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World J Diabetes. Jun 15, 2021; 12(6): 839-854
Published online Jun 15, 2021. doi: 10.4239/wjd.v12.i6.839
New perspectives on angiotensin-converting enzyme 2 and its related diseases
Li-Ping Liu, Xiao-Li Zhang, Jian Li
Li-Ping Liu, Jian Li, Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, School of Medicine, Hunan Normal University, Changsha 410013, Hunan Province, China
Xiao-Li Zhang, TheFifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg 68135, Baden-Württemberg, Germany
ORCID number: Li-Ping Liu (0000-0003-1738-6125); Xiao-Li Zhang (0000-0003-0076-0854); Jian Li (0000-0002-6210-7415).
Author contributions: Liu LP and Zhang XL wrote the manuscript; Li J designed and revised the review.
Supported by National Natural Science Foundation of China, No. 81873861; and Key Grant of Research and Development in Hunan Province, No. 2020DK2002.
Conflict-of-interest statement: The authors declare no conflicts of interest related to this manuscript.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jian Li, PhD, Associate Professor, Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, School of Medicine, Hunan Normal University, No. 371 Tongzhipo Road, Changsha 410013, Hunan Province, China. lijianyxy@hunnu.edu.cn
Received: February 18, 2021
Peer-review started: February 18, 2021
First decision: March 16, 2021
Revised: March 30, 2021
Accepted: April 20, 2021
Article in press: April 20, 2021
Published online: June 15, 2021

Abstract

Since the worldwide outbreak of coronavirus disease 2019, angiotensin-converting enzyme 2 (ACE2) has received widespread attention as the cell receptor of the severe acute respiratory syndrome coronavirus 2 virus. At the same time, as a key enzyme in the renin-angiotensin-system, ACE2 is considered to be an endogenous negative regulator of vasoconstriction, proliferation, fibrosis, and proinflammation caused by the ACE-angiotensin II-angiotensin type 1 receptor axis. ACE2 is now implicated as being closely connected to diabetes, cardiovascular, kidney, and lung diseases, and so on. This review covers the available information on the host factors regulating ACE2 and discusses its role in a variety of pathophysiological conditions in animal models and humans.

Key Words: Angiotensin-converting enzyme 2, COVID-19, Salt, Renin-angiotensin-system inhibitors, Diabetes and cardiovascular disease, Renal and lung disease

Core Tip: Angiotensin-converting enzyme 2 (ACE2) as the key cell receptor for the severe acute respiratory syndrome coronavirus 2 virus has received widespread attention. This paper will review the new perspectives on ACE2, covers available information on the host regulative factors of ACE2, and discusses its role in a variety of pathophysiological conditions. This review will help us with a better understanding of the biological function and role of ACE2 in coronavirus disease 2019 and its treatment.



INTRODUCTION

Angiotensin-converting enzyme 2 (ACE2), as the key enzyme in the renin angiotensin system (RAS) and key cell receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has received considerable attention[1] since coronavirus disease 2019 (COVID-19) has spread worldwide. Patients with diabetes and renal and cardiovascular diseases are widely treated with ACE inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs), which are deemed to potentially increase ACE2 expression in the body; the consequent increased expression of ACE2 could facilitate infection with SARS-CoV-2. The paradox of the use of ACEI/ARB treatment to interfere with the RAS because ACE2 reduces inflammation (which has been suggested as a therapy for inflammatory lung diseases, diabetes, and hypertension) and the probable contribution of ACE2 to an increased risk of COVID-19 have puzzled clinicians and attracted much attention[2,3]. Therefore, it is necessary to further understand the characteristics of ACE2 and accurate details of the molecular mechanisms of ACE2 that underlie these phenomena. This review will focus on the biological function of ACE2 and its host regulatory factors. Moreover, we will discuss the role of ACE2 in a variety of pathophysiological conditions, including cardiovascular, kidney, and lung diseases and diabetes in animal models and humans. We aim to provide new perspectives on ACE2 and help us better understand the role of ACE2 in SARS-CoV-2 infection and its treatment nowadays (Figure 1).

