT₂ receptor stimulation counteracts some or all of the abovementioned effects mediated via AT₁ receptors,^7–14 although activation of AT₂ may, in some tissues, result in parallel rather than opposite effects to AT₁ activation.¹⁵ The RAS is one of the most important systems in cardiovascular control and in the pathogenesis of cardiovascular diseases. Targeting the RAS has resulted in the successful development of ACE inhibitors (ACEi), AT₁ blockers, and recently the third generation of renin inhibitors. These drugs are currently used in the treatment of cardiovascular diseases such as hypertension and heart failure, which constitutes a major advance in cardiology.

The kallikrein–kinin system (KKS) was discovered in 1909, when it was learned that the injection of urine (rich in kinins) decreased blood pressure,¹⁶ and high-molecular weight kininogen was first identified in urine in 1930.¹⁷ Kinins have been found in jellyfish toxin, wasp and snake venom and the skin and bladder of frog, as well as in the mammalian tissues and exocrine secretions such as saliva, sweat and urine.¹⁸ Kinins are synthesized from their precursors, kininogens in the blood and different tissues, under the action of different kinin-forming enzymes known as kininogenases such as plasma and tissue kallikrein. Kinins are rapidly metabolized into inactive peptides or agonists of B1 receptors by several kininases, including aminopeptidases, carboxypeptidase N and M, ACE, neutral endopeptidase (NEP), platelet cathepsin A and intracellular enzymes such as prolylendopeptidase.¹⁹ Due to the short half-life of bradykinin (~0.5 min),²⁰ bradykinin is generally considered to be synthesized at tissue sites where it exerts its biological action. This is supported by the fact that the different components required to generate bradykinin locally are present in the heart and vessel wall^21,22 and that tissue bradykinin levels are higher than those in circulating blood²³ and bradykinin is released from tissue sites into the circulation.²⁴ The biological effects of bradykinin are mediated by the stimulation of specific receptors, classified as B1 and B2.²⁵ B2 receptors are constitutively and functionally expressed in many tissues and mediate the major physiological action of bradykinin while B1 receptors are inducible and exert their actions in response to endotoxin,^26,27 proinflammatory cytokine,²⁸ tissue injury, inflammation, anoxia²⁹ and myocardial infarction.³⁰ Another particularity of B1 receptors is that B1-mediated responses are not as tachyphylactic as B2-mediated responses.³¹ The inducible property and weak tachyphylaxis make B1 receptors play an important role in various pathophysiological states, including chronic inflammation, pain, hypotension, trauma and proliferation of cancer.^25,32–34 Therefore, targeting B1 receptors by developing specific B1 antagonists may represent a pharmacological strategy to treat chronic inflammation and cancer,²⁵ while blocking B2 receptors during the acute phase of endotoxemia may be beneficial.^35,36 B1 receptors may also be constitutively presented in some tissues,^37
–43 but their stimulation produces less potent effects than the stimulation of B2 receptors.^38,39 The KKS plays an important role in the regulation of cardiovascular function. In the cardiovascular system, the primary action of bradykinin is vasodilation, which is mediated in most vascular beds by the release of nitric oxide, prostacyclin and perhaps endothelium-derived hyperpolarizing factor.⁴⁴ Contrary to other endothelium-dependent vasodilators such as acetylcholine and calcium channel blocker amlodipine whose vasodilator potency is impaired due to vascular endothelial dysfunction in the heart failure state,^45,46 the vasodilator effect of bradykinin has been shown to be preserved under these conditions in animals and in humans.^46,47 Although the concentration of kinins in the blood is not high enough to affect blood pressure under physiological conditions, kinogen deficiency occurring in Brown Norway Katholiek rats or targeted disruption of the B2 receptor gene in mice leads to the development of salt-induced hypertension in the early life of animals,^48,49 while adult mice lacking B2 receptors suffer from hypertension, left ventricular (LV) remodeling, and functional impairment.⁵⁰ Mice lacking tissue kallikrein are unable to generate significant levels of kinins in most tissues and develop cardiovascular abnormalities such as cardiac chamber dilation, wall thinning and functional impairment early in adulthood despite normal blood pressure.⁵¹ The KKS participates in the regulation of coronary vascular tone in humans.⁵² Its dysfunction contributes to abnormal coronary vasomotion.⁵³ Endogenous bradykinin contributes to cardioprotection in heart failure⁵⁴ and in myocardial ischemia.^55,56 Moreover, chronic treatment with bradykinin prevents the progression of heart failure induced by rapid pacing⁵⁷ and normalizes cardiac contractile function and vascular endothelial function through upregulation of cardiovascular endothelial and neuronal nitric oxide synthase in dogs with dystrophin deficiency-induced cardiomyopathy.^58,59 An entire kinin system is present in the kidney and plays a significant role in the regulation of renal blood flow and water-electrolyte balance.¹⁸ The KKS participates in the process of hemostasis. Kininogens inhibit thrombin-induced platelet activation and block the fixation of thrombin to platelets.⁶⁰ By binding to calpain at the platelet membrane, kininogens inhibit platelet aggregation.⁶¹ In addition, kinins play an essential role in fibrinolysis. Plasma kallikrein is capable of generating plasmin from plasminogen while bradykinin stimulates tissue plasminogen activator release from endothelium; this latter converts plasminogen to the active plasmin, thus allowing fibrinolysis to occur.⁶² Some components of the KKS may be angiogenic as indicated by the fact that local administration of a B1 receptor agonist enhanced collateral vascular growth in ischemic skeletal muscle.⁶³ The KKS is involved in the therapeutic actions of ACEi. The cardioprotective effects such as reduction of postischemic reperfusion injuries in isolated rat hearts or the reduction in infarct size in dogs and rabbits, the antihypertrophic effects in rats with aortic binding, and the increasing effect on myocardial capillary density in stroke-prone spontaneously hypertensive rats of ACEi can be attenuated or abolished by a specific bradykinin B2 receptor antagonist, Hoe-140.^64–66 In pacing-induced canine heart failure, ACEi increase blood levels of kinins while Hoe-140 attenuates by more than 50% the blood pressure-lowering effect of enalaprilat.^67,68 The KKS also contributes to the effects of AT₁ receptor blockers. AT₁ receptor blockade limits infarct size, attenuates cardiac remodeling, and improves cardiac function in the myocardial infarction model. These effects are partially mediated via activation of the AT₂-bradykinin-nitric oxide pathway^69–71 and/or increase in cardiac bradykinin via neutral endopeptidase observed in the rat myocardial infarction model.⁷² In addition, several studies showed that the vasodilator effect of dihydropyridine calcium channel blockers involves the activation of the KKS. Amlodipine, a long-acting calcium channel blocker used as an anti-hypertensive and in the treatment of angina, increases nitric oxide production in coronary microvessels of failing canine and human hearts and this effect can be attenuated by Hoe-140, indicating a kinin-mediated mechanism,^73,74 while in uni-nephrectomized streptozotocin diabetic Wistar-Kyoto rats, benidipine attenuates the development of diabetic renal impairment and the decrease in urinary active kallikrein excretion.⁷⁵

