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New aspects of the renin–angiotensin system: angiotensin-converting enzyme 2 – a potential target for treatment ofhypertension and diabetic nephropathyDaniel BaMarı´a Jose´ and Jan W aDivision of Nephrology and Hypertension, Department of Medicine, The Feinberg School of Medicine, Whereas angiotensin-converting enzyme promotes the formation of angiotensin II, Northwestern University, Chicago, Illinois, USA and bDepartment of Nephrology, Hospital del Mar, angiotensin-converting enzyme 2 promotes the degradation of angiotensin II to Universitat Auto`noma de Barcelona, Barcelona, Spain angiotensin-(1–7). We review recent studies dealing with angiotensin-converting Correspondence to Daniel Batlle, MD, Division of enzyme 2 in kidney disease and hypertension, and discuss the potential therapeutic Nephrology and Hypertension, Department of benefit of increasing angiotensin-converting enzyme 2 activity in the treatment of these Medicine, The Feinberg School of Medicine,Northwestern University, 320 E. Superior, Chicago, Tel: +1 312 908 8342; fax: +1 312 503 0622;e-mail: In glomeruli from diabetic mice, angiotensin-converting enzyme 2 expression isdownregulated, and pharmacological inhibition of angiotensin-converting enzyme2 leads to worsening of albuminuria, increased mesangial matrix deposition and Current Opinion in Nephrology andHypertension 2008, 17:250–257 fibronectin expression. The deletion of the angiotensin-converting enzyme 2 gene inmice leads to worsening of angiotensin II-induced hypertension and has also beenshown to cause glomerulosclerosis in aging male mice.
SummaryAngiotensin-converting enzyme 2 is a key enzyme in the renin–angiotensin system thatfavors the degradation of angiotensin I and angiotensin II. Angiotensin-convertingenzyme 2 inhibition by pharmacological means and by genetic deletion worsens kidneydisease in diabetic mice. Strategies geared to increasing angiotensin-convertingenzyme 2 activity may provide a novel therapeutic target within the renin–angiotensinsystem by enhancing angiotensin II degradation that may complement the currentapproach of inhibiting angiotensin II formation and action. Amplifying angiotensin-converting enzyme 2 activity may have a potential therapeutic role for kidney disease andhypertension.
Keywordsangiotensin-converting enzyme, angiotensin-converting enzyme 2, diabeticnephropathy, hypertension Curr Opin Nephrol Hypertens 17:250–257ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins Initially, ACE2 was thought to be restricted to the kidney, heart and testes; however, subsequent studies The renin–angiotensin (Ang) system (RAS) in its classical demonstrated that this enzyme is widespread in the conception consists of a cascade of enzymatic reactions organism inviting research on the possible role primarily aimed to the formation of Ang II – the best- ACE2 in various disease states. Notably, ACE2 pro- studied and most active peptide within the system.
tects mice from severe acute lung injury induced by Ang-converting enzyme (ACE) 2 acts as a carboxypepti- acid aspiration, sepsis and severe acute respiratory syn- dase removing single amino acids from the C-terminus of drome (SARS) virus infection Our group first its substrates, whereas ACE acts predominantly as a pep- suggested that ACE2 could be renoprotective, especially tidyl dipeptidase removing C-terminal dipeptides. ACE2 when associated with low levels of ACE In this facilitates the conversion of Ang II to Ang-(1–7) and the review we will discuss recent publications dealing with conversion of Ang I to Ang-(1–9) Ang-(1–7), a ACE2 expression in the kidney, and the possible role of heptapeptide, is increasingly recognized as a potentially alterations in this enzyme in renal disease and hypert- important peptide for its vasodilatory, antifibrotic and 1062-4821 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
New aspects of the renin–angiotensin system Batlle et al.
proximal tubule Moreover, the presence of Mas receptor, identified as a receptor for Ang-(1–7), in rat proximal tubular cells has been documented .