Figure 1
Figure 1 Composition and function of the renin-angiotensin system and its main regulators and inhibitors. RAS: Rennin angiotensin system; ACEI: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin II receptor blocker; ACE: Angiotensin-converting enzyme; ACE2: Angiotensin-converting enzyme 2; AT1R: Angiotensin type 1 receptor; AT2R: Angiotensin type 2 receptor; MasR: Mas receptor; MLN-4760: A specific ACE2 inhibitor; Organ damage: Renal damage, lung damage, cardiovascular damage, etc.
BIOCHEMICAL CHARACTERISTICS AND DISTRIBUTION OF ACE2

ACE2 is a type I membrane protein that includes an N-terminal peptidase domain (PD) and a C-terminal collectrin-like domain. The PD of ACE2 provides a direct binding site for the S protein of coronavirus[4]. ACE2 was discovered in 2000 when Tipnis et al[5] and Donoghue et al[6] cloned ACE2 from a human heart failure (HF) cDNA library and a human lymphoma cDNA library and found to be a homolog of the ACE gene. The gene is located in the Xp22 region and has a total length of approximately 39.98 kb, including 18 exons and 17 introns. ACE2 can be hydrolyzed by depolymerase into soluble ACE2, and therefore, ACE2 has two forms, the membrane-linked type and the soluble type. Membrane-linked ACE2 is an extracellular enzyme that is distributed on the cell membrane surface and consists of four parts: The N-terminal signal peptide region, the zinc binding motif (amino acid residues 374 to 378), the transmembrane region (amino acids 740 to 768), and the C-terminal intracellular domain. Dissolved ACE2 is distributed mainly in the plasma and urine due to the lack of a transmembrane region and a C-terminal intracellular domain[5]. ACE2 is widely expressed in many organs, including the heart, kidney, testis, adipose tissue, brain tissue, vascular smooth muscle cells, gastrointestinal tract, and lung (type 2 alveolar epithelial cells) and is highly specific in tissues[7].

FUNCTIONS OF ACE2

ACE2 is a key enzyme in the RAS and is considered to be an endogenous negative regulator of vasoconstriction, proliferation, fibrosis, and proinflammation caused by the ACE-angiotensin II (Ang II)-angiotensin type 1 receptor (AT1R) axis[8]. In the RAS, ACE cuts Ang I to convert it into Ang II, and then Ang II binds to the G protein-coupled receptor AT1R, which causes vasoconstriction and increased blood pressure [9]. The function of ACE2 is opposite to that of ACE. ACE2 cuts Ang II and converts it into angiotensin 1-7 (Ang 1-7), which can lower blood pressure[10]. Increasing evidence demonstrates that ACE2 plays an important role in a variety of pathophysiological conditions. In the tumor microenvironment, ACE2 acts on Ang II to produce endogenous Ang 1-7. Ang 1-7 binds to the Mas receptor (MasR) and exerts antitumor effects such as antiproliferation, antiangiogenesis, anti-invasion, and antimetastasis effects through a series of signal transduction pathways. In diabetes, upregulation of ACE2 can improve hyperglycemia, and Ang 1-7 can improve metabolic syndrome through glucose intake and oxidative stress related to insulin resistance[11]. The expression of ACE2 is related to atherosclerosis[12]. The overexpression of ACE2 can improve endothelial-dependent vascular relaxation, increase the proliferative activity of endothelial cells, and facilitate the migration of endothelial cells. ACE2 exerts anti-infective properties through Ang 1-7[13]. The decrease in aortic ACE2 expression increases the expression of proinflammatory factors, such as tumor necrosis factor α, interleukin-6, monocyte chemotactic protein 1, vascular cell adhesion molecule 1, matrix metalloproteinase (MMP)-2 and MMP-9, which are conducive to the adhesion of leukocytes to endothelial cells and blood vessel walls. In addition, ACE2 can also regulate the adhesion of macrophages to endothelial cells[14]. The combination of Ang 1-7 and MasR can also inhibit the formation of thrombi[15] and liver fibrosis[16]. In ischemic stroke, Ang 1-7 can reduce the area of cerebral infarction and brain dysfunction by regulating the release of nitric oxide from different sources to protect the brain. In addition, Ang 1-7 in brain tissue can regulate learning and memory functions. In the reproductive system, Ang 1-7 can regulate endometrial function, spermatogenesis, follicular maturation, ovulation, and pregnancy-related processes[11]. ACE2 can also regulate the immunity of intestinal epithelial cells through amino acid homeostasis, expression of antimicrobial peptides, and regulation of the balance of intestinal microbes[17].

