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(Hypertension. 1995;26:221-229.)
© 1995 American Heart Association, Inc.

Articles

Kallikreins and Kinins

Some Unanswered Questions About System Characteristics and Roles in Human Disease

Harry S. Margolius

From the Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston.

Correspondence to Harry S. Margolius, MD, PhD, Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425-2251. E-mail harry_margolius.pharmacology@smtpgw.musc.edu.

	Abstract

Top Abstract Introduction New Insights Into Component... System Component Regulation Interrelations With Other... Kallikreins, Kinins, and... Kallikrein-Kinin System Function... Summary References

 
Abstract Kinins can affect many aspects of cellular function, but their roles in human homeostatic mechanisms and disease are just beginning to be understood. In this brief review, some of the interesting new observations about kallikrein-kinin system characteristics, roles in cell behavior, and aberrancy in diseases of relevance to readers interested in hypertension will be discussed. Along the way, questions raised by these observations will be posed. They show that we still have much to learn about the contributions of kinins to human cardiovascular diseases but now have in addition both a strong rationale for asking them and the tools to make them operational.

Key Words: kallikrein-kinin system • kininogens • bradykinin

	Introduction

Top Abstract Introduction New Insights Into Component... System Component Regulation Interrelations With Other... Kallikreins, Kinins, and... Kallikrein-Kinin System Function... Summary References

 
Tissue kallikreins and their kinin products appear to be important regulators of cardiovascular function. They are being increasingly noted as likely participants in the actions of drugs that affect the heart, kidney, and circulation.¹ This phylogenetically ancient system of substrates, proteases, peptides, peptidases, and inhibitors has some responsibility for the regulation of local and perhaps systemic hemodynamics, vascular permeability, the inflammatory response, activation of neuronal pathways, and the movement of electrolytes, water, and metabolic substrates across epithelia and into other tissues.² Indeed, it is difficult to name a mammalian cell type devoid of kinin receptors and responsiveness to kinins, implying many regulatory roles for kinins that are still undescribed. These conclusions are the result of important discoveries concerning the cellular sites of system component gene expression and the regulation of such expression; better descriptions of the meaning of structural features of system molecules, including the kininogens, kallikreins, kininases, and kinin receptors; newly detected relations among these molecules and other cardiovascular regulatory hormones and mechanisms; and finally, new findings illustrating system abnormality in cardiovascular insults or diseases including hypertension, disorders of cardiac function, and diabetes mellitus. This brief review will survey some recent findings, many of which are covered in greater detail in more encyclopedic efforts.^{2 3 4}

	New Insights Into Component Structure and Function

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Kininogens
The single human kininogen gene is localized to chromosome 3q26qter close to two closely related genes, the -2-HS-glycoprotein and the histidine-rich glycoprotein.^{5 6} It codes for the production of both HMW (626aa, 88 to 120 kD) and LMW (409aa, 50 to 68 kD) kininogens via alternative splicing from 11 exons spread over a 27-kb pair span.⁷ Fig 1 (modified from Müller-Esterl et al⁸ ) illustrates the relationships between the human kininogen gene and the mRNAs for the HMW and LMW kininogens. The nine exons upstream of the kinin sequence code for the same amino acids in both kininogens; the portion of exon 10 downstream of the kinin sequence is unique to HMW kininogen mRNA, whereas exon 11 is expressed in only LMW kininogen mRNA.

View larger version (17K): [in this window] [in a new window]   Figure 1. Schematic representation (modified from Müller-Esterl et al8 ) of the human kininogen gene and mRNAs for high molecular weight (HMW) and low molecular weight (LMW) kininogens. Protein-coding regions are indicated by the open boxes, cap sites are stippled, and the bradykinin (BK) sequences are indicated by the black bars. Note that only a short segment of exons 10 and 11 are transcribed in LMW kininogen mRNA, whereas all of exon 10 but not exon 11 is transcribed in HMW kininogen mRNA.