ACE2 is a type 1 integral membrane protein that shares42% homology with the metalloprotease catalytic domains ACE2 is also present in the glomerulus although the level of ACE ACE2 contains only a single active site domain of expression in mouse kidneys is low as compared to and consists of 805 amino acids . The elucidation renal tubules Our laboratory found that ACE2 of the three-dimensional structure of the extracellular colocalizes with glomerular epithelial cell (podocyte) domain of ACE2 revealed that the catalytic mecha- markers and its presence in the podocyte/slit diaphragm nism of ACE2 closely resembles that of ACE. The sub- complex was confirmed by immunogold labeling .
strate-binding pockets, however, differ significantly Glomerular ACE, by contrast, did not colocalize with explaining the differences in substrate specificity between podocyte markers such as synaptopodin, podocin and the two enzymes and the failure of ACE inhibitors to bind nephrin In normal mouse glomerulus, we could to and inhibit ACE2 Other mammalian homologues not find ACE2 staining using endothelial cell markers of ACE such as collectrin and, more recently, ACE3 have or by immunogold staining, but we found modest staining been described ACE2, however, is the only in glomerulus using a mesangial cell marker These known homologue of ACE with enzymatic activity findings showed the presence of ACE2 in podocytes and Recent in-vitro and in-vivo studies have demon- mesangial cells, but not in glomerular endothelial cells.
strated interesting physiological roles of collectrin relatedto insulin secretion, formation of primary cilia, renal cyst The presence of ACE2 has also been documented in formation and amino acid transport Two recent immortalized cultured mouse podocytes These papers on the role of ‘collectrin’ in amino acid transport studies also examined the processing of angiotensin by the proximal tubule suggest that the loss-of- substrates Wysocki et al. showed that the function in this novel protein may be a key factor in the addition of an ACE2 inhibitor, MLN-470, increases pathogenesis of aminoaciduria in Fanconi’s syndrome the content of Ang I and II peptides, thereby indicating In several species ACE3 seems to lack catalytic activity as a the importance of ACE2 for the metabolism of these zinc metalloprotease Moreover, in humans, no evi- peptides. Velez et al. showed that podocytes express dence could be found that the ACE3 gene is expressed, a functional intrinsic RAS characterized by neprilysin, and the presence of deletions and insertions in the aminopeptidase A, ACE2 and renin activities, which sequence suggests that in humans ACE3 is a pseudogene predominantly lead to Ang-(1–7) and Ang-(1–9) for- mation. The abundance of ACE2 in podocytes, and itsanatomic localization within the glomerular filtrationbarrier in close proximity to the glomerular endothelial cells, may be important in regulating Ang II levels by degrading local Ang II or promoting the conversion of Immunohistochemical analysis of ACE2 distribution filtered Ang II to Ang-(1 –7) . Velez et al.  within the kidney showed that renal tubules have the found modest ACE activity in podocytes, although only highest intensity of immunostaining In micro- after cells were incubated with higher concentrations of dissected rat nephron segments, semiquantitative reverse Ang I. Our laboratory did not find ACE protein expres- transcription-PCR revealed that ACE2 mRNA was sion either by Western blot or immunofluorescence in widely expressed, with relatively high levels in proximal cultured mouse podocytes We think therefore that straight tubule In both kidney sections and cultured the podocyte must generate Ang II by an ACE-indepen- polarized renal epithelial cells, ACE2 localized predomi- dent pathway. We think that ACE2 in the podocyte is a nantly to apical surface where it can undergo key enzyme for Ang II degradation to Ang-(1 –7) ( Moreover, ACE2 also degrades Ang I Thus, angio-tensin peptides can be degraded quite efficiently within In stably transfected polarized Madine Darby canine the podocyte. If ACE2 is decreased in the glomeruli in kidney (MDCKII) cells, ACE2 predominantly localizes certain pathological states, such as diabetic nephropathy, to apical membranes (92%). This is in contrast to ACE, this would lead to impaired Ang II degradation with its which is found on both apical (55%) and basolateral consequent accumulation within the glomerulus.