ACE2 AND SALT

It has been widely demonstrated that a high-sodium (HS) diet activates the RAS. Animal experiments have proven that salt intake is a powerful regulator of ACE2 expression in animal models[18]. Studies by Samuel et al[19] found that the relative expression patterns of ACE and AT1R increased, renin levels decreased, and ACE2, AT2R, and MasR remained unaltered in HS-fed lean Zucker rats. On the other hand, HS intake caused an increase in the cortical expression of ACE and a decrease in ACE2, accompanied by increased blood pressure. Elevated blood pressure is associated with a significant increase in Ang II levels in the renal cortex in obese rats and a decrease in the expression of the ACE2-AT2R-MasR axis in obese Zucker rats. In a study of a left nephrectomy rat model[20], HS diet intake increased the glomerular ACE/ACE2 ratio, which was associated with decreased ACE2. In ACE2 KO mice, ACE2 deficiency significantly increased renal oxidative stress by reducing the production of Ang 1-7. In another study, the consumption of a HS diet in normotensive animals reduced ACE2 protein expression and raised renal oxidative stress[21]. Another study showed that the ACE/ACE2 protein ratio was increased in the kidneys of spontaneously hypertensive rats (SHRs) when fed diets with high levels of NaCl. At the same time, compared to the other SHR groups, there was an increase in kidney ACE2 protein and activity in the group fed a long-term low salt diet[18]. Similarly, Varagic et al[22] used an SHR model to prove that HS intake decreased cardiac ACE2 mRNA and protein expression. In Dahl salt-sensitive hypertensive rats, a HS diet reduced ACE2 mRNA expression and augmented the local RAS, which induced hypertension[23]. The HS diet also decreased ACE2 protein expression as assessed using immunohistochemistry compared to a normal-salt diet[24].

In summary, these findings show that a HS diet can reduce the expression of ACE2, thereby affecting the RAS. Further studies have reported that interventions that augment ACE2 expression or activity can be helpful to prevent cardiovascular damage[25]. Therefore, elucidating the precise mechanisms involved in the interaction of sodium intake and ACE2 will be conducive to predicting the physiological and pathological changes caused by a HS diet (Table 1).

Table 1 List of animal studies on the high-sodium diet and angiotensin-converting enzyme 2.
Animal
Study details
Main findings
Ref.
Zucker ratsLean and obese Zucker rats were fed a normal-sodium diet (0.4%) or a high-sodium diet (8%) for 2 wkACE2 mRNA and protein expression was significantly reduced in HS-fed obese Zucker ratsSamuel et al[19]
Wistar ratsRats were fed three salt concentrations (0.2%, 1.2%, 8.2%) for 4 wk after uninephrectomy of the left kidneyHS diet increased the glomerular ACE/ACE2 ratioBernardi et al[20]
Wistar ratsAfter 4 wk of induction of hypertension (2-kidney 1-clip model), rats were fed a normal-sodium diet (0.4%) or a high-sodium diet (8%) for 2 wkHS diet decreased urinary angiotensinogen, ACE, and ACE2 expression in the clipped and unclipped kidneysShimoura et al[21]
SHRRats were fed three NaCl content diets (0.03%, 0.3%, 3%) for 6 moHS diet decreased ACE2 protein expression in kidney tissuesBerger et al[18]
SHRRats were fed an 8% salt diet for 5 wkHS diet decreased cardiac ACE2 mRNA and protein levelsVaragic et al[22]
DS and DR ratsDS and DR rats were fed low-sodium chow (0.45%) or high-sodium chow (7%) for 8 wk and treated with or without eplerenone (100 mg/kg/d), candesartan (10 mg/kg/d), or both drugs for 8 wkHS diet increased angiotensinogen mRNA and decreased ACE2 mRNA in the hearts of DS rats; candesartan increased ACE2 mRNA levels in the heartTakeda et al[23]
SD ratsRats were fed an 8% NaCl high-salt or 0.4% NaCl (normal-salt) diet for 3 wk, with or without antioxidant supplementation with tempolHS diet decreased ACE2 expression; tempol reversed the imbalance of renal RAS components (decrease in Ang II and AT1R and increase in AT2, ACE2, Ang 1-7, and MasR staining intensity)Cao et al[24]
ACE2 AND RAS INHIBITORS

Some studies in animal models have demonstrated that both ACEIs (lisinopril, enalapril, and ramipril) and ARBs (losartan, olmesartan, and telmisartan) can upregulate ACE2 expression. Ferrario et al[26] showed that ACE2 mRNA expression increased in the left ventricle of normotensive Lewis rats after 12 d of lisinopril or losartan treatment. Lisinopril increased ACE2 levels by 5-fold, while losartan increased ACE2 levels by 3-fold. A rat study from Ocaranza et al[27] showed that enalapril prevented the decrease in mRNA levels and activities of ACE2 in late ventricular dysfunction after myocardial infarction. The results of Ishiyama et al[28] indicated that the level of ACE2 mRNA increased after ARB treatment in rats with coronary artery ligation. A mouse study by Soler et al[29] showed that ACE2 is preferentially localized in the tunica media of kidney arterioles, and its expression is amplified after administration of telmisartan. On the other hand, some association studies have shown no increase in ACE2 mRNA after ACEI or ARB treatment. An animal study by Burrell et al[30] found that ramipril attenuated cardiac hypertrophy and inhibited cardiac ACE but had no effect on cardiac ACE2 mRNA in rats after coronary artery ligation. Subsequent studies by Burchill et al[31] provided evidence that there was no increase in ACE2 mRNA or protein expression in rats after coronary artery ligation and treatment with valsartan, ramipril, or both when compared to the control group. In general, these studies on experimental animals did not provide consistent evidence to prove the effect of ARB/ACEI administration on ACE2 protein expression. In the case of simulating human drug delivery, further experimental studies are needed.

