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(Hypertension. 2003;42:117.)
© 2003 American Heart Association, Inc.

Brief Review

Intracellular Renin and the Nature of Intracrine Enzymes

Richard N. Re

From the Research Division, Ochsner Clinic Foundation, New Orleans, La.

Correspondence to Dr Richard N. Re, Research Division, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121. E-mail rre{at}ochsner.org

	Abstract

Top Abstract Introduction Intracrine Prorenin/Renin Intracrine Enzymes The Intracrine Perspective References

 
Recently, the binding of renin and prorenin to cellular receptors with the subsequent generation of second messengers and the production of physiological effects has been demonstrated. In addition, the internalization of prorenin by target cells has been associated with increased cellular synthesis of angiotensin and cardiac pathology. Also, a renin transcript lacking the sequences encoding a secretory signal has been reported, and this transcript appears to produce a renin that acts in the cell that synthesized it. Some years ago, we coined the term intracrine for a peptide hormone or factor that acts in the intracellular space either after internalization or retention in its cell of synthesis. Thus defined, a wide variety of peptides display intracrine functionality, including hormones, growth factors, transcription factors, and enzymes. For example, considerable evidence indicates that angiotensin II is an intracrine. Also, general principles of intracrine functionality have been developed. Thus, recent evidence demonstrates that the prorenin/renin molecule is an intracrine enzyme. Here, the actions of intracrine enzymes (angiogenin, phosphoglucose isomerase, phospholipase A2, granzyme A and B, thioredoxin, platelet-derived endothelial growth factor, and serine protease inhibitors) are reviewed. The relation of prorenin/renin to other intracrine enzymes, and to intracrines in general, is discussed.

Key Words: renin • platelet-derived growth factor • enzymes • angiotensin II • phospholipases

	Introduction

Top Abstract Introduction Intracrine Prorenin/Renin Intracrine Enzymes The Intracrine Perspective References

 
Renin gene expression leads to the synthesis of prorenin in the juxtaglomerular cells of the kidney, activation and secretion of renin by these cells, the generation of angiotensin I by renin enzymatic activity, and the subsequent generation of angiotensin II either in the plasma or tissues. However, renin, angiotensin I, and angiotensin II can also be taken up by tissues with subsequent enzymatic conversions occurring locally. Moreover, there is considerable evidence, both in animal models and in humans, in favor of the local synthesis of each of the components of the renin-angiotensin system (RAS) in various tissues leading to locally determined angiotensin generation.¹ In addition to evidence indicating local synthesis and uptake in tissues of RAS components, there is growing evidence to indicate the uptake and synthesis of components of the RAS by individual cells, thereby suggesting a new arena for the action of this physiological system.² Important among these new observations are studies demonstrating that (1) prorenin and renin can bind to specific cellular receptors with the generation of physiological effects, (2) prorenin, and to a lesser extent, renin, can be internalized by cells whereupon angiotensin II is produced, and (3) there exists a renin transcript in some cells that encodes a renin that is expected to be synthesized as an active, as opposed to a prorenin, and that is expected to remain in the cell because it lacks the sequence encoding the secretory signal piece (renin exon 1A).^2–13 These observations not only reveal prorenin and renin to be hormones in their own right, they suggest that prorenin and renin are intracrines.

Over the last 3 decades, considerable evidence has been developed to indicate that a variety of peptide hormones and growth factors act either after internalization by target cell and/or by remaining in the cells that synthesized them to act at an intracellular locus.^1–75 In some cases, one isoform is secreted and acts as an intercellular signaling molecule, while a second isoform acts in its cell of synthesis in a manner either similar or dissimilar to that of the secreted hormone.^14–26 Years ago, we applied the term intracrine to the intracellular action of a peptidic factor/hormone irrespective of whether the factor (or isoform) was internalized by its target cell before acting or was retained in its cell of synthesis to act.^14,15 A list of representative intracrines is found in the Table. The biology of these factors as well as our suggestions regarding their origins and mechanisms of action are discussed in depth elsewhere.^{1,2,16–19,23–26} Against this background, we will concern ourselves with the following questions: (1) Is the prorenin/renin molecule an intracrine? (2) Is the intracrine nature of prorenin/renin and of other enzymes consistent with what is known of intracrines, or must it be viewed as an aberration?