Kininogens are single-chain glycoproteins with a common amino-terminal heavy chain and smaller, variable carboxy-terminal light chains with the kinin moiety intervening. Separate functions are being deduced for each domain of the molecules with the use of antibodies against various regions and the ligand binding of prekallikrein.^{9 10} The most detailed studies thus far show that HMW kininogen binds calcium via domain 1, inhibits important cysteine proteinases such as cathepsins and calpain via domains 2 and 3, binds to surfaces such as endothelium via domain 5 just downstream of bradykinin in domain 4, and binds plasma prekallikrein and factor XI via domain 6 of the light chain (Fig 2, modified from Weisel et al¹⁰ ). Recent work with electron microscopy of rotary shadowed preparations describes the shape changes of HMW kininogen before and after association with prekallikrein and its activation to cleave out the kinin.¹⁰

View larger version (19K): [in this window] [in a new window]   Figure 2. Schematic representation (modified from Weisel et al10 ) of high molecular weight kininogen (top), kininogen interacting with plasma prekallikrein (middle), and changes with activation (bottom). The domains are labeled as described in the text. Electron microscopic observations10 indicate the flexibility of the prekallikrein-kininogen complexes so that the enzyme can either extend from the substrate laterally or lie on top of it, probably to cleave bradykinin. After bradykinin is cleaved, there is a conformational change that enhances binding to the endothelial cell surface. PK indicates prekallikrein; lc, light chain; and hc, heavy chain.

Additional functional properties of the two kininogens include their ability to bind to platelets and neutrophils, to modulate thrombin-induced platelet activation, and to inhibit the binding of fibrinogen to platelets while releasing kinin after their cleavage by kallikreins. These facts suggest that kininogens are continually and intimately involved as mediators and modulators of vascular inflammation and local injury.¹¹ What remains to be determined is the extent of their contributions to the early (or late) phases of damage associated with, for example, hypertensive or diabetic vascular disease. No work has been carried out in this area. Interesting patients with total kininogen deficiency and no clinical hemostatic problems have been described.¹² A model of this disorder, the Brown Norway Katholiek rat, which can synthesize but not secrete kininogen, is being used to assess roles of kinins in blood pressure regulation,¹³ but studies of the effect of kininogen deficiency or modification on vascular, renal, or other tissue function are still sparse.

The cardiovascular system is presented with kininogens that are synthesized primarily in the liver¹⁴ then secreted and transported in plasma in high concentrations (HMW kininogen, 90 mg/L; LMW kininogen, 170 mg/L), as well as on the membranes of platelets and neutrophils.^{15 16 17} In addition, human vascular endothelial cells contain mRNA for HMW kininogen,¹⁸ and kininogen is found in rat vascular smooth muscle cells grown in the absence of serum.¹⁹ Recently, it was shown that bradykinin upregulates the expression of kininogen binding sites on the surface of human vascular endothelial cells.²⁰ These important sites are not yet characterized, but such binding protects HMW kininogen from cleavage by kallikreins and may serve to attenuate kinin generation at vascular injury sites.²¹ Much less is known about the regulation and intravascular roles of LMW kininogen.

Kallikreins and Kallikrein Inhibitors
The "true" tissue kallikrein, exemplified by renal kallikrein, is a gene product of a small gene family of 3 in the human, up to 20 in the rat, and 24 in the mouse.² All tissue kallikrein genes consist of five exons and four introns. The human genes are clustered on chromosome 19 at q13.2-13.4 and expressed in the epithelial or secretory cells of various ducts, including salivary, sweat, pancreatic, prostatic, intestinal, and the distal nephron. Although no human vascular wall data have established the presence of kallikrein gene expression, rat aortic smooth muscle cells in culture¹⁹ and rat arteries and veins show kallikrein mRNA and release enzyme to surrounding media.²² The human neutrophil also contains tissue kallikrein mRNA, showing that expression can occur here.²³ The assembly, trafficking, and localization of tissue kallikrein either in the sites where it has been long known to exist or in cells of the cardiovascular system are still areas of only fragmentary understanding, with many issues pertinent to local kinin generation not understood. Given the almost ubiquitous responsiveness of these tissues and cells to kinins (and the hundreds of articles describing such responses), more thought needs to be given to how the kinin gets there in the first place.

The tissue kallikreins of human and rodent are acidic glycoproteins, variably and extensively (20% molecular weight) glycosylated. The purified human renal enzyme is synthesized as a zymogen (prokallikrein) with an attached 17–amino acid signal peptide preceding a 7–amino acid activation sequence that must be cleaved to activate the enzyme. Although several proteinases are capable of activating prokallikrein in vitro, the in vivo activating enzyme is unknown, as are the factors that regulate tissue kallikrein processing and storage. Given the great importance of processing enzymes and their regulation in all biological systems, this lack of knowledge is especially striking. This is in contrast to knowledge available concerning the activation of plasma kallikrein, another serine proteinase different from the tissue enzyme but nevertheless carrying the same name.²