With the pandemic of COVID-19 spreading since January 2020, it has been inferred that increased ACE2 expression in the lungs correlated with a higher risk of SARS-CoV-2 infection in patients with cardiac and renal diseases, hypertension, and diabetes treated with ACEIs or ARBs. However, a review from Sriram and Insel[32] showed that there was no clear evidence that elevated ACE2 expression when using ACEIs/ARBs could increase the risk of SARS-CoV-2 infection. In a study of 362 hospitalized hypertensive COVID-19 patients, there was no significant difference between severe and noncritical patients or between non-survivors and survivors according to the use of ACEIs and/or ARBs[33]. Conversely, in a recent meta-analysis from Chu et al[34], it was suggested that ACEI treatment reduced the risk of infection with SARS-CoV-2 and that blocking the RAS might decrease all-cause mortality in COVID-19 patients. This study also reported that ACEIs reduced the risk of non-COVID pneumonia and all-cause mortality caused by non-COVID pneumonia. The effect of ACEIs/ARBs on the expression of ACE2 and the effect on human infection with SARS-CoV-2 remain unknown and complex. Some research has supported the hypothesis that ACE inhibition by ACEIs might stimulate negative feedback, upregulating ACE2 expression but decreasing overall inflammation in the absence of angiotensin II[35]. Thus, the effects of ACEIs/ARBs vary depending on the clinical stage: Negative in the initial infection phase but positive in the tissue inflammation stage[36,37]. Most researchers believe that the use of ARB or ACEI drugs should not be stopped for the purpose of reducing SARS-CoV-2 infection. Stopping maintenance treatment may cause blood pressure imbalance or HF. The guidelines should be revised quickly based on various clinical data, and personalized treatment should be carried out in accordance with clinical manifestations[38] (Table 2).

Table 2 List of animal studies on renin angiotensin system inhibitors and angiotensin-converting enzyme 2.
Animal
Model
Study details
Main findings
Ref.
Lewis ratsNormotensiveRats were assigned to drink water containing losartan or lisinopril at 10 mg/kg/d for 12 dLisinopril or losartan increased cardiac ACE2 mRNA, but the combination did not produce this effectFerrario et al[26]
SD ratsMIEnalapril was given to rats after sham operation or LCA ligationEnalapril prevented the decrease of ventricular ACE2 mRNA levels and activities post-MIOcaranza et al[27]
Lewis ratsMILosartan and olmesartan was administered for 28 d after coronary artery ligationThe level of ACE2 mRNA increased after treatment with losartan and olmesartanIshiyama et al[28]
C57BLKS/J miceNormotensiveMice were treated with telmisartan at 2 mg/kg/d for 2 wkTelmisartan increased ACE2 expression in the tunica media of renal arteriolesSoler et al[29]
SD ratsMISD rats received ramipril at 1 mg/kg/d for 28 d after MI operationRamipril inhibited cardiac ACE but had no effect on cardiac ACE2 mRNA after MIBurrell et al[30]
SD ratsMIRamipril (1 mg/kg/d) and valsartan (10 mg/kg/d) were given for 28 d after MI operationCardiac ACE2 expression was not augmented after either treatment alone or in combinationBurchill et al[31]
ACE2 AND DISEASES

The functional components of the RAS are in balance with each other to maintain the health of the body. Under certain pathological conditions, Ang II, AT1R, or ACE levels can increase or become unbalanced, which is detrimental. It has been two decades since the discovery of ACE2. During this period, efforts towards the characterization of this enzyme have provided greater insights into the RAS. The ongoing studies provoked more questions, particularly regarding the role of ACE2 in the development and progression of hypertension and renal injury, as well as other pathologies, including diabetes, HF, liver fibrosis, and lung injury (Tables 3 and 4).

