Published online before print December 19, 2005, doi: 10.1161/01.HYP.0000196266.23639.c6
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(Hypertension. 2006;47:509.)
© 2006 American Heart Association, Inc.
Novartis Award |
Views of the Renin–Angiotensin System
Brilling, Mimsy, and Slithy Tove
From the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Ga.
Correspondence to Ken Bernstein, Rm 7107 WMB, 101 Woodruff Circle, Atlanta, GA 30322. E-mail kbernst{at}emory.edu
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Abstract |
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 Top Abstract IntroductionMice Lacking ACEPromoter Swapping as a...ACE, an Enzyme With...ACE and Male FertilityFuture AdvancesReferences |
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The renin–angiotensin system plays a role in many physiological systems, as proven by the phenotype of angiotensin-converting enzyme (ACE) knockout mice. We have used homologous recombination to create novel lines of mice with limited and unusual expression patterns of ACE. These mice show that, as long as an animal can regulate renin, they can tolerate both unusual patterns and reduced expression of ACE. We have also created mice in which one of the two ACE catalytic sites is nonfunctional. These new lines of mice give great insight into the function of the renin–angiotensin system in blood pressure control, response to stress, hematopoiesis, and reproduction.
Key Words: angiotensin • angiotensin-converting enzyme • renin • mice • blood pressure • renin-angiotensin system
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Introduction |
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TopAbstractIntroductionMice Lacking ACEPromoter Swapping as a...ACE, an Enzyme With...ACE and Male FertilityFuture AdvancesReferences |
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Imagine that you are a hepatocyte. One cell among millions. A worker cell producing albumin and clotting factors and lipoproteins. Too boring? Then consider life as a glomerular mesangial cell. Specialized. Somewhat mysterious. And part of a structure that selectively filters. Still not sexy enough? Then think of life as a single sperm. Sleek and very motile (a Ferrari among cells). Extremely specialized, but always ready for a good time. Too dirty? Then how about viewing yourself as a smooth muscle cell. Long and strong. Rarely flashy. A builder of tubes of all sizes. Although all these cells may seem dissimilar, the truth is that they share far more similarities than differences. Like all cells, they respond to their environment in a fashion best described as parallel processing. Cells can easily integrate many dozens of concurrent chemical signals. Their ease in dealing with many simultaneous events is quite different from the nature of human cognition; we think single thoughts at any one time. The different operational basis between human thought and the reality of living organisms has many consequences, and not the least is the tendency for individual scientists to focus on a limited subject area. Thus, our own work focuses on the renin–angiotensin system (RAS), and we tend to interpret blood pressure control and cardiovascular disease with the prejudice that angiotensin-converting enzyme (ACE) and angiotensin II are central. In contrast, Dr David Harrison, a colleague of ours at Emory University, and one of the winners of the 2004 Novartis Prize, sees nitric oxide as central to blood pressure and cardiovascular pathology. If we could intellectually parallel process, we would envision blood pressure control as quite multivariate and complex, with many concurrent physiological influences. Fortunately, a current favorite of biological research, the genetic manipulation of mice, leads to analysis of a complex living organism, which, in turn, encourages the visualization of physiological responses as attributable to multiple systems and pathways.
There is a second train of thought that unifies the hepatocyte, glomerular mesangial cells, developing sperm, and smooth muscle cells: all of these cells are affected by ACE and/or angiotensin II. The RAS influences many different tissue types and gives rise to the intellectual dilemma that individual tissue types respond quite differently to the stimulation of the angiotensin II type 1 (AT1) receptor. Thus, someone who wishes to understand the RAS must often make a choice. Do we study the small, the cell, and the detailed biochemistry that enable one to understand tissue responses to angiotensin II, or do we study the large, the animal, the normal physiology, and the abnormal pathology observed in a complex system, such as a mouse? This article deals with the large: studies of mice that illuminate some of the physiological actions of the RAS. However, we acknowledge that our approach leaves unexamined the cellular biochemistry that underpins observable physiological responses.