Once activated, human tissue kallikrein cleaves LMW kininogen to release lys-bradykinin (kallidin), whereas plasma kallikrein releases bradykinin. The two peptides are generally equipotent, and it is not known whether there is any functional significance to this difference in peptide production. Several inhibitors of the tissue kallikreins exist. The most familiar are aprotinin; the bovine basic pancreatic trypsin inhibitor, a 6.5-kD, 58aa polypeptide; and a recently described serine protease inhibitor (serpin) called kallistatin.²⁴ The former is commercially available and widely used experimentally (and clinically in some countries) as a tissue kallikrein inhibitor, although it is not entirely specific in this regard. The latter, a 58-kD acidic protein, slowly forms heat-stable complexes with active tissue kallikrein and other serine proteinases that can be blocked by heparin.²⁴ Its in vivo target is unknown, and it inhibits tissue kallikrein slowly and incompletely, but there appears to be a difference in the binding of this protein from comparable tissue extracts of SHR versus WKY to purified kallikrein.²⁵ The behavior of the entity in the serum of the two strains is similar. Based on available data, it seems unlikely that this protein has a significant role in kinin system function. However, our understanding of the limitations placed on the activity of true tissue kallikrein is rudimentary.

Kinins and Kinin Receptors
Kinins formed within various organs are detectable in secretory products (eg, urine, saliva, sweat), interstitial fluid, and under some circumstances (ie, kininase inhibition) even in venous blood. The systemic half-life of the kinins is very short (15 to 30 seconds), and concentrations of kinins in biological fluids are quite low—for example, a few nanograms per liter (approximately 10^-11 mol/L) in human plasma—but for years were overestimated by assays using inadequate inhibition of kinin-generating enzymes or nonspecific antisera that falsely elevated the estimates. These errors resulted in some faulty conclusions that, for example, seemed to eliminate the possibility of a kinin role in the effects of converting enzyme inhibitors. On the other hand, the potency with which kinins exert effects on biological targets has if anything been underestimated, because an understanding of the contributors to kinin catabolism is still incomplete.²⁶

Kinin receptors are presently characterized as B₁, B₂, and perhaps B₃. B₁ receptors are less prominent than B₂ and are notably present in the rabbit vasculature,²⁷ especially after insult with, for example, E coli endotoxin or lipopolysaccharide. Then, the principal ligand for such entities, des-Arg⁹-bradykinin, will produce a marked vasodilation and hypotension, an effect not noted in normal tissue although the peptide can also produce contraction of some vascular smooth muscle. This receptor has now been described in several species and cell lines, and its cDNA has been cloned recently from a human embryonic lung fibroblast cDNA library.^{28 29} Although there are relatively few ligand binding and second messenger studies of the B₁ receptor, it appears to be G protein coupled and to activate phospholipase C.^{27 28} The amino acid sequence is 36% identical with that of the B₂ receptor. There are suggestions that this receptor is implicated in the chronic inflammatory and pain-producing responses to kinins, but studies of the localization, regulation, and roles of B₁ receptors in human cells and tissues are only beginning.

The B₂ receptors mediate most of the actions of kinins. Both the rat and human B₂ receptor genes have been cloned and expressed.^{30 31} The first rat B₂ receptor cDNA was obtained from a uterus library using Xenopus oocytes to assay for expression, based on bradykinin-induced ion currents.³⁰ The predicted protein sequence is 366aa with a molecular weight of 41 696 D and seven putative transmembrane domains. Strong homology is present to the histamine H₂ receptor as well as to neurotensin and tachykinin receptors. The potencies of bradykinin and lys-bradykinin are equal (EC₅₀, approximately 1.9 to 2.9 nmol/L), insofar as ion current responses and B₁ receptor agonists have no effect. Receptor message is widely distributed, with amounts in heart, lung, brain, and testes being generally equivalent and somewhat less than in uterus.³⁰ An effort to knock out this receptor appears to have been successful, and the accomplishment of this genetic deletion will generate great interest and possibly a valuable tool for the study of the roles of kinins via this receptor. cDNA or DNA encoding the human B₂ receptor has been isolated recently.^{31 32} The predicted amino acid sequence from each is 81% identical to the rat smooth muscle B₂ receptor. The level of human B₂ receptor density was highest in kidney although also detectable in heart, lung, brain, uterus, and testes. The isolation and structural characterization of these receptors from either human or rodent tissues will be helpful for discerning kinin roles and for therapeutic advances based on receptor antagonism or stimulation.^{33 34} At present, few studies have appeared that examine either the regulation or behavior of these receptors in response to ligand binding or pathological circumstance.^{35 36 37} The presence of structural variation or gene polymorphisms with functional consequence to the cardiovascular system still remains to be explored.