View this table: [in this window] [in a new window]   Intracines

	Intracrine Prorenin/Renin

Top Abstract Introduction Intracrine Prorenin/Renin Intracrine Enzymes The Intracrine Perspective References

 
Renin is synthesized in the juxtaglomerular cells of the kidney, salivary glands, cells of the adrenal cortex, neurons, and other tissues either in health or disease. Although the great majority of circulating renin is derived from the kidney, local secretion occurs in other sites of renin synthesis, such as the adrenal where local renin production can support aldosterone synthesis in nephrectomized animals. Similarly, prorenin is synthesized by the kidney, ovary, and uterus, among other tissues, and, like renin, is found in the circulation. Thus prorenin and renin fulfill the requirement that intracrines be found in the extracellular space.^1,2

In recent years, several reports have indicated the presence on various target cells of receptors of various sorts for renin or prorenin.^3,10,11 The IGFII/mannose-6-phosphate receptor was shown to bind and internalize glycosylated prorenin, with subsequent activation to renin, but the preponderant opinion is that this represents a clearance receptor.^10,11 Recently, a receptor was described in mesangial cells and vascular smooth muscle cells that binds prorenin, and, to a lesser extent, renin, after which second messengers are activated leading to a physiological response.^5,6 In addition, receptor-bound prorenin appears to be enzymatically activated, leading to enhanced angiotensin generation at the target cell surface and presumably therefore in proximity to cell surface angiotensin II receptors. This report establishes a signaling role for extracellular prorenin and renin and thereby led to the conclusion that renin and prorenin are in fact hormones as well as enzymes.^5,6

Additional evidence suggests that renin, like angiotensin, can act within cells either after internalization or retention in the cell that synthesized it.^{1,2,7–19,23–26,32–36} Moreover, a recent study that used transgenic animals expressing nonglycosylated prorenin in the liver demonstrated the uptake and activation of this renin in cardiac myocytes, resulting in enhanced production of angiotensin and the development of cardiac pathology.⁷ These observations again raise the possibility that complete intracellular renin-angiotensin systems exist in some cells.^{13–15,32–36} These intracrine renin-angiotensin systems (iRAS) could offer a new therapeutic target, given the differential ability of various inhibitors to act at intracellular sites. Parenthetically, regulatory loops linking the iRAS components angiotensinogen with p53 and renin with nucleolin mirror the regulatory relations of other intracrines with p53 and nucleolin.^23,27 In summary, recent findings reveal similarities between the actions of prorenin/renin and those of other intracrines. Not only angiotensin II but renin/prorenin is an intracrine. At the same time, prorenin/renin is atypical in that it has not been demonstrated to traffic to the nucleus.

Given the intracrine nature of prorenin/renin, one is next led to ask if other enzymes operate in a similar intracrine fashion.

	Intracrine Enzymes

Top Abstract Introduction Intracrine Prorenin/Renin Intracrine Enzymes The Intracrine Perspective References

 
Just as peptide hormone functionality is traditionally viewed as unidimentional and focused on intercellular signaling, just as transcription factors are traditionally viewed unidimentionally as intracellular regulators of gene expression, so too enzymes are traditionally viewed unidimentionally as biological catalysts. Just as the intracrine view reveals the intracellular regulatory roles of some peptide hormones and the extracellular signaling role of some transcription factors and DNA binding proteins, so too does the intracrine perspective reveal a commonality of functions between enzymes and other intracrines.^2,19,23 There is now good evidence that at least several enzymes are both regulators of intracellular functions and extracellular signaling molecules.^2,23 Now that the phenomenon of intracrine enzyme action has been discovered, it is likely that other examples will soon be reported.

Angiogenin has long been recognized as a tumor-produced, angiogenenic factor. It is also a weak RNase, and that enzymatic activity, like the translocation of angiogenin from its cell surface receptors to nucleolus, is essential for its angiogenic activity. Moreover, stimulation of rDNA transcription after reaching the nucleolus is also required for activity; in this, angiogenin is similar to FGF2, which also traffics to the nucleolus and stimulates rDNA transcription in the process of stimulating proliferation.^{2,16,18,20–23,30} Because of the intimate association of many intracrines with nucleolus, the site of ribosome synthesis, it could be suggested that the RNA-binding properties of angiogenin are critical to its action rather than its enzymatic activity. For example, PTHrp binds tightly to RNA as part of its intracellular activity.^2,16,18,23 Thus, it could be argued that the enzymatic activity of angiogenin was incidental to its RNA-binding activity and that angiogenin should not be considered an enzymatic intracrine at all. Were this view extrapolated to explain the action of all enzyme intracrines, one would not expect enzymes directed against non-RNA substrates to be intracrines. However, this is not correct. The substrates of intracrine enzymes are quite varied. Finally, recent evidence indicates that like the intracrine defensins and the intracrine lactoferrin, some angiogenins are antimicrobial and function as part of the innate immune system of the gut.³⁷