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Mice Lacking ACE |
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TopAbstractIntroductionMice Lacking ACEPromoter Swapping as a...ACE, an Enzyme With...ACE and Male FertilityFuture AdvancesReferences |
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Much of our recent work is motivated by the study of mice completely lacking ACE.1,2 While these animals live, they present with a marked reduction of blood pressure. Thus, whereas a wild-type mouse has a systolic blood pressure (as measured using a tail-cuff device) of &110 mm Hg, mice lacking all ACE (ACE-null mice) have stable systolic blood pressures of &73 mm Hg. ACE-null mice are also unable to effectively concentrate urine. This is because of, in part, a renal structural defect characterized by expansion of the renal pelvis and thickening of renal arterioles. Mice null for ACE expression are mildly anemic. They also have a mild increase of serum and urinary potassium levels. Male ACE-null mice have a marked defect in fertility because of the lack of the testis isozymes of ACE.
An important aspect of the ACE-null phenotype is that is it precisely duplicated by mice lacking angiotensinogen or all of the AT1 receptors.3–6 Furthermore, the phenotype of a mouse null for ACE and also lacking the bradykinin B2 receptor is not significantly different from that present in an animal only lacking ACE.7 These observations suggest that, at least in mice, the major described phenotypes are because of the selective absence of angiotensin II generation and not because of other ACE substrates. ACE is known to degrade bradykinin, and ACE inhibition is associated with elevation of bradykinin levels. In humans, it has been suggested that bradykinin plays a role in the cough sometimes seen in patients on ACE inhibitors.8 Thus, the observation in mice that pathology is a direct result of angiotensin II underlines the caveat that mice are not an exact model of human biology. Nonetheless, work from many laboratories suggests that angiotensin II production is the critical catalytic function of ACE; the lack of angiotensin II accounts for most of the pathology in ACE-null mice.
A second lesson from ACE-null mice is that ACE and angiotensin II play major physiological roles in several different systems. These include blood pressure control, electrolyte balance, urinary concentrating mechanism, proper ureteral function, hematopoieses, reproduction, and so forth. This idea is consistent with the known distribution of angiotensin II receptors and reflects the increasingly broad role that angiotensin II is now recognized as playing in normal physiology. Given this backdrop, our group set about a series of studies to more precisely define the tissue-specific roles of the RAS.
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Promoter Swapping as a Means of Targeting ACE Expression |
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TopAbstractIntroductionMice Lacking ACEPromoter Swapping as a...ACE, an Enzyme With...ACE and Male FertilityFuture AdvancesReferences |
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Our group has championed an approach in which targeted homologous recombination is used to position a new tissue-specific promoter to control ACE gene expression.9 For example, Figure 1 shows the normal organization of the ACE gene in which the endogenous somatic ACE promoter determines the temporal and tissue-specific expression of this protein. Using targeted homologous recombination, we can position a neomycin cassette to block the effects of the endogenous ACE promoter. Furthermore, a tissue-specific promoter, such as the albumin promoter, can then be positioned to control the expression of the ACE gene. Mice homozygous for this genetic change have a marked elevation of hepatic ACE expression.10 In contrast, because ACE expression is now under the control of the albumin promoter, endothelial cells (which do not recognize this promoter) do not make ACE. This approach is unique in that the resulting mouse does have substantial quantities of ACE, only now, the protein is no longer produced by endothelium but by hepatocytes. In analyzing this model, we directly ask whether endothelial expression of ACE is physiologically required. The simple answer is no. ACE 3/3 mice (animals homozygous for the genetic change targeting ACE expression to the liver) have a normal blood pressure, normal renal function, and normal hematocrit. Study of this model and other mouse models strongly supports the idea that normal physiological balance is maintained through the ability of the kidney to regulate renin production and to compensate for the abnormal tissue distribution of ACE; these models underline the significance of renin expression as a means of maintaining homeostasis. In fact, the sheer importance of the RAS in blood pressure control gives insight into why ACE inhibitors are so effective in the treatment of blood pressure and cardiovascular disease. Finally, our studies underscore the idea that human hypertension can occur only with the acquiescence/misfunction of renal homeostatic mechanisms.