A third bradykinin receptor (B₃) may exist in bovine aortic endothelial cells, in the microvasculature of the guinea pig hindbrain, and in cultured guinea pig tracheal smooth muscle cells.^{4 38} At these sites, variant responses to B₁ or B₂ agonists and antagonists suggest a possible interaction with another receptor. The tracheal cells appear to activate phospholipase D in response to bradykinin, and this response is not affected by either B₁ or B₂ receptor antagonists. Definitive proof awaits further cloning efforts and the evolution of additional receptor antagonists.

Kininases
The true half-life of kinins in biological fluids is a function of their rate of destruction. Peptidases that hydrolyze kinins are known as kininases, although none are known to be specific for kinins. Both aminopeptidases and carboxypeptidases can terminate biological activity, but the latter clearly predominate. The contributions of various enzymes to kinin destruction have been studied extensively, and in general the dipeptidase kininase II called angiotensin-converting enzyme appears to be most important within the cardiovascular system or kidney, with the exception of rat urine where another dipeptidase, neutral endopeptidase 24.11, is the major kinin-destroying enzyme.³⁹ Two additional carboxypeptidases, called M and N—the former concentrated in membrane fractions of various human tissues such as kidney, lung, endothelial cells, and fibroblasts and the latter in plasma and liver—are efficient kininases cleaving the C-terminal arginine of kinins. All four of these human kininases have been cloned and sequences established. However, it is important to note that the time sequence and extent of their contributions to the destruction of endogenously produced kinin at, for example, the endothelial surface are still not clear. As noted by Erdös,²⁶ the fact that carboxypeptidase M is widely distributed and has a high affinity for the C-terminal arginine of kinins could suggest a ready source of substrate for the endothelial synthesis of the relaxing factor nitric oxide.⁴⁰ Exploration of this possibility has not yet appeared in the literature.

For a considerable time, all therapeutic actions of angiotensin-converting enzyme inhibitors were considered to result from inhibition of angiotensin II formation. It is now quite clear that retardation of kinin destruction is likely to play a role in not only their efficacy but also toxicity. For example, the ability of these inhibitors to reduce myocardial infarct size or attenuate postischemic reperfusion injury was shown to be abolished by blockade of kinin B₂ receptors with icatibant (Hoe 140).⁴¹ Such data, along with the corroborating kinin plasma level changes, suggest that locally produced kinins, at least in cardiac tissue, contribute to the beneficial effects of converting enzyme inhibitors.

Although there is still controversy and uncertainty about the extent of kinin contributions,¹ a recent case report probably best illustrates the therapeutic rationale for more aggressive examinations of kinin participation in cardiovascular homeostasis. Davidson et al⁴² note that anaphylactoid reactions have been described in adults undergoing low-density lipoprotein apheresis while taking angiotensin-converting enzyme inhibitors. They found in a 13-year-old child with homozygous familial hypercholesterolemia and progressive cardiac deterioration that improved with captopril that even discontinuation of the drug 72 hours before apheresis did not prevent the severe headaches, nausea, vomiting, and profound hypotension that occurred within 3 minutes of reinfusion of the cleared plasma. On the other hand, icatibant infused for an hour (200 µg/kg) before treatment and then during plasma reinfusion (100 µg/kg per hour) completely prevented all symptomatology and hypotension in five subsequent treatments, with captopril discontinued only 12 hours before treatment. Although the observation requires full clinical evaluation (as well as simple measurement of the kinin level of the cleared, reinfused plasma), it probably reflects the pathophysiological potential of kinins, which has been generally unappreciated.

	System Component Regulation

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Questions concerning local (or systemic) roles for kallikrein-kinin systems ultimately reach the issues of system regulation in situ. At present, little information is available concerning the coordinate regulation of system components in response to various biochemical, physiological, or pathological stimuli. However, bits of regulatory information are appearing at an increasing rate. HMW kininogen synthesis in cultured hepatocytes can be increased by glucocorticoids, and maternal estrogens are responsible for high circulating kininogen levels in neonatal rats.¹⁴ Female rat liver kininogen mRNA levels are fourfold higher than in males. Estradiol increases while progesterone decreases liver kininogen mRNA, but both increase kallikrein mRNA in the kidneys of the same animals. More information is available about the regulation of tissue kallikrein, with renal kallikrein being the most studied.² Female rat renal kallikrein mRNA is twice that in males. Various hormones affect these renal mRNA and protein levels, including mineralocorticoids, glucocorticoids, testosterone, thyroxine, and insulin. Other hormones known to affect synthesis, activity, or release of renal kallikrein include vasopressin, catecholamines, and angiotensin. Thus, there is now ample opportunity to examine coordinate alterations in substrate and formative enzyme gene expression, processing, and storage or release in relation to pharmacologically induced or pathological changes in organ function. This conclusion is reinforced by some recent studies of renal kinin receptors.^{35 43} These studies showed that after prolonged low sodium intake B₂ binding site density was markedly reduced concomitant with increased renal and urinary kallikrein. This work suggests that there is an inverse relation between presumptive renal kinin levels and B₂ receptor density. Most recently, these clues are being augmented by new technology that is allowing the direct measurement of renal interstitial kinin levels and disclosing that such levels change markedly in response to various stimuli (Fig 3).^{44 45}