Phosphoglucose isomerase (PGI), the second enzyme in the glycolytic pathway, catalyzes the conversion of glucose-6-phosphate to fructose-6-phosphate.³⁸ It is a well-established enzyme in intermediary metabolism. However, PGI is identical to neuroleukin (NLK), a secreted growth factor that interacts with its specific receptor, gp 78, and is involved in neuron growth and survival, cell motility and differentiation, and maze learning.^38–43 Yet another functionality is associated with the PGI molecule. PGI has been shown to be an autocrine motility factor (AMF), a tumor-secreted cytokine that promotes tumor cell mobility through the stimulation of receptor-mediated second messengers. AMF also stimulates so-called nucleokinesis—the trafficking of the nucleus to the far side of the cell in certain tumor cells. Lacking a secretory signal, AMF is secreted by a nonclassic pathway. Neuroleukin/AMF/phosphoglucose isomerase is internalized by a clatherin-mediated pathway to multivesicular bodies and by a caveolae-mediated pathway to the endoplasmic reticulum; it can be detected in the perinuclear space. Moreover, AMF/NLK/PGI is angiogenic, stimulates the motility of endothelial cells, and upregulates the FLT-1 vascular endothelial growth factor (VEGF) receptor on endothelial cells.⁴³ PGI is also maturation factor (MF) and regulates the development of myeloblast precursor cells into mature monocytes.³⁸ Thus, the PGI/NLK/AMF/MF molecule contains 4 distinct functionalities, including that of a metabolic enzyme (intracellular) and 3 cytokine actions (extracellular/signaling). PGI/NLK/AMF/MF is therefore an intracrine.^38–43 Although PGI exists in cytoplasm and in plant chloroplasts and traffics to the perinuclear space after internalization, unlike many other intracrines, it has not been reported in the nucleus. Of note, the PGI enzymatic activity is not sufficient for its neuroleukin or AMF activity—rather, each protein functionality probably is related to a distinct domain of the molecule. On the other hand, the enzymatic activity of PGI and the cytokine activities of the molecule may be complementary. For example, enhanced glycolysis and NLK binding to gp78 are both associated with enhanced learning, and these are 2 activities of the PGI/NLK/AMF/MF molecule.³⁹ Similarly, hypoxia, a state associated with enhanced glycolysis, induces the secretion of angiogenic AMF by tumor cells.⁴¹ Thus, in these cases, the various physiological activities of the PGI molecule can be considered complementary.

Phospholipase A2-I (PLA2-I) is a secreted enzyme that is found, for example, in gastric juice.^44–47 It also acts as a growth factor for a variety of cell types. For example, PLA2-I binds to uterine stromal target cell receptors, is internalized, and traffics to nucleus to stimulate cellular proliferation. Nuclear receptors for the enzyme have been described. As in the cases of angiogenin, FGF 2, and PTHrP, nuclear translocation appears to be essential for PLA2-I stimulation of proliferation because in nonproliferating untreated cells the enzyme is cytoplasmic, whereas it is nuclear in untreated proliferating cells.⁴⁴ PLA2-I also stimulates progesterone secretion by isolated corpora lutea.⁴⁵ Receptors for PLA2-I are found on mesangial cells, and PLA2-I binding to these receptors stimulates secretion of PLA2-II and prostaglandin E2 production.⁴⁴ Thus, the enzyme is found in cells, is secreted, is a growth factor and signaling molecule, is internalized, and traffics to the nucleus.