surfaces (45%) The high level of both enzymes,ACE and ACE2, in proximal tubule cells may helpdirectly counterbalance Ang II levels by balancing the formation and degradation of local Ang II by ACE and ACE2, respectively. In rat kidney, ACE2 and Ang-(1 –7) The levels of ACE2 activity in mouse kidney cortex are have been colocalized immunohistochemically to the about 10 to 20-fold higher than in the heart, whereas in Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Figure 1 Key elements of the glomerular filtration barrier: podocyte, glomerular basement membrane and glomerular endothelialcell The proposal is that ACE2 is present in thepodocyte, but not in the GEC. Accordingly, thedegradation of Ang II to Ang-(1–7) isdependent on ACE2 in the podocyte, but not inthe GEC. ACE, by contrast, is present in GECbut not in podocytes. ACE, angiotensin-converting enzyme 2; Ang, angiotensin; GEC,glomerular endothelial cell; GBM, glomerularbasement membrane.
serum ACE2 activity is barely detectable Different kidneys, which show much lower levels of ACE2 activity approaches to assess ACE2 activity have been used includ- than mouse kidneys, this substrate was more sensitive than ing high-performance liquid chromatography (HPLC) the 7-Mca-YVADAPK(Dnp) substrate (Wysocki et al., An HPLC-based method has been used to measureACE2 activity in cardiac membranes and other tissues ACE2 activity is very low or undetectable in plasma from and body fluids Another method which also uses mice Likewise in humans, the levels of circulat- Ang II as the ACE2 substrate, utilizes surface-enhanced ing ACE2 are undetectable or very low, at least in healthy laser desorption/ionization time-of-flight mass spectrom- individuals ACE2 activity and protein have been etry with ProteinChip Array technology The most detected in human urine from healthy subjects and widely used methods for ACE2 activity measurements ACE2 activity has been measured in urine and serum utilize fluorogenic peptide substrates such as Mca-YVA- from sheep It would be of interest to measure urinary ACE2, ideally in conjunction with ACE activity, escence signal of Mca-YVADAPK(Dnp) is partially in disease states such as diabetic nephropathy. It should quenched by specific inhibitors of both ACE and ACE2 be noted that the pattern of ACE and ACE2 expression in Wysocki et al. took advantage of the dual cleavage the glomerulus of diabetic mice is just the opposite of of Mca-YVADAPK by ACE and ACE2 to develop an assay what it is found in cortical tubules . As a consequence to measure ACE and ACE2 activity concurrently. Another of this, one must take into account that the final urine substrate, Mca-APK(Dnp), is useful in measuring ACE2 may not reflect the site of the nephron where the altera- activity, but we find it very dependent on the supplier. For tion in the expression of these enzymes primarily resides instance, in a previous study we could not measure ACE2 activity successfully in mouse kidney tissues usinga custom synthesized fluorogenic peptide (Genemed Gembardt et al. analyzed the ACE2 expression in Synthesis, South San Francisco, California, USA), because different tissues of mice and rats. ACE2 mRNA in both cleavage of this substrate was neither quenchable by species showed the highest expression in the ileum. In rnACE2 inhibitor (MLN-4760) nor by EDTA. Using mice, ACE2 was more heavily expressed than in the rat Mca-APK(Dnp) from another source (AnaSpec, San Jose, both in kidney and colon In concordance with California, USA), however, we were able to detect ACE2 mRNA data, ACE2 activity was also high in the ileum activity in both mouse and rat kidneys. Moreover, in rat and kidney from mice, but weak in the rat. ACE2 activity Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
New aspects of the renin–angiotensin system Batlle et al.
in the lung of both species was relatively low. Lely the level of the podocyte may result in increased glomer- et al. reported that in kidney biopsies from human ular permeability as a result of Ang II accumulation. In subjects ACE2 is expressed in tubular and glomerular addition, by leading to decreased cleavage of Ang II to epithelium, as well as in vascular smooth muscle cells and Ang-(1–7), ACE2 downregulation may result in further the endothelium of interlobular arteries.
deleterious effects related to decreased Ang-(1–7) for-mation .