Table 3 List of animal studies on the role of angiotensin-converting enzyme 2 in diabetes, hypertension, cardiovascular disease, and acute lung injury.
Disease
Animal
Study details
Main findings
Ref.
Diabetesdb/db miceMice were randomly assigned to four treatment groups: (1) Control group fed normal chow; (2) Control group fed rosiglitazone diet; (3) db/db group fed normal chow; and (4) db/db group fed rosiglitazone dietProtein expression of glomerular ACE2 was decreased in the kidneys of db/db mice, while tubular ACE2 and ADAM17 were increased. Rosiglitazone treatment of db/db mice normalized hyperglycemia, attenuated renal injury, and decreased urinary ACE2 and renal ADAM17 protein expressionChodavarapu et al[45]
db/db miceMice were treated for 16 wk with a specific ACE2 inhibitor (MLN-4760) alone or combined with telmisartan.ACE and ACE2 colocalized on the apical surface of the proximal tubules, whereas in glomeruli, ACE2 is present in podocytes and, to a lesser extent, in glomerular mesangial cells, whereas ACE is present only in endothelial cells. Telmisartan prevented the increase in UAE associated with the ACE2 inhibitorYe et al[46]
db/db miceACE and ACE 2 expression was measured in the kidney and heartACE2 protein in renal cortical tubules was increased, whereas ACE protein was decreased. In heart tissue, there were no significant differences between db/db and db/m mice in either ACE or ACE2 expressionYe et a l[48]
STZ-induced diabetic SD ratsACE2 and ACE gene and protein expression was measured in the kidneyACE2 and ACE mRNA levels were decreased in diabetic renal tubules by approximately 50% and were not influenced by ramiprilTikellis et al[47]
STZ-induced diabetic Wistar ratsDiabetic Wistar rats were treated with DIZETreatment with DIZE restored ACE2 expression in glomeruli and increased the expression of AT2 receptors in whole kidney and isolated glomeruliGoru et al[44]
Akita and Ace2-/- miceAce2-/- mice were crossed with Akita mice (Ins2WT/C96Y), and four groups of mice were studied: Ace2+/yIns2WT/WT, Ace2-/yIns2WT/WT, Ace2+/yIns2WT/C96Y, and Ace2-/y Ins2WT/C96Y. The Ace2+/yIns2WT/C96Y and Ace2-/y Ins2WT/C96Y mice were treated with the ARB (irbesartan)Deletion of the ACE2 gene was associated with accelerated kidney injury and reduced ACE2 expression in diabetic mice. Irbesartan reduced urinary albumin excretion rate in Ace2-/y Ins2WT/C96Y miceWong et al[49]
STZ-induced diabeticC57BL/6J mice and ACE2 knockout (KO) miceControl and diabetic C57BL/6J and ACE2 KO mice, after 5 wk without treatment, were randomized to receive the ACE inhibitor perindopril. Wild-type mice were further randomized to receive the selective ACE2 inhibitor MLN-4760Induction of diabetes in wild-type mice was associated with a reduction in renal ACE2 expression and decreased Ang 1-7. In diabetic mice receiving MLN-4760 and in ACE2 KO mice, diabetes-associated albuminuria was enhancedTikellis et al[50]
Akita miceMale diabetic Akita mice (Ins2 (WT/C96Y)) and control C57BL/6J mice (Ins2(WT/WT)) were injected daily with placebo or with rhACE2 (2 mg/kg) for 4 wkTreatment with rhACE2 increased plasma ACE2 activity, normalized blood pressure, and reduced the urinary albumin excretionOudit et al[51]
STZ-induced diabetic Wistar ratsDiabetic Wistar rats were divided into 5 groups: No-treatment group, adenoviral (Ad)-ACE2 group, Ad-green fluorescent protein (GFP) group, ACEI group receiving benazepril and Ad-ACE2 + ACEI groupRats in Ad-ACE2 group exhibited reduced SBP, urinary albumin excretion, creatinine clearance, glomeruli sclerosis index, and renal malondialdehyde level; downregulated transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF), and collagen IV protein expression; and increased renal superoxide dismutase activity. Ad-ACE2 and ACEI had similar effects, whereas combined use of Ad-ACE2 and ACEI offered no additional benefitsLiu et al[52]
HypertensionSalt-sensitive Sabra hypertensive rats, SHR, and SHRSPACE2 expression levels were determined in the kidneysACE2 levels were reduced in all of these hypertensive rat strainsCrackower et al[56]
ACE2-deficient miceAng II peptide was administered by i.v. infusion in wild-type and ACE2-deficient miceBlood pressure measurements were substantially higher in the ACE2-deficient miceGurley et al[57]
SHR and Wistar Kyoto (WKY) ratsExpression of ACE2 was examined in the kidney from SHR and normotensive WKY ratsThe tubular expression of ACE2 fell while glomerular expression of ACE2 was paradoxically increased in the SHRTikellis et al[60]
SheepSheep were administered with betamethasone or vehicle at the 80th day of gestation and delivered at termAntenatal steroid treatment resulted in the chronic alteration of ACE and ACE2 in the circulatory and tubular compartments of adolescent sheep, which may contribute to the higher blood pressure in this model of fetal programming–induced hypertensionShaltout et al[61]
Transgenic ratsTransgenic rats were generated in an SHRSP genetic background expressing human ACE2 in vascular smooth muscle cells by the use of the SM22 promoter (SHRSP-ACE2 model)Mean arterial blood pressure was reduced in SHRSP-ACE2, and the vasoconstrictive response to intraarterial administration of angiotensin II was attenuatedRentzsch et al[62]
SHRMale WKY rats were randomized to receive either placebo or rhACE2 and were subsequently infused with Ang IITreatment with rhACE2 partly corrected the hypertension, NADPH oxidase activation, and increased superoxide generation in the heart, kidney, and blood vesselsLo et al[63]
MiceACE2 activity was measured in kidney cortex from mice that had received injection of MLN-4760 or DX600A marked increase in serum ACE2 activity. Mouse ACE2 abolished the hypertension induced by Ang II infusion. These effects were blocked by MLN-4760 but not by DX600Ye et al[64]
Cardiovascular diseaseACE2-deficient miceACE2 mutant mice were generated, and heart parameters were measuredGenetic inactivation of ACE2 using homologous recombination resulted in increased AngII peptide levels, upregulation of hypoxia genes in the heart, and severe cardiac dysfunctionCrackower et al[56]