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It is worthwhile to discuss a specific experimental example that convinced my group of the importance and power of renin in controlling blood pressure. This is our analysis of the ACE 1/3 mouse line.11 ACE 1/3 mice are compound heterozygotes for the ACE gene, meaning that these mice have 2 different copies of the ACE gene. The ACE 1 allele is a knockout allele that produces no ACE. The ACE 3 allele uses the albumin promoter to direct ACE expression. Thus, ACE 1/3 mice are different from wild-type mice in 2 distinct ways. First, the presence of the knockout allele means that only a single functional ACE 3 allele directs ACE synthesis. As such, these animals have less ACE expression than animals with a typical complement of 2 functional ACE genes. Furthermore, the single functional ACE gene has been engineered to direct ACE expression to hepatocytes. Thus, ACE 1/3 mice not only express no endothelial ACE, but they also express roughly half the liver ACE concentration observed in ACE 3/3 mice (Figure 2). In an ACE 3/3 mouse, the normal process of ACE liberation from tissue results in ACE plasma levels roughly 80% those of a wild-type mouse. In contrast, an ACE 1/3 mouse has reduced hepatic expression of ACE with the result that plasma ACE levels are only &40% of normal. Despite all of these physiological differences from wild-type mice, ACE 1/3 mice have a systolic blood pressure indistinguishable from that of wild-type mice.
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In analyzing this experiment, we realized that basal blood pressure was not a complete characterization of the function of the RAS, because this system is one that comes into play during physiological stresses, such as dehydration, salt depletion, or blood loss. So, perhaps it is not surprising that, under laboratory conditions of free access to food and water, ACE 1/3 mice are phenotypically normal. To examine a stress situation, the mice were placed on a sodium-free diet for 2 weeks.11 We then analyzed the resulting blood pressure and urinary salt excretion. Because of an increased ability to concentrate urine, mice tolerate salt restriction far better than humans. Thus, in response to 2 weeks of salt depletion, wild-type mice have a reduction of systolic blood pressure, but this averaged <4 mm Hg. ACE 1/3 mice were not able to achieve quite as profound a reduction of urinary sodium excretion as wild-type mice. As a consequence, these animals had a somewhat greater loss of systolic blood pressure (9 mm Hg) in response to salt depletion. Although the stress of 2 weeks without salt does uncover a difference between wild-type and ACE 1/3 mice, the magnitude of this difference is not particularly great. Thus, ACE 1/3 mice, despite lacking all vascular ACE and with 1 ACE allele totally nonfunctional, still maintain near-normal physiological parameters after major physiological stress!
How can the ACE 1/3 mice maintain near-normal physiology? The answer is the ability of the kidney to produce renin. During a normal sodium diet, ACE 1/3 mice compensate for both the positional change of ACE location and the quantity of expressed ACE by upping renin production (Figure 3). This actually results in plasma angiotensin II levels that are abnormally high. In fact, we hypothesize that the elevated plasma angiotensin II levels are, in part, a compensation for the lack of local, tissue-based production of angiotensin II. From the prospective of angiotensin II receptors on smooth muscle cells or within the adrenal, it is the local concentration of angiotensin II that is important, not whether the peptide is produced within the circulation or locally within adjacent tissues. Under normal physiological conditions, the angiotensin II that binds to receptors is a combination of angiotensin II made locally by endothelium and angiotensin II made within the systemic circulation. In ACE 1/3 mice, local production of angiotensin II has been removed (no endothelial ACE), and the circulating ACE present in plasma is only 40% of normal. This induces physiological compensation, namely, elevated renin production, elevation of angiotensin I, increased angiotensin II production, and elevated angiotensin II levels in plasma. Plasma circulates with the result that the local concentration of angiotensin II within most tissues is similar to that found in wild-type mice. Consistent with this hypothesis, aldosterone levels in ACE 1/3 mice are normal; from the perspective of the adrenal, angiotensin II levels are physiological despite the abnormal location of angiotensin II production.
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The real question is what happens to this compensated system when the animal is exposed to 2 weeks without sodium. This is also shown in Figure 3 and can be summarized as "more of the same." The reduction of dietary sodium induces a massive elevation of renin. Although not completely compensatory, this physiological change permits renal retention of sodium and only a slightly increased drop of systolic blood pressure in response to sodium deprivation.