Granzyme A and Granzyme B are enzymes found in cytotoxic T cells and natural killer cells.^2,23,48,49 When a cytotoxic T cell contacts a target cell, Granzyme B is released into a cellular synapse formed with the target cell, enters the target cell as a result of the action of sublytic concentrations of cosecreted perforin, traffics to the nucleus, and induces apoptosis. Granzyme A acts in a similar fashion but has also been shown to bind to nucleolin. Thus, granzyme A and B are secreted molecules, enter target cells, traffic to the nucleolus, and regulate cell growth. They are intracrines. Yet, every feature of their action seems atypical: they are secreted into a local synapse; they enter cells with the help of a membrane active factor rather than through a receptor; and they induce apoptosis probably through their enzymatic activity. This atypicality must be viewed not as aberrant but rather as instructive. We have argued that intracrines must be defined on the basis of function rather than on the basis of structure or details of their mechanism of action. We have further argued that intracrine functionality grew out of early metazoan development and was subsequently refined.^2,19,23 Thus, variety of structure and function is to be expected among the intracrines, and this variety can point to earlier forms of intracrine action. For example, the plant homeotranscription factor KNOTTED is produced by cells and transported to nearby cells through plasmodesmata to regulate transcription in the target cell and thereby produce a wave of gene activation along the plant stem. The plant transcription factors LEAFY and SHORTROOT act in a similar fashion.^2,18,19,23 Also, the plant virulence factor AvrXa7 is synthesized by pathogenic bacteria and secreted into plant target cells by type III secretion (a process akin to injection), whereupon it traffics to the nucleus to alter gene transcription.^2,18,19,23 These activities are intracrine and are in many ways similar to the actions of Granzymes A and B. Just as KNOTTED is a somewhat atypical transcription factor intracrine, so too are granzymes somewhat atypical enzyme intracrines.^2,19,23 Yet, all are intracrines, and the actions of all are instructive.

Thioredoxins are a family of protein-disulfide reductases that are maintained in reduced state by thioredoxin reductase.^50–56 Thioredoxin 1 is a cytosolic protein that can translocate to the nucleus, where it regulates AP-1 activity and transcription. It can also be secreted. Moreover, thioredoxin reductase and thioredoxin coordinately regulate apoptotic cell death by activating p53-dependent responses.^52,55 A large form of thioredoxin (like renin) is found in mitochondria. Thioredoxin is a secreted cytokine and is chemotactic for monocytes. It is identical to adult T-cell leukemia–derived factor (ATL). A truncated form of thioredoxin is known as eosinophil cytotoxicity-enhancing factor (ECEF), which is released by normal monocytes; the cytotoxicity-enhancing activity of ECEF is independent dithiol reductase activity because the truncated molecule lacks this activity. Thus, the thioredoxins have both intracellular gene regulatory and extracellular signaling functions. Thioredoxin binds to the external surface of target cells, but it is not known if it is internalized by these cells.

Platelet-derived endothelial cell growth factor (PD-ECGF) was originally identified as an angiogenic factor.^57–61 Subsequently, it was discovered that this molecule is identical to thymidine phosphorylase (TP), an enzyme involved with intracellular thymidine metabolism and homeostasis. PD-ECGF/TP is also gliostatin (GS), a protein purified from human neurofibroma having neurotrophic actions and effects on glial differentiation. PD-ECGF/TP/GS stimulates angiogenesis by inducing endothelial cell migration and it is probably not actually a growth factor per se.⁵⁹ The angiogenic activity of PD-ECGF/TP is dependent on its enzymatic activity.⁵⁸ Nonetheless, it is an intracellular regulator of metabolism and an extracellular signaling protein. Like AMF and angiogenin, PD-ECGF/TP is a secreted enzyme that stimulates target cell migration and is angiogenic.^43,60,62 Moreover, it is upregulated in a variety of neoplasms and appears to have clinical prognostic implications.

In addition to enzymes, certain enzyme inhibitors are intracrines.^{2,16,18,23,63–65} For example, pigment epithelium-derived factor (PEDF) is a member of the serine protease inhibitor (serpin) family, although it lacks inhibitory action. It is neurotrophic and antiangiogenic. It is expressed in and secreted by retinal pigment epithelial cells during early retinal development. It is located both in the nucleus and cytoplasm. Similarly, maspin is a noninhibitory, antiangiogenic, secreted serpin that also is found in nucleus—including the nuclei of breast and ovarian cancer cells. Other serpins probably are intracrines as well. Of possible interest in this regard is the observation that angiotensinogen and des-angiotensin-I–angiotensinogen are noninhibitory, antiangiogenic serpins.⁶⁶ Angiotensinogen clearly is secreted, and an extracellular angiotensinogen receptor has recently been reported; it is unknown if angiotensinogen functions or binds to physiologically relevant sites within the cell.⁶⁷ If such intracellular binding or action were found, angiotensinogen could be classified as a serpin intracrine.