ACE2-deficient miceAng II peptide was administered by i.v. infusion in WT and ACE2-deficient miceNo evidence for a role of ACE2 in the regulation of cardiac structure or function was foundGurley et al[57]
SD ratsLentiviral vector encoding mouse ACE2 (lenti-mACE2) or GFP was injected intracardially in Sprague–Dawley ratsACE2 overexpression resulted in protective effects on AngII-induced cardiac hypertrophy and fibrosisHuentelman et al[71]
SHRLentiviral vector encoding mouse ACE2 (lenti-mACE2) or GFP was injected intracardially in SHR and normotensive WKY ratsACE2 overexpression exerted protective effects on high BP and cardiac pathophysiology induced by hypertension in the SHRDíez-Freire et al[72]
Rabbits66 male New Zealand white rabbits were fed an atherogenic chow and were randomly divided into three groups: Treatment with a suspension of Ad-ACE2, treatment with a suspension of Ad-EGFP, and no treatmentACE2 inhibited the development of early atherosclerotic lesions by suppressing the growth of VSMCs and improving endothelial functionZhang et al[73]
Acute lung injuryACE2 mutant miceAcid aspiration-induced, sepsis-induced, and endotoxin-induced acute lung injury animal models were generated. Mice received intraperitoneal injections of rhACE2 proteinACE2 and AT2 protected mice from severe acute lung injury. rhACE2 can protect mice from severe acute lung injuryImai et al[82]
ACE2 knockout miceMice were intranasally inoculated with SARS-CoV virusSARS-CoV receptor ACE2 had a protective role in acute lung failureKuba et al[84]
BALB/c miceLPS-induced acute lung injury mice were treated with ACE2 activator resorcinolnaphthalein (RES) or ACE2 inhibitor MLN-4760ACE2 activation can reduce the severity of LPS-induced acute lung injury via the AMPK/mTOR pathwayZhang et al[87]
c57BL/6J miceTransgenic mice expressing the human ACE2 receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2)Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice resulted in high levels of viral infection in lungsWinkler et al[91]
c57BL/6J miceMice expressing hACE2 in the lung were transduced by oropharyngeal delivery of the recombinant human adenovirus type 5 that expresses hACE2 (Ad5-hACE2)Mice were infected with SARS-CoV-2 and developed interstitial pneumonia associated with perivascular inflammation, accompanied by a higher viral load in the lungsHan et al[92]
Table 4 List of epidemiological studies on the role of angiotensin-converting enzyme 2 in diabetes, hypertension, cardiovascular disease, and acute lung injury.
Disease
Source country
Patients
Main findings
Ref.
DiabetesCanadaRenal biopsies from 13 diabetic and 8 control patientsACE2 mRNA and protein expression were significantly reduced in both the glomeruli and proximal tubules of the diabetic patientsReich et al[53]
Japan66 nondiabetic and 8 diabetic patients with biopsy-proven renal diseasesACE2 mRNA expression was not significantly changed in the diabetic patientsKonoshita et al[54]
China275 Uygur T2D patients and 272 nondiabetic Uygur individualsACE2 SNPs rs1978124, rs2048683, rs2074192, rs233575, rs4240157, rs4646156, rs4646188, and rs879922 were associated with T2DLiu et al[55]
HypertensionAustralia503 Caucasian subjects with type 2 diabetesGenetic variation in ACE2 was associated with hypertension and reduced systolic function in men, and hypertension and increased LV mass in womenPatel et al[65]
China275 Uygur T2D patients and 272 nondiabetic Uygur individualsACE2 SNPs rs2048683, rs233575, rs4240157, rs4646156, rs4646188, and rs879922 were associated with increased SBP, while rs2074192, rs4646188, and rs879922 were associated elevated DBPLiu et al[55]
China402 hypertensive patients and 233 normotensive individualsACE2 variant rs2074192 was associated with EH, while rs4240157, rs4646155, and rs4830542 were associated with EH- and hypertension-related atrial fibrillation and left atrial remodelingLuo et al[66]
China3408 untreated hypertensive patientsThe T allele of ACE2 rs2106809 was found to confer a 1.6-fold risk for hypertension in womenFan et al[67]
China96 patients with EH and 96 healthy controlsAberrant methylation of the ACE2 promoter may be associated with EH riskFan et al[68]
Cardiovascular diseaseUnited States11 individuals with dilated cardiomyopathy, 15 individuals with hypertrophic cardiomyopathy, and 16 controls with nonfailing hearts from the Penn Human Heart Tissue BiobankACE2 expression was downregulated in fibroblasts, pericytes, and vascular smooth muscle but upregulated in cardiomyocytes in dilated cardiomyopathy and hypertrophic cardiomyopathyFan et al[67]
Hungary45 healthy individuals, 239 hypertensiveindividuals,141 patients with heart failure (HF) and reduced ejection fraction (HFrEF), and 47 patients with HF and preserved ejection fraction (HFpEF)ACE2 activity was further increased in HFrEF patients. Serum ACE2 activity was negatively correlated with left ventricular systolic function in HFrEFÚri et al[74]
United States113 patients with chronic systolic heart failureElevated plasma soluble ACE2 (sACE2) activity was associated with greater severity of myocardial dysfunction and was an independent predictor of adverse clinical eventsEpelman et al[75]
14 countries across five continents10753 Prospective Urban Rural Epidemiology participantsIncreased concentration of plasma ACE2 was associated with a higher risk of incident heart failure, myocardial infarction, stroke, and diabetesNarula et al[76]
ItalyHealthy subjects (C) and EH and Bartter's/Gitelman's (BS/GS) patientsACE2 was significantly elevated in BS/GS compared with either C or EHCalò et al[77]
China275 Uygur T2D patients and 272 nondiabetic Uygur individualsACE2 SNPs rs2074192 and rs879922 were associated with carotid arteriosclerosis stenosis and ACE2 SNPs rs2048683, rs4240157, rs4646156, rs4646188, and rs879922 were linked to heavier left heart remodelingLiu et al[55]
Acute lung injuryUnited States44 patients with acute respiratory distress syndrome (ARDS)GSK2586881, a rhACE2, was well-tolerated in patients with ARDS, and has been found to reduce Ang II levels and increase Ang 1-7 levelsKhan et al[94]
ACE2 and its role in the kidney and diabetes