View larger version (17K): [in this window] [in a new window]   Figure 3. Bar graph shows renal interstitial fluid bradykinin of anesthetized rats consuming a low (0.15%), normal (0.28%), or high (4.0%) sodium diet (n=5 for each diet). Hatched bars indicate renal cortex; solid bars, renal medulla. *P<.01 compared with normal diet; +P<.01 compared with corresponding medulla. (Modified from Siragy et al.45 )

	Interrelations With Other Regulatory Hormones and Autacoids

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The only certain in situ biochemical connection is that angiotensin I–converting enzyme also efficiently catabolizes kinins. Another connection previously suggested as a result of some in vitro studies was that kallikrein could serve as a prorenin activating enzyme. This possibility seems to have been discounted. Similarly, because a tissue kallikrein can generate angiotensin II from a plasma protein fraction in vitro, suggestions of alternative pathways for the formation of the pressor peptide were made. Again, no convincing evidence for such a role in vivo exists. Thus, the two systems appear likely to function in concert, at least in the kidney, to maintain blood flow and excretory capability. That is, while diets low in sodium (or high in potassium) or with other systemic challenges (eg, water deprivation) stimulate renin gene expression and synthesis and increased systemic levels of angiotensin and aldosterone in defense of systemic and renal circulatory homeostasis, some of the same stimuli augment renal kallikrein and kinin production in a possible local defense of renal blood flow and glomerular filtration rate by vasodilator effects on renal cortical blood vessels and perhaps, particularly, afferent arterioles. Whether such concerted activity between the two systems occurs at other vascular sites where components and their receptors are present has not been studied.

The reasons for changes in system activity in opposite directions, such as occurs in the two-kidney, one clip rat (with high renin and angiotensin II levels but lowered renal kallikrein), are not yet convincingly explained. The notion that such a change in kallikrein (among the earliest observed in the kidney enzyme) may only be a secondary response to a more important interstitial kinin level or kinin receptor change³⁵ —especially in the nonclipped kidney, which collectively promotes a compensatory excretory response to the contralateral insult—is now an operational question, given the availability of specific receptor blockers and other resources (eg, the Brown Norway rat). These and other chemical and biological tools (eg, the receptor knockout mouse) will help unravel the related roles of these intertwined peptide systems, especially in relation to vascular function and integrity in diseases such as diabetes mellitus and hypertension.

Relations to other regulatory hormones are being sought. Tissue kallikrein was found capable of forming ANP from its precursors as well as catabolizing the active peptide in vitro.^{46 47} Administration of this powerful natriuretic, diuretic agent affects renal kallikrein excretion, but the significance of this effect is unclear.⁴⁸ Conversely, cardiac tissue contains a kallikrein-like enzyme that colocalizes in ANP-containing granules.⁴⁹ There also appears to be ANP synthesis in and secretion from renal cortical connecting tubule cells of the mouse and rat that also synthesize kallikrein.⁵⁰ ANP receptors, activation of which may modulate renal sodium reabsorption, exist downstream in the inner medullary collecting ducts. Thus, the local synthesis of the peptide seems analogous to kinin production at the same areas of the nephron. It is now clear that kinins affect medullary collecting duct function,⁵¹ but exploration of interrelations between ANP and kinin production and responsiveness at this site remains to be carried out.

Enormous numbers of studies have evaluated and shown connections between kinins and eicosanoid synthesis.² Regardless, surprisingly few have explored, or more importantly established, connections between abnormalities in components of both systems and resultant pathophysiology. That is, there are many studies of abnormal kallikrein-kinin system components or eicosanoids in, say, endotoxin shock or hypertensive models, but very few that show that a linked biochemical aberrancy is responsible for a functional disorder.