Angiotensin-converting enzyme 2 expression In agreement with the hypothesis previously advanced by in rodent models of diabetic kidney disease us the deletion of the Ace2 gene was recently Our laboratory has shown that glomerular immunostaining found to accentuate diabetes-related glomerular damage for ACE2 is attenuated in 8-week-old db/db mice In In this study, Ace2 knockout mice were crossed with sharp contrast, ACE expression in glomeruli from diabetic Akita mice – a model of type 1 diabetes mellitus. Diabetic db/db is increased as compared to glomeruli from their Ace2 knockout mice (Ace2-/yIns2WT/C96Y) exhibited a respective age matched nondiabetic controls In rats two-fold increase in urinary albumin excretion compared made diabetic by streptozotocin (STZ), the opposite with Akita mice not depleted in Ace2 gene. Increased pattern was reported The reason for the difference mesangial matrix scores and glomerular basement mem- is not clear but it could represent species differences.
brane thicknesses in Ace2-/yIns2WT/C96Y mice were Glomerular ACE2 staining is weaker than tubular stain- accompanied by increased fibronectin and a-smooth ing in human and mouse kidney, whereas in the rat muscle actin staining in the glomeruli. Although kidney levels of Ang II were not increased in the diabetic mice, sharp contrast to the findings in the glomeruli, we have treatment with an Ang II receptor blocker (ARB) reduced found increased expression of ACE2 in kidney cortex urinary albumin excretion rate in Ace2-/yIns2WT/C96Y from the db/db and STZ models of diabetes in mice mice, suggesting that acceleration of glomerular injury Wong et al. recently found increased ACE2 anddecreased ACE expression at the kidney cortex level,which is consistent with our findings in db/db and Studies in animals with ACE2 genetic ablation have shownthe development of glomerular lesions, but only in aging The effect of the administration of a specific ACE2 inhibi- male mice In this model of genetic ACE2 ablation, tor, MLN-4760, on albumin excretion was recently studied early accumulation of fibrillar collagen in glomerular in two mouse models of diabetes The adminis- mesangium was followed by development of glomerulo- tration of MLN-4760 for 16 weeks resulted in worsening of sclerosis by 12 months of age. These structural changes in albuminuria in the db/db mice and this was associated with the glomeruli of male ACE2 mutant mice were prevented increased glomerular expression of fibronectin The by treatment with the AT1 receptor antagonist irbesartan concomitant administration of Telmisartan, a specific Ang This study showed therefore that, at least in aging II type 1 (AT1) receptor blocker, completely prevented the male mice, the absolute deficiency of ACE2 leads to worsening of albuminuria associated with the ACE2 glomerular disease. In kidney biopsies from patients with inhibitor. This suggested that the effects of ACE2 inhibi- diverse primary and secondary renal diseases (hyperten- tor were mediated by Ang II acting on the AT1 receptor sive nephropathy, IgA glomerulopathy, minimal change nephropathy, focal glomerulosclerosis, vasculitis and mem- increased albuminuria after MLN-4760 administration branous glomerulopathy) and renal transplant biopsies associated with an increase in glomerular mesangial expan- no differences in ACE2 expression were found .
sion and vascular thickness. Interestingly, the expression Interestingly, neoexpression of ACE2 was found in of ACE was increased in glomerulus and renal vasculature glomerular and peritubular capillary endothelium .
(but not in the tubules) from STZ-treated mice and wasfurther increased after MLN-4760 administration  In a study performed in unilaterally nephrectomized rats On the basis of these findings, we proposed that there is a loaded with bovine serum albumin as a model of protei- dual mechanism of RAS activation in glomerulus and renal nuric renal injury, ACE2 protein expression was decreased vasculature during chronic ACE2 inhibition: decreased and this was associated with tubulointerstitial injury.