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ACE, an Enzyme With 2 Catalytic Domains |
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TopAbstractIntroductionMice Lacking ACEPromoter Swapping as a...ACE, an Enzyme With...ACE and Male FertilityFuture AdvancesReferences |
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Somatic ACE is a single polypeptide chain. However, it is composed of 2 separate catalytic domains that are a reflection of an ancient gene duplication.12 Each of these catalytic domains binds zinc and is able to independently convert angiotensin I to angiotensin II. In vitro analysis has shown that the 2 ACE catalytic domains, often termed the N-terminal and C-terminal domains, have roughly equivalent catalytic constants for angiotensin I.12 However, ACE is a rather nonspecific peptidase and is capable of hydrolyzing a variety of other peptide substrates. For instance, ACE degrades bradykinin; bradykinin accumulation in response to ACE inhibition has been associated with side effects of therapy. Apart from bradykinin, the role of ACE in degrading nonangiotensin peptides in not well understood in vivo.
One peptide that does accumulate during ACE inhibition is acetyl-SerAspLysPro (acetyl-SDKP). This peptide was initially purified from bone marrow and described as a regulator of hematopoiesis.13 In vitro, acetyl-SDKP inhibits the proliferation of hematopoietic stem cells.14,15 One of the more interesting features of ACE-null mice (animals with an elevation of acetyl-SDKP) is that they are anemic. Indeed, there is a whole clinical literature describing changes of human hematocrit in response to ACE inhibitors.16
One hypothesis concerning ACE inhibition (in humans) or the lack of ACE (in mice) is that accumulated acetyl-SDKP may play a role in reducing hematocrit. To study this and to create mouse models allowing in vivo identification of the physiological effects of each ACE catalytic domain, we created mice in which amino acid point mutations were introduced into either the N-terminal or C-terminal catalytic domains. These mutations specifically inactivate 1 of the ACE domains. An advantage of this strategy is that the amino acid point mutations were introduced in a fashion designed to minimize differences in expression of the ACE protein. For instance, the first mouse created was called ACE 7/7 (Figure 4).17 This animal was engineered such that 2 histidine residues (amino acids 395 and 399) were converted to lysine, a change that makes it impossible for the N-terminal catalytic domain to bind zinc. Without zinc, the N-terminal catalytic domain is inactive. ACE 7/7 mice produce the modified ACE protein at levels indistinguishable from wild-type mice. Furthermore, this protein retains its C-terminal catalytic activity.
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My group studied the physiology of 2 related mouse lines termed ACE 7/7 (homozygous for the point mutations) and ACE 1/7 (an ACE compound heterozygote in which the ACE 1 allele is null).17 Whereas ACE 7/7 mice produced normal quantities of ACE protein, ACE 1/7 mice produced &50% normal levels. Despite the lack of N-terminal ACE activity, both ACE 7/7 and ACE 1/7 mice have a normal blood pressure and hematocrit. In fact, we tested the ability of these mice to recover from an acute anemia induced by phenylhydrazine; both ACE 7/7 and ACE 1/7 mice recovered hematocrit equivalent to that of wild-type mice. Thus, these experiments show that acetyl-SDKP has little influence on hematocrit, at least in mice. In fact, experiments in ACE-null mice infused with angiotensin II by minipump suggest that it is angiotensin II that has effects on hematocrit.16 At present, the biochemical mechanisms by which angiotensin II contribute to hematopoiesis are not well understood.
My group has also used targeted homologous recombination to introduce point mutations into the C-terminal catalytic domain of ACE. Although the results of this manipulation are not yet published, it is important to underline that 1 of the major considerations for doing this experiment is to investigate the role of ACE in male reproduction.
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ACE and Male Fertility |
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TopAbstractIntroductionMice Lacking ACEPromoter Swapping as a...ACE, an Enzyme With...ACE and Male FertilityFuture AdvancesReferences |
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As indicated in the introduction, ACE is made by developing male germ cells. However, these cells produce a unique isozyme of the ACE protein that is roughly half the size of the protein made by somatic tissues.12 The molecular explanation for this unique isozyme, termed testis ACE, is that the ACE genetic locus contains 2 distinct promoter regions: the somatic promoter, which is recognized by endothelium and leads to the production of the typical form of ACE, and a testis promoter located in the twelfth intron of the ACE gene (Figure 1).18,19 This second promoter is only recognized by developing male germ cells with the result that developing sperm initiate testis ACE transcription in the middle of the ACE gene. With the exception of a few amino acids at the amino terminus, testis ACE protein is identical to the carboxyl terminal half of somatic ACE. Thus, testis ACE has only a single catalytic domain, equivalent to the C-terminal domain of the somatic isozyme.