The same can be said for nitric oxide, another mediator now strongly implicated in kinin-induced vasodilation and hypotension.⁵² Interesting recent work has disclosed that in rat and dog renal vasculature, kinin-induced vasodilation depends significantly on nitric oxide synthesis.⁵³ These studies now bring consideration of a relationship between local kinin production at sites of vascular injury, acute or chronic, to nitric oxide production. Questions concerning this relation may be of great interest, in part because there is clear renal vascular hyperresponsiveness to bradykinin in the SHR, insofar as both nitric oxide–dependent and –independent effects are concerned.⁵³

Finally, it is becoming clearer that kinins have very interesting effects on the growth of various cells, notably, vascular smooth muscle and renal mesangial cells.⁵⁴ The full evaluation of these interesting responses and determination of their homeostatic relevance are going to become exciting areas of study for researchers interested in kinins.

	Kallikreins, Kinins, and Physiological Functions

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Speculations about the role of kallikreins and kinins in hemodynamic, excretory, and metabolic processes originated in 1909 when the hypotensive property of human urine, now known to represent excreted renal kallikrein, was discovered.⁵⁵ But any insights into physiological roles were slow to appear. Study of the system was not stimulated even after two discoveries: (1) of a clear reduction in kallikrein excretion in human hypertension in 1934⁵⁶ and (2) in the same decade that "the average kallikrein excretion of diabetics agrees with that of healthy persons when they are treated with insulin. Twelve patients excreted an average of 193 kallikrein units per day. The situation was different in diabetics who received only a diabetic diet but no insulin: in middle-aged persons the daily excretion was then between 20 and 48 kallikrein units and hence was greatly reduced."⁵⁷ These clinical observations, clearly true, did not receive any attention for almost 40 years.

Some of the earliest definitive studies of kinin effects of any organ were carried out by Webster and Gilmore⁵⁸ and Gill et al.⁵⁹ They established the natriuretic/diuretic capabilities of a kinin in dogs and humans and were followed by work showing that stimulation of water and electrolyte excretion was a function of increased renal blood flow. Indeed, the most consistently observed effect of kinins is to reduce vascular resistance. Unlike several other endogenous vasodilators, bradykinin can increase renal blood flow without significant change in glomerular filtration rate or absolute proximal reabsorption but with a marked increase in fluid delivery to the distal nephron.⁶⁰ This latter effect may contribute to the always observed increased urine volume and sodium excretion seen with exogenously administered kinin into kidneys. It appears that natriuresis and diuresis are the result of an effect of kinins on renal papillary blood flow, which inhibits sodium reabsorption distally secondary to a washout of the medullary solute gradient, rather than on cortical blood flow, or as mentioned above, glomerular filtration rate.⁶¹ Support for this contention is derived from several studies using either inhibitors of renal kininases such as captopril and phosphoramidon (the latter an inhibitor of neutral endopeptidase 24.11) or long-term treatment with deoxycorticosterone, also known to raise endogenous kinin levels, followed by specific blockers of renal kinin B₂ receptors. The work generally indicates that increases in papillary blood flow, urine volume, and sodium excretion induced by kininase inhibition or deoxycorticosterone can be either attenuated or abolished by kinin B₂ receptor blockade.⁶²

Thus, it now seems clear that endogenously produced kinin significantly affects renal hemodynamics and excretory function. This conclusion is supported by studies of renal function just beginning to appear in kininogen-deficient Brown Norway Katholiek rats. These rats show a brisk hypertensive response to a 2% NaCl diet seemingly unrelated to sodium and fluid retention.⁶³ Repetition of these studies in bradykinin B₂ receptor knockout mice, when generally available, may provide even more definitive conclusions. What is still uncertain at present is whether the observed natriuretic/diuretic responses are all a result of effects on renal hemodynamics in the papilla or might include a component of distal tubular inhibition of electrolyte reabsorption (or stimulation of electrolyte secretion). Some additional evidence in this regard is now available.⁵¹ Regardless, the weight of present opinion suggests that intrarenal kinins modulate renal excretory function predominantly by effects on renal vasculature. Comparably detailed studies of the roles of the tissue kallikrein-kinin system in the vascular beds of skeletal or cardiac muscle or on blood flow in the splanchnic circulation are just beginning to appear.^{64 65 66} Many questions about roles of endogenously generated kinins in these vascular beds in relation to their developmental biology, to blood flow regulation in physiological circumstances, and of course in specific pathological disorders remain to be asked.