degradation of Ang II as a result of ACE2 downregulation Decreased tubular ACE2 expression was abolished with and enhanced formation of Ang II as a result of increased the inhibition of renal nuclear factor-kB activation, indi- ACE activity This combination in itself could cating that ACE2 is downregulated by nuclear factor-kB in fully account for much of the detrimental effect of renal tubular cells in vivo . In a model of acute renal ACE2 downregulation by leading to Ang II accumulation, failure (ARF) and endotoxemia after lipopolysaccharide under certain pathologic conditions. ACE2 deficiency at administration, Gupta et al. showed decreased ACE2 Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
gene expression in kidney tissue as compared with kidneys were reduced. It was, therefore, concluded that the from control rats. Interestingly, activated protein C (APC) decrease in renal Ang-(1–7) content in the absence of injection in this model of ARF modulated the RAS by a concomitant decrease in ACE2 implicates the participa- reducing ACE, angiotensinogen and increasing ACE2 tion of other Ang-(1 –7)-forming or degrading enzymes mRNA levels in the kidney. This suggests that the poten- tial protective role of APC in the kidney might bemediated, in part, by enhanced renal ACE2 expression.
The phenotype of ACE2 knockouts studied by Gurleyet al. and Crackower et al. does not include overthypertension. In mice on the C57BL/6 genetic back- Angiotensin-converting enzyme 2 in models ground, ACE2 deficiency was associated with a modest increase in blood pressure, whereas the absence of ACE2 Ace2 maps to the X chromosome in humans and a quan- had no effect on baseline blood pressures in 129/SvEv mice titative trait locus (QTL) has been mapped to the X After Ang II challenge, however, plasma concen- chromosome in several rat models of hypertension .
trations of Ang II were almost three-fold higher in The finding that Ace2 gene maps to a defined QTL on the ACE2-deficient mice than in controls and, moreover, X chromosome suggested Ace2 as a candidate gene under- blood pressures were substantially higher in the ACE2- lying the loci linked to hypertension Crackower et al.
deficient mice than in wild-type In ACE2-deficient showed that ACE2 was reduced at the gene and mice infused with large load of Ang II an increased protein level in kidneys from three separate rat models of accumulation of Ang II in the kidney was documented spontaneous and diet-induced hypertension. In a sub- This study provided strong evidence that complete sequent study in the adult spontaneous hypertensive rat ACE2 insufficiency can worsen hypertension under con- (SHR) model, kidney ACE2 expression was decreased ditions of Ang II excess. Oudit et al. using a different when compared with Wistar-Kyoto (WKY) rats . Of Ace2 knockout reported an age-dependent dilated cardio- note, SH rats treated with retinoic acid displayed a myopathy associated with increased oxidative stress.
significant upregulation of ACE2 expression in heart Moreover, Yamamoto et al. showed that Ace2 knockout mice develop cardiac hypertrophy and dilatation inresponse to pressure overload.
Tikellis et al. more recently showed that the devel-opmental pattern of ACE2 expression in the SHR kidney In renal biopsies from humans, the ratio of ACE to ACE2 was altered before the onset of hypertension. Over the gene expression was significantly higher in subjects with course of renal development, ACE2 expression did not hypertension than in subjects without hypertension significantly change in the SHR kidney, whereas at the Keidar et al. found that prehypertensive patients had same time ACE2 expression increased in the control higher ACE2 activity in monocyte-derived macrophages as compared to hypertensive subjects. These results maysuggest that the elevated ACE2 activity in prehyperten- Ferrario et al. studied the effect of ACE inhibitors and sive subjects might have a protective effect, perhaps ARB administration on ACE2 expression in another model through the ability of this enzyme to counteract the of experimental hypertension. In this study, renin trans- Ang II vasopressor effect Studies in humans exam- genic hypertensive rats (mRen2)27 were crossed with ining a possible association of Ace2 gene polymorphisms Lewis normotensive rats, creating the Lew.Tg (mRen2) congenic strain As expected, in the Lew.Tg (mRen2) recently reviewed no consistent picture has rats, decreasing Ang II activity either by reducing its emerged from these studies, perhaps because of meth- synthesis or preventing the ligand from binding to odological differences as well as ethnic differences of the the AT1 receptor, normalized blood pressure In addition, however, both ACE inhibitor and ARB admin-istration increased ACE2 gene expression and proteinactivity in renal cortical tissue from Lew.Tg (mRen2) converting enzyme 2 amplificationRecent in-vitro studies have shown that ACE2 over- ACE2 may be altered in pregnancy-related hypertension.