Although the different ACE isozymes are interesting to those who specialize in this protein, what gives this topic biological relevance is that testis ACE plays an important role in male fertility. This became apparent with the analysis of ACE-null mice.2 Although these animals were originally thought to be infertile, this is now known to be incorrect in the sense that ACE-null mice can give rise to rare offspring.1 However, there is a very marked difference in the fecundity of wild-type and male ACE knockout male mice: both the number of litters and the size of litters is very much reduced in knockout animals. Additionally complicating this topic is a recent publication by Kondoh et al20 where the authors identified glycosylphosphatidylinositol (GPI)-releasing activity in testis and attributed this enzymatic action to ACE. They claim that it is the GPI-releasing activity and not the dicarboxypeptidase action of ACE that is important to male fertility.
An important consideration of creating mice with the point mutations inactivating the ACE C-terminal catalytic domain is that this is the only domain present in the testis ACE isozyme. Thus, we predict that these mice (termed ACE 13/13) will make a somatic ACE protein with N-terminal catalytic activity intact but that the dicarboxypeptidase activity of testis ACE will be completely eliminated. This addresses 2 important questions. First, the introduction of point mutations will not change expression levels of testis ACE. Now, we will test whether the mere presence of testis ACE protein (although catalytically inactive) is sufficient for normal male fertility. Second, point mutations in the zinc-binding domain of testis ACE should not interfere with the GPI-releasing activity described by Kondoh et al.20 Thus, we can directly examine whether it is dicarboxypeptidase activity of the testis isozyme that plays a role in male fertility. Conceivably, these experiments could have direct human applications in stimulating pharmaceutical development of a compound that blocks the C-terminal catalytic activity of ACE while leaving N-terminal function intact. In theory, such a scheme could play a part in developing a male contraceptive.
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Future Advances |
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TopAbstractIntroductionMice Lacking ACEPromoter Swapping as a...ACE, an Enzyme With...ACE and Male FertilityFuture AdvancesReferences |
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Our studies of the RAS began in 1987 while a fellow in the research laboratory of Drs Gary and Liliane Striker. This was a time of great excitement, because it was just after the demonstration by Dr Barry Brenner and colleagues that renal glomerular pressures were a major pathologic feature of progressive renal disease. Since then, understanding of the RAS has continued with almost breathtaking regularity. For example, the primary sequence of ACE was determined by cDNA cloning, leading to the discovery that ACE is composed of 2 homologous catalytic domains.21,22 The molecular mechanisms controlling testis ACE expression were at least partially elucidated.23,24 Receptors for angiotensin II were cloned.25,26 Substantial progress was made in understanding the extremely complex signaling associated with angiotensin II.27 Clinically, the use of ACE inhibitors has extended from the treatment of hypertension to include many forms of cardiac and renal disease. Perhaps now, it is inevitable to question whether additional important discoveries remain to be found. We strongly believe that the answer is yes. In fact, there are clues to future important areas of investigation already available in the literature. For example, an article by Deshayes and Nahmias28 poses the broad question of whether some role in cancer biology will be added to the known effects of the RAS on blood pressure and cardiovascular, renal, reproductive, and hematologic activities already described. Other articles29,30 focus on the very important role of the RAS in macrophage function. These and other such studies may directly influence how we view the pathogenesis of arthrosclerosis, the leading killer of Americans.
We began the article by noting that cells have no difficulty in accepting and integrating many simultaneous signaling events. An important corollary is that biological systems have adapted the RAS into something that influences many different physiological processes apart from blood pressure control. One of the great challenges scientists face is to develop a comfort level viewing biological systems and, in particular, the RAS, as part of multifactorial parallel processing. This type of thinking goes against-the grain in that it is much more natural to simplify angiotensin II as something simply influencing blood pressure. However, as long as we remember that the history of the RAS is one of expanding biological influence and not close our minds to the possibility that much remains unknown, we feel that the RAS will continue to reveal itself and provide opportunities to modify disease for the betterment of humankind.