Although this review cannot claim to be exhaustive, it does serve to indicate the spectrum of intracrine enzyme action and structure and it serves as a background for consideration of the implications of the intracrine status of prorenin/renin.

	The Intracrine Perspective

Top Abstract Introduction Intracrine Prorenin/Renin Intracrine Enzymes The Intracrine Perspective References

 
There are 3 axes of intracrine action: intracellular regulation, establishment of memory, and extracellular signaling. Although these functionalities are not definitional, most intracrines demonstrate all three to varying degrees. In addition, intracrines frequently display other distinctive characteristics such as nucleolar localization, binding to RNA, regulation of rDNA transcription, internalization by target cells, synthesis as multiple isoforms, and others. Thus, it is possible to qualitatively assess the degree to which any intracrine has the characteristics of an archetypal intracrine such as PTHrP. Intracrine enzymes fall all along this spectrum of functionality, with angiogenin at one end and PD-ECGF/TP/GS at the other. Viewed in this way, enzyme intracrine action is not as startling as might at first be expected. Also, in this context, prorenin/renin is more or less typical in its functionality among the intracrine enzymes and, indeed, among the intracrines in general. The intracrine nature of prorenin/renin, however startling it might at first appear, is not aberrant.

That said, the intracrine hypothesis suggests that intracrines developed from molecules that used intracellular feedback loops to produce memory and differentiation and that linked ribosomal function and related metabolic functions with gene regulation in cells and throughout tissues.^{2,16,18,19,23} Although many of these features are exemplified by prorenin/renin, it remains unclear to what extent they apply to other intracrine enzymes or to their precursors. Further investigation will be required to determine whether intracrine enzymes participate in sustained feedback loops and directly or indirectly regulate ribosomal function and protein synthesis.

One related question immediately comes to mind. Did the multiple functionalities of intracrine enzymes evolve simultaneously in the intracrine molecule or were the functions of several genes/proteins consolidated in the modern intracrine enzyme gene? The intracrine hypothesis suggests that these functionalities evolved simultaneously in these molecules and that in fact, it was the requirement that cellular memory be linked with tissue-wide differentiation that drove intracrine evolution. Indeed, the multifunctionality of intracrine action is seen in all metazoan intracrines, suggesting a very early origin for this strategy. The multifunctionality of human proteins is receiving considerable attention now that the Human Genome Project has identified fewer genes in the human genome than many expected. It could be argued that intracrine multifunctionality is simply one manifestation of this phenomenon. Although the intracrine hypothesis cannot speak to this question in general, it does suggest that the multifunctionality of intracrines is intrinsic to their development and regulatory functions. The intracrine hypothesis suggests that metabolic and genetic regulation, cellular memory and differentiation, and intercellular signaling often evolved simultaneously in metazoans using the product(s) of a single gene in all 3 roles. Just as the bacterial operon allows the coordinated regulation of multiple related functionalities through the coupled regulation of multiple genes, so the metazoan intracrine gene allows the coordinated regulation of multiple functionalities through the regulation of one gene.¹⁶ The coordinated evolution of all 3 functions in a single molecule (and its isoforms) could then have occurred as an intrinsic part of the evolution of intracrine genes, thereby relieving the organism of the necessity to develop independent parallel mechanisms to transmit information about developmental or adaptive gene expression to other sites within a tissue. This view makes explicable the signaling activities of transcription factors and DNA binding proteins as well as the intracellular regulatory actions of signaling molecules such as peptide hormones. It also potentially makes explicable the origins of intracrine enzymes. As noted above, further investigation will be required to determine how similar the actions of enzyme intracrines are to those of other intracrines and therefore how likely they are to have evolved along a similar path. At the same time, given the similarities between the functioning of intracrine enzymes and that of other intracrines, this line of thought suggests that the developmental actions of the iRAS and of other intracrine enzymes may be fruitful areas for further investigation. This is so because the intracrine hypothesis implies that intracrine feedback loops are intimately involved in differentiation and in the development of stem cells. Recent reports support this view of intracrine action and thus confirm some earlier predictions of the theory.^{2,16,18,19,23,68–72} It will be of interest to determine to what extent the intracrine enzymes behave in a similar fashion. The close relation of several intracrine enzymes with monocyte differentiation and angiogenesis, coupled with recent evidence indicating the existence of pluripotent stem cells in certain monocyte populations, gives further support to investigation in this area.^{38,51,70,72,73}

Received April 9, 2003; first decision May 1, 2003; accepted June 9, 2003.

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