Experimental and clinical evidence demonstrates multiple cross-talks between the RAS and the KKS.^76,77 As shown in Figure 1, these cross-talks occur at different levels. The following sections will discuss these cross-talks in more detail.

Figure 1.

The cross-talks between the renin-angiotensin system (RAS) and the kallikrein-kinin system (KKS). ACE: angiotensin I-converting enzyme; ACE2: carboxypeptidase; APA: aminopeptidase A; BK: bradykinin; CNP: carboxypeptidase N; HMW: high molecular weight; LMW: low molecular weight; NEP: neutral endopeptidase; PRCP: prolylcarboxypeptidase; PREP: prolylendopeptidase.

Prolylcarboxypeptidase

The enzyme prolylcarboxypeptidase (PRCP), also known as Pro-X carboxypeptidase, lysosomal Pro-X carboxypeptidase, peptidyl prolylamino acid hydrolase or angiotensinase C, has been shown to be an angiotensin II degrading enzyme, initially discovered by Erdös and Yang.^78,79 PRCP is a serine protease inhabitable by diisopropyl fluorophosphates, phenylmethylsulfonyl fluoride, antipain, leupeptin, corn trypsin inhibitor, and high concentrations of mercuric chloride.⁷⁹ Interestingly, PRCP is also a prekallikrein activator.^80–82 PRCP can be increased in response to stimulation of AT₂ receptors⁸³ or overexpression of AT₂ receptors⁸⁴ and contributes to the release of bradykinin in mouse coronary artery endothelial cells.⁸⁴ Furthermore, PRCP depletion induces vascular dysfunction with hypertension and faster arterial thrombosis in mice.⁸⁵ Therefore, PRCP may represent a therapeutic target for the treatment of cardiovascular diseases. However, recently, inhibiting PRCP has been proposed as a new drug target for the treatment of obesity because of its property to degrade hypothalamic α-melanocyte-stimulating hormone (α-MSH) that plays a central role in regulating energy uptake and expenditure and because of the observation that PRCP null mice display elevated α-MSH in the hypothalamus, lower body weight, and are protected from diet-induced obesity.⁸⁶