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Acknowledgments |
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This work was supported by National Institutes of Health grants R37 DK039777, R01 DK051445, and R01 DK055503. We thank Ellen Bernstein. This article is written in memory of Dr Liliane Striker, who died in 2005.
Received September 15, 2005; first decision October 6, 2005; accepted October 21, 2005.
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References |
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TopAbstractIntroductionMice Lacking ACEPromoter Swapping as a...ACE, an Enzyme With...ACE and Male FertilityFuture AdvancesReferences |
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- Krege JH, John SWM, Langenbach LL, Hodgin JB, Hagaman JR, Bachman ES, Jennette JC, O’Brien DA, Smithies O. Male-female differences in fertility and blood pressure in ACE-deficient mice. Nature. 1995; 375: 146–148.[CrossRef][Medline] [Order article via Infotrieve]
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[Abstract/Free Full Text] - Xiao HD, Fuchs S, Cole JM, Disher KM, Sutliff RL, Bernstein KE. The role of bradykinin in angiotensin-converting enzyme (ACE) knockout mice. Am J Physiol. 2003; 284: H1969–H1977.
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[Abstract/Free Full Text] - Corvol P, Williams TA, Soubrier F. Peptidyl dipeptidase A: angiotensin I-converting enzyme. Methods Enzymol. 1995; 248: 283–305.[Medline] [Order article via Infotrieve]
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[Abstract/Free Full Text] - Bonnet D, Lemoine FM, Khoury E, Pradelles P, Najman A, Guigon M. Reversible inhibitory effects and absence of toxicity of the tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) in human long-term bone marrow culture. Exp Hematol. 1992; 20: 1165–1169.[Medline] [Order article via Infotrieve]
- Jackson JD, Ozerol E, Yan Y, Ewel C, Talmadge JE. Activity of acetyl-Ser-Asp-Lys-Pro (AcSDKP) on human hematopoietic progenitor cells in short-term and long-term bone marrow cultures. J Hematother Stem Cell Res. 2000; 9: 489–496.[CrossRef][Medline] [Order article via Infotrieve]
- Cole J, Ertoy D, Lin H, Sutliff RL, Ezan E, Guyene TT, Capecchi M, Corvol P, Bernstein KE. Mice deficient in angiotensin converting enzyme (ACE) have anemia due to a lack of angiotensin II facilitated erythropoiesis. J Clin Invest. 2000; 106: 1391–1398.[Medline] [Order article via Infotrieve]
- Fuchs S, Xiao HD, Cole JM, Adams JW, Frenzel K, Michaud A, Zhao H, Keshelava G, Capecchi MR, Corvol P, Bernstein KE. Role of the N-terminal catalytic domain of angiotensin-converting enzyme investigated by targeted inactivation in mice. J Biol Chem. 2004; 279: 15946–15953.
[Abstract/Free Full Text] - Howard TE, Shai S-Y, Langford KG, Martin BM, Bernstein KE. Transcription of testicular angiotensin-converting enzyme (ACE) is initiated within the 12th intron of the somatic ACE gene. Mol Cell Biol. 1990; 10: 4294–4302.
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[Abstract/Free Full Text] - Kondoh G, Tojo H, Nakatani Y, Komazawa N, Murata C, Yamagata K, Maeda Y, Kinoshita T, Okabe M, Taguchi R, Takeda J. Angiotensin-converting enzyme is a GPI-anchored protein releasing factor crucial for fertilization. Nat Med. 2005; 11: 160–166.[CrossRef][Medline] [Order article via Infotrieve]
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is a positive regulator of testis ACE transcription. Proc Natl Acad Sci U S A. 1996; 93: 12262–12266.[Abstract/Free Full Text] - Murphy TJ, Alexander RW, Griendling KK, Runge MS, Bernstein KE. Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor. Nature. 1991; 351: 233–236.[CrossRef][Medline] [Order article via Infotrieve]
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