The kidney possesses a fully functional local RAS capable of producing Ang II, a major contributor to the progression of chronic kidney disease. ACE2 is highly expressed in the kidney and predominantly localized to proximal tubules and glomerular podocytes[39,40]. Several lines of evidence indicate that ACE2 serves as a key protective enzyme to prevent progressive renal damage by reducing oxidative stress, inflammation, and fibrosis[41-43].

The study of ACE2 in the context of diabetes has focused primarily on the kidney. ACE2 may be an important target for the treatment and prevention of diabetic nephropathy (DN). ACE2 expression in the kidney has been studied in both type 1 diabetes (T1D) and type 2 diabetes (T2D) models. The majority of animal studies indicate that ACE2 expression is downregulated in the glomeruli in diabetes, whereas tubular ACE2 expression is upregulated[41,44-46]. Tikellis et al[47] first reported that ACE2 expression was reduced in the kidneys of rats with longstanding diabetes mellitus. In 8-wk-old db/db mice, a model of early T2D, ACE2 expression is elevated, while ACE expression is decreased in both glomeruli and the cortex[48] prior to the development of DN. In another study of db/db mice, Chodavarapu et al[45] demonstrated that the protein expression of ACE2 was reduced in glomeruli, while tubular ACE2 and a disintegrin and metalloprotease 17 were increased. In two models of T1D [streptozotocin (STZ)-induced and Akita mouse (Ins2WT/C96Y) models], ACE2 gene deletion accelerated the development of DN[49,50], which could be ameliorated by perindopril or irbesartan. Moreover, treatment with recombinant human ACE2 (rhACE2) in male Akita mice led to reductions in albuminuria, hypertension, plasma Ang II levels, activation of NADPH oxidase, glomerular hypertrophy, and mesangial matrix expansion, thereby preventing the progression of DN[51]. In another rat study, the injection of adenoviral (Ad)-ACE2 in STZ-induced diabetic rats for 4 wk improved many signs of DN[52]. Furthermore, Ad-ACE2 and ACEI had similar effects, whereas the combined use of Ad-ACE2 and ACEI offered no additional benefits[52].