Kallikrein

Renin, a key enzyme in the formation of angiotensin II, is produced from its inactive form, prorenin, which circulates in plasma. Acidification of human plasma at 4°C initiates a process by which prorenin is converted into active renin. This process involves the activation of prekallikrein by factor XII and the conversion of prorenin into renin by the action of kallikrein itself or by other proteases activated by kallikrein.^87–90 In addition, rat submandibular gland kallikrein can generate directly angiotensin II from angiotensinogen or angiotensin I.⁹¹ Thus, kallikrein is involved in the generation of both a pressor and depressor substance, which constitutes another level of cross-talks between the RAS and the KKS. This may explain why both the RAS and KKS are upregulated following tissue injury where they influence vascular function, inflammation, cell growth and differentiation, and angiogenesis.^92,93

ACE

Since the discovery of ACE by Skeggs and colleagues,⁹⁴ the discovery of a bradykinin-potentiating factor presented in the venom of Bothrops jararaca by Ferreira,⁹⁵ and the discovery by Erdös and colleagues that the enzyme kininase II, which degrades bradykinin, and the ACE, which forms angiotensin II, is one and the same,^96,97 the function of ACE and the cross-talk at the ACE level between the RAS and the KKS have been recognized. This cascade of events led to the discovery of the first ACEi captopril and to the study of the mechanisms of action of ACEi. It is well established that ACE not only converts angiotensin I to angiotensin II, but also degrades bradykinin by the removal of two carboxyl-terminal amino acids. This has further been supported by in vivo experimental studies showing that ACEi decrease blood angiotensin II concentration but increases blood concentration of bradykinin in normal human subjects,⁹⁸ in dogs with pacing-induced heart failure and in patients with congestive heart failure, which contributes to the pressure-lowering effect of ACEi.^67,68,99 The activation of the KKS also contributes to the reduction of myocardial collagen accumulation and cardioprotection afforded by ACEi.^{64–66,100–104} Furthermore, cellular studies showed that ACE has an even stronger affinity toward bradykinin than toward angiotensin I,^105,106 and studies in intact animals demonstrated that the inhibition of bradykinin degradation contributes more to the pressure-lowering effect of ACEi than the inhibition of angiotensin II formation.^46,67,107 Additional evidence supporting the action of ACE on the metabolism of bradykinin is that ACEi potentiates the bradykinin-induced vasoconstriction in isolated rabbit jugular vein,¹⁰⁸ the endothelium-dependent dilator response to bradykinin in isolated vessels^109,110 and perfused rat heart^111,112 and the hemodynamic effects of bradykinin in conscious dogs,^46,67 although the bradykinin potentiation induced by ACEi may also be related to the preservation of high-affinity B2 receptors and to the blockade of B2 receptor desensitization and internalization.¹¹³ In addition to the development of ACEi, an attempt has been made to develop the dual ACE/NEP inhibitors to expect a complementary effect because NEP degrades vasodilatory peptides such as kinins, natriuretic peptides, and adrenomedullin. A clinical trial showed some advantage of this type of inhibitors over ACEi in patients with heart failure.¹¹⁴ However, other studies did not confirm the superiority of the dual ACE/NEP inhibitor over ACEi but observed an increase in side effects such as angioedema, likely owing to accumulation of kinins.¹¹⁵

Angiotensin-(1-7) and bradykinin

In addition to the cross-talks between the RAS and the KKS illustrated in the Figure and discussed above, there are still other interactions between the two systems.

Angiotensin-(1-7) is a member of the angiotensin family. It can be generated from angiotensin I under the action of neutral endopeptidase,^116–118 prolylendopeptidase,^119–121 aminopeptidase A and neprilysin.¹²² It can also be produced from angiotensin II under the action of PRCP¹²³ and especially, carboxypeptidase (ACE2).^124–127 Interestingly, contrary to angiotensin II, this peptide exerts a vasodilator effect through Mas receptors and through potentiation of bradykinin.^34,128–132 In this regard, angiotensin-(1-7) acts as an ACEi to potentiate bradykinin.^130,133 Angiotensin-(1-7) is both a substrate and an inhibitor of ACE.^133–136 It is cleaved by N-domains of ACE at approximately one-half the rate of bradykinin but negligibly by C-domains of ACE. It inhibits C-domains of ACE at an order of magnitude lower concentration than N-domains of ACE.¹³³ Angiotensin-(1-7) is increased during ACE inhibition, which is related to the elevated angiotensin I induced by ACEi and to the fact that ACE degrades angiotensin-(1-7). The effect of angiotensin-(1-7) on bradykinin seems also to involve AT₂ receptors, since the AT₂ receptor antagonist PD123319 partially blocked the angiotensin-(1-7) as well as bradykinin-induced relaxation.¹²⁸ Thus, the cross-talk between angiotensin-(1-7) and ACE affects both the RAS and the KKS. In this respect, the ACE2/angiotensin-(1-7)/Mas pathway may be a target to counteract angiotensin II in the cardiovascular system. In this regard, an activator of ACE¹³⁷ and Mas agonists such as angiotensin-(1-7) in oral formulation¹³⁸ or its nonpeptide analog AVE0991¹³⁹ have been tested in animal models of cardiovascular diseases.