expression inhibits hypoxia-induced collagen production Joyner et al. found that during normal pregnancies by cardiac fibroblasts Transduction of fibroblasts there are concurrent changes of ACE2 and Ang-(1–7), with lentiviral ACE2 resulted in a viral dose-dependent suggesting that ACE2 plays a role in regulating renal increase in ACE2 activity and was associated with a levels of Ang-(1–7) at mid to late gestation. In contrast, in significant attenuation of both basal and hypoxia/reoxy- hypertensive pregnant rats the ACE2 activity in cortex genation-induced collagen production by the fibroblasts and medulla were unchanged while Ang-(1 –7) levels ACE2 has also been shown to modulate insulin/ Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
New aspects of the renin–angiotensin system Batlle et al.
Akt–endothelial nitric oxide synthase (NOS) signaling in to be protective against severe acute lung injury in mice a human endothelial cell line (EAhy926) Ang II Therefore, it has been proposed that recombinant diminished insulin-stimulated phosphorylation of Akt ACE2 could be used to treat SARS-CoV infection Our and NOS and nitric oxide generation, and these effects recent studies show that administration of human recom- were reversed by ACE2 gene transfer in endothelial cells binant ACE2 to mice increased circulating ACE2 activity levels in a dose-dependent manner It is, therefore,quite possible that administration of exogenous recombi- Approaches employed so far to amplify ACE2 activity in nant ACE2 could be an effective means of intercepting the vivo have included the lentiviral delivery of ACE2 SARS-CoV and preventing binding to its cellular receptor.
and more recently the administration of recombinant We think that investigation of the potential therapeutic ACE2 In hypertensive rats, ACE2 overexpression use of recombinant ACE2 should not be compromised by by lentiviral delivery was associated with a protective concerns regarding the potential exposure to SARS infec- effect on cardiac hypertrophy In addition, in the SHR rats, lenti-ACE2 treatment resulted in 18% reductionin left ventricular wall thickness and a significant attenu-ation of perivascular fibrosis Persistent overexpres- sion of ACE2 in the rostral ventrolateral medulla by There is increasing evidence that alterations in ACE2, lentivirus ACE2 delivery caused significant attenuation the only enzymatically active homologue of ACE, may be involved in disease states, such as experimental diabetickidney disease and hypertension. Investigating the role The findings that ACE2 appears downregulated in of ACE2 in these prevalent diseases and whether its experimental mice models of diabetic nephropathy at effects are mediated by Ang II or Ang-(1–7) and other the glomerular level, and decreased in kidney cortex from biologically active peptides, which are also substrates of hypertensive rats, suggest that maneuvers aimed at ACE2, opens the way for developing new therapeutic upregulating ACE2 activity may have a therapeutic poten- targets. Amplification of ACE2 activity should provide tial in these conditions. To assess the role of ACE2 on a new paradigm in the therapeutic approach to RAS blood pressure and Ang II metabolism, we recently targeting, i.e. enhancing Ang II degradation, which used recombinant ACE2 administered over a period may complement current strategies aimed at blocking of 3 days via osmotic minipumps with or without Ang II Ang II formation and activity by the administration of infusion The increase in blood pressure produced ACE inhibitors, renin inhibitors and Ang II blockers.
by Ang II alone was prevented by the concomitant Whether the potential therapeutic action of ACE2 ampli- administration of recombinant ACE2 Moreover, fication may be related, in part, to enhanced formation of plasma Ang II levels following Ang II infusion were Ang-(1–7) also needs to be further investigated.
markedly reduced by recombinant ACE2 administration,thereby demonstrating the important role of this enzymein the degradation of Ang II This suggests that References and recommended readingPapers of particular interest, published within the annual period of review, have the administration of recombinant ACE2 may have a role in the treatment of Ang II-dependent hypertension and that increasing ACE2 activity may provide a novel Additional references related to this topic can also be found in the Current approach to reduce high blood pressure.
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