Kinin B₂ receptors are coupled to cellular systems in polarized epithelia that lead to marked changes in vectorial ion and water transport.^{67 68} Many epithelia have been shown to secrete anions, predominantly chloride but also bicarbonate, in voltage-clamp experiments in response to kinin; these actions are partially eicosanoid dependent and can be blocked by Na⁺-K⁺-Cl^- cotransport. However, the actions of locally generated kinins on ion, water, and substrate transport are still poorly defined. The use of more specific system modulators such as receptor blockers⁵¹ or animals subject to transgenic or homologous recombination manipulations will be required to shed light on issues of this kind.

Similarly, the understanding of roles of kinins in both glucose transport and metabolism requires more intensive evaluation than has occurred so far, now that the extent of kallikrein-kinin system abnormality in humans and animal models of diabetes mellitus has been established.^{69 70 71 72}

	Kallikrein-Kinin System Function in Systemic Diseases

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Hypertension
The notion that reduced urinary kallikrein excretion might represent a deficiency in an endogenous vasodilator system that was contributory to the hypertensive state was not accepted enthusiastically when first proposed.⁵⁶ Progress in addressing this possibility has been slow, unlike the enormous and sustained interest provoked on behalf of the renin-angiotensin system by the Goldblatt experiment. Today, interest in possible kallikrein-kinin contributions to the pathogenesis of human hypertension is growing rapidly because of a series of provocative findings reaching from epidemiological surveys to gene-polymorphism-cosegregation analyses.⁷³ Nevertheless, the case for system involvement is still weaker than the easily demonstrable importance of vasoconstrictor influences in human hypertension.

Although it is clear that patients with essential hypertension excrete less kallikrein than do normotensive subjects, there is much overlap in the population studies carried out over the past 25 years.⁷⁴ Many hypertensive subjects show normal kallikrein excretion. Black people, adults and children, excrete markedly less kallikrein than whites, regardless of blood pressure, with black hypertensive subjects generally showing the lowest measured levels.^{75 76} In recent years studies of kallikrein and other system components in some more homogeneous human populations have begun to appear. For example, Japanese patients with low-renin hypertension show significant reductions in both active urinary kallikrein and kinin excretion.⁷⁷ They also demonstrate higher levels of a kallikrein inhibitory material in urine and reduced urinary kininogen and increased urinary kininases.⁷⁷ These studies are now providing a stimulus for exploration of system component genotypes in relationship to phenotypic characteristics of hypertensive populations.

Epidemiological surveys in children stimulated interest in the relations between renal kallikrein and blood pressure.⁷⁸ These efforts examined blood pressure, kallikrein, and other variables repetitively over long intervals and showed that kallikrein excretion was familially aggregated and that families of healthy children with the lowest mean kallikrein excretions showed significantly higher blood pressures than did families of children with the highest kallikrein excretions. These efforts have been extended in recent years. For example, urinary kallikrein and diastolic pressure are negatively correlated even in newborn infants 2 to 4 days old, and such correlations are detectable in infants up to 18 months of age.⁷⁹ Berry et al⁸⁰ examined family histories of hypertension in a large population in 57 Utah pedigrees and found that individuals with a higher urinary kallikrein excretion genotype were less likely to have one or two hypertensive parents than those with a low kallikrein genotype, suggesting to them that the higher excretion rate represents a genotype associated with a reduced risk of essential hypertension. Such studies should only be provocative of extension and attempted confirmation; that is, kallikrein was measured in these efforts because it became easy to measure,⁸¹ not because it was the most likely component of kallikrein-kinin systems to demonstrate association. Few efforts have been carried out to assess whether there might be better markers for system abnormality in cardiovascular disease or populations with varying susceptibility to the same.

Work in rodent forms of hypertension is proceeding more rapidly. Goldblatt hypertensive rats were the first animal model shown to have reduced urinary kallikrein excretion.^{82 83} The reduced renal levels occur principally in the compromised kidney of two-kidney, one clip rats, and levels in the contralateral kidney are either normal or reduced to a lesser extent. These changes are now being studied in relation to the different salt-handling properties of the two kidneys. In addition, these differences are now being elaborated on by examination of kinin B₂ receptor density, which is increased to a greater extent in the contralateral kidney than in the clipped one.³⁵ These increases could signify an augmented kinin-induced eicosanoid and/or nitric oxide production in compensatory response to the higher perfusion pressure that this kidney faces. This contralateral kidney is known to show higher renal blood flow, glomerular filtration rate, and sodium excretion. Extension of such studies is predictable.