Angiotensin AT₁/AT₂ receptors and bradykinin B2 receptors

In the cortical thick ascending limb, bradykinin exerts negative modulatory effects on angiotensin II-induced (Ca²⁺)_i responses, depending on tyrosine kinase and mitogen-activated protein kinase (MAPK) pathways. Bradykinin also suppresses angiotensin II-induced Na⁺ transport.¹⁴⁰ These effects suggest an interaction between AT₁ and B2 receptors. It has been reported that the AT₁ and B2 receptors form constitutive heterodimers,¹⁴¹ suggesting that AT₁ and B2 receptors also communicate directly with each other. The AT₁/B2 heterodimers display increased sensitivity toward angiotensin II and are found in platelets and in omental vessels of preeclamptic women¹⁴² and are more abundant in renal mesangial cells isolated from spontaneously hypertensive rats compared with normotensive controls, which mediate an enhanced angiotensin II-stimulated Galphaq/11 activation and an increased endothelin-1 secretion of mesangial cells from hypertensive rats.¹⁴³ Therefore, the AT₁/B2 heterodimers may be a pharmacological target to treat hypertension. However, the universality of the formation of AT₁/B2 receptor heterodimers has been questioned.¹⁴⁴ In cultured COS-7, HEK293, and NIH3T3 cells, although both the AT₁ and B2 receptors were functional, there were no AT₁/B2 heterodimers to be detected.¹⁴⁴

The cross-talk between the RAS and KKS at the receptor level also involves AT₂ and B2 receptors. B2 receptor activation participates in the effects of AT₂ receptor-mediated effects observed after AT₁ receptor blockade,^7,145,146 where AT₂ receptor density and ACE2 gene expression were increased.^147,148 However, the interaction between AT₂ and B2 receptor activation is not yet fully understood. It has been proposed that angiotensin II decreases the intracellular pH in endothelial cells, which subsequently activates kininogenases that cleave bradykinin from intracellularly stored kininogens.¹⁴⁹ Another possibility is that AT₂ and B2 receptors form heterodimers whose stimulation induces B2 receptor-dependent effects. However, this hypothesis remains to be proved.

The cross-talk at the transcriptional level

In mouse inner medullary collecting duct cells, angiotensin II produces dosage- and time-dependent increases in B2 receptor mRNA and protein levels, which can be abrogated by actinomycin D, an inhibitor of gene transcription. In this setting, angiotensin II stimulates phosphorylation of cAMP response element binding protein (CREB) on Ser-133 and assembly of p-CREB on the B2 promoter and induces hyperacetylation of B2 promoter-associated H4 histones.¹⁵⁰ Interestingly, angiotensin-(1-7) at medium and high doses increases bradykinin B2 receptor mRNA and protein expression, whereas only high-dose angiotensin-(1-7) increases bradykinin B1 receptor expression in the brain.¹⁵¹ In addition, exogenous ACE added to vascular smooth muscle cell culture strongly upregulates the gene expression of bradykinin B1 and B2 receptors, which can be abolished by actinomycin D.¹⁵² A cross-talk between AT₁ and B1 receptors may also occur, since AT₁ blocker increases protein and mRNA level of B1 receptors, while AT₁ overexpression reduces B1 receptor expression in the rat myocardial infarction model.¹⁵³ Therefore, the cross-talk between the RAS and the KKS occurs also at the transcriptional level.

Conclusion and perspectives

The multiple cross-talks between the RAS and the KKS indicate that the two systems are interdependent and finely regulated. The changes in one system are obligatorily accompanied by changes in the other system. In some circumstances, the changes occur in the opposite manner, which are often expressed as an increased RAS and a depressed KKS.^154,155 This supports the concept that the KKS counterbalances the RAS. However, in some circumstances, the changes in both the RAS and KKS occur in the same direction. This can be seen in the case of tissue injury where both the RAS and KKS are upregulated.^92,93 Therefore, taking the interactions between the RAS and the KKS into account may help us to understand the physiopathological mechanisms of some cardiovascular diseases, to explain the mechanisms of action of some drugs currently used in the treatment of cardiovascular diseases, and finally, to develop new drugs targeting different components of the RAS and the KKS.

Footnotes

Conflict of interest

None declared.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Different cross-talk sites between the renin–angiotensin and the kallikrein–kinin systems

Abstract

Keywords

Introduction

Prolylcarboxypeptidase

Kallikrein

ACE

Angiotensin-(1-7) and bradykinin

Angiotensin AT1/AT2 receptors and bradykinin B2 receptors

The cross-talk at the transcriptional level

Conclusion and perspectives

Footnotes

Conflict of interest

Funding

References

Angiotensin AT₁/AT₂ receptors and bradykinin B2 receptors