All genetic models of rat hypertension, including the SHR, Dahl, Milan, New Zealand, Fawn-hooded, and Sabra strains, show kallikrein abnormalities. It is important to point out that few studies have been carried out longitudinally with respect to age, and it has been generally unclear whether kallikrein system abnormalities preceded or followed the appearance of hypertension. Furthermore, even fewer studies have examined multiple components of the system over time. One early study in Milan rats showed significantly lower kallikrein levels in newborn rats of the hypertensive versus the control strain.⁸⁴ A more recent effort showed that renal tissue active kallikrein in SHR was only 53% of values in WKY within 12 hours of birth, whereas the total enzyme level (including prokallikrein) was not different between the strains.⁸⁵ The difference persisted between SHR and WKY up to 12 weeks of age. This is the only work in a hypertensive model to suggest a possible defect in renal prokallikrein processing or activation rather than in synthesis rate. Studies of the assembly, storage, and conversion of the tissue kallikrein gene products have not begun in even normal animals, tissues, or cells, much less in circumstances of disease.

More definitive connections between kinins and blood pressure regulation are appearing as the B₂ receptor antagonists are being used to show that long-term blockade of such receptors in rats treated with deoxycorticosterone⁸⁶ causes rises in blood pressure in a manner similar to that seen when the kininogen-deficient Brown Norway Katholiek rats are stressed with moderate salt intake.⁶³ Studies of kinin receptor behavior or of cellular messengers transducing receptor responses in such models are nonexistent. However, a recent study shows that long-term blockade of kinin B₂ receptors of Wistar rats during the prenatal and postnatal periods resulted in significantly increased systolic pressure and heart rate, not to hypertensive levels but indicating that endogenously produced kinins contribute to an "adult cardiovascular phenotype."⁸⁷

Diabetes Mellitus
The first modern study reaffirming a connection between the tissue kallikrein-kinin system and the diabetic state showed that rats with streptozotocin-induced diabetes mellitus developed significant hypertension along with altered renal kallikrein-kinin system activity.⁶⁹ Early in the course of the diabetic state these rats, treated with insulin, also show glomerular hyperfiltration along with increased renal kallikrein synthesis, levels, and urinary excretion.^{70 71} Treatment of such rats with aprotinin or a kinin B₂ receptor antagonist reduced renal blood flow and glomerular filtration rate to levels equal to those in normal rats,⁷¹ thus establishing a role for the system in the renal response to the diabetic state. These animal studies find support in an evaluation of patients with type I (insulin-dependent) diabetes in whom glomerular filtration rate, renal blood flow, and sodium reabsorption were measured.⁷² Subjects with glomerular hyperfiltration showed greater active kallikrein and prostaglandin E₂ excretion than patients with normal glomerular filtration rate or otherwise healthy subjects. Kallikrein levels correlated directly with glomerular filtration rate and distal tubular sodium reabsorption (derived from lithium clearance). These findings in diabetic rat models and patients show that the renal kallikrein-kinin system is a contributor to the renal adaptation to diabetes and plays a role in the nephropathy. Some recently described effects of kinins in vascular proliferative responses (or the inhibition of such) will compel a closer examination of vascular kallikrein-kinin system components in human diabetic states.

	Summary

Top Abstract Introduction New Insights Into Component... System Component Regulation Interrelations With Other... Kallikreins, Kinins, and... Kallikrein-Kinin System Function... Summary References

 
The last 25 years have produced significant advances in understanding tissue kallikrein-kinin system component structure, localization, and regulation; system abnormalities in disease; and the ability to manipulate components with various stimuli and, most importantly, specific receptor antagonists. The work has revealed enough about the contributions of the system to cellular and organ function to allow optimism about the likelihood that new therapeutic strategies based on stimulation or interdiction of kinin actions will be important to the treatment or perhaps even the prevention of some common diseases.

	Selected Abbreviations and Acronyms

 

ANP = atrial natriuretic peptide HMW = high molecular weight LMW = low molecular weight SHR = spontaneously hypertensive rat(s) WKY = Wistar-Kyoto rat(s)

	Acknowledgments

 
The support of National Institutes of Health grants HL-44671, HL-17705, and HL-07260 is gratefully acknowledged. The assistance of Tammy Sugarman is also acknowledged.

Received April 3, 1995; first decision April 26, 1995; accepted April 26, 1995.

	References

Top Abstract Introduction New Insights Into Component... System Component Regulation Interrelations With Other... Kallikreins, Kinins, and... Kallikrein-Kinin System Function... Summary References

 
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