In humans, the expression of ACE2 was significantly reduced in both the glomeruli and proximal tubules in biopsy samples collected from patients with T2D-induced kidney disease[53]. Conversely, in a real-time polymerase chain reaction study, ACE2 mRNA expression was not significantly changed in eight diabetic patients with overt proteinuria compared with 66 nondiabetic patients with renal disease[54]. The differences in the results obtained in human studies of T2D nephropathy might be due to the different stages of diabetes. To date, no human studies of early-stage diabetes have been conducted. Moreover, genetic variation in and around the gene encoding ACE2 is most often detected using single nucleotide polymorphisms (SNPs). In a recent study, 14 ACE2 polymorphisms were genotyped by matrix-assisted laser desorption ionization time-of-flight mass spectrometry in the Uygur population of the Xinjiang region of China. Among them, the ACE2 SNPs rs2074192, rs4240157, rs4646188, and 879922 were associated with increased microalbuminuria in T2D patients[55].

Taken together, the above studies suggest that ACE2 might play a protective role against the development of DN.

ACE2 and hypertension

The role of ACE2 has been intensively studied in models of hypertension. Crackower et al[56] first reported that ACE2 transgenic mice exhibited lower blood pressure than wild-type mice. Subsequent studies reported that ACE2 probably has a small effect on blood pressure in mice under normal conditions[57-59]. However, it plays a much more prominent role in the regulation of hypertension, especially when Ang II levels are elevated. Existing studies have shown that ACE2 was reduced in kidneys from rat models of hypertension, such as salt-sensitive Sabra hypertensive rats, SHRs, and stroke-prone SHRs (SHRSP)[56,60]. Moreover, in a sheep model of fetal programmed hypertension, the administration of betamethasone on the 80th day of gestation markedly reduced ACE2 activity in the proximal tubules and urine in adolescent sheep[61]. Rentzsch et al[62] assessed the role of ACE2 in the pathogenesis of hypertension. These authors generated transgenic rats in a SHRSP genetic background, called SHRSP-ACE2, which expressed human ACE2 in vascular smooth muscle cells under the control of the smooth muscle 22α promoter. They found that endothelial function was significantly improved in SHRSP-ACE2 rats compared with SHRSP rats. These data indicate that vascular ACE2 overexpression in SHRSP reduces hypertension, probably through local Ang II degradation and by improving endothelial function. Existing animal studies have shown that the administration of recombinant ACE2 (rACE2) degrades Ang II, lowers blood pressure, and attenuates Ang II–induced organ injury. One study showed that in the SHR model, rhACE2 partly corrected hypertension and NADPH oxidase activation and increased superoxide generation in the heart, kidney, and blood vessels over a 14-d period[63]. Moreover, the prevention of Ang II-induced hypertension by mouse rACE2 was completely abolished by the specific ACE2 inhibitor MLN-4760, a nonpeptide inhibitor no longer available from Millennium Pharmaceuticals[64].

In human studies, Patel et al[65] found that in Caucasians with T2D, genetic variation in ACE2 is associated with hypertension and reduced systolic function in men and hypertension and increased left ventricular mass in women. Liu et al[55] found that the ACE2 SNPs rs2048683, rs233575, rs4240157, rs4646156, rs4646188, and rs879922 were associated with increased systolic blood pressure (SBP), while rs2074192, rs4646188, and rs879922 were associated with elevated diastolic blood pressure in Uygur T2D patients. Luo et al[66] revealed that the ACE2 variant rs2074192 was associated with essential hypertension (EH), while three ACE2 variants (rs4240157, rs4646155, and rs4830542) were associated with EH- and hypertension-related atrial fibrillation and left atrial remodeling in south Xinjiang, China. In another study, the ACE2 rs2106809 T allele was found to confer a 1.6-fold risk for hypertension in women[67]. Additionally, one study showed that aberrant methylation of the ACE2 promoter may be associated with EH risk[68].

These findings indicate that ACE2 is a key regulator that maintains the balance of blood pressure. In animal studies, it has been demonstrated that the administration of recombinant ACE2 has a beneficial effect on the treatment of hypertension. Currently, large clinical trials to explore this and related alternative interventions are underway.

ACE2 and cardiac function, ventricular remodeling, and HF

SARS-CoV-2 enters the upper respiratory epithelium and lungs predominantly through ACE2. Nevertheless, in a single-center report of 416 patients hospitalized with COVID-19, 19.7% showed evidence of cardiac injury, suggesting a possible pathologic role for myocardial ACE2 expression[69]. ACE2 is present on endothelial cells and can undergo so-called shedding into the circulation. In patients with cardiovascular disease, increased ACE2 activity in the circulation predicts adverse cardiovascular outcomes in patients with HF, coronary artery disease, and aortic stenosis[70].

Crackower et al[56] demonstrated the first evidence that ACE2 may have a role in cardiac function. They found that ACE2 deletion in mice resulted in a severe heart contractility defect, increased levels of Ang II in the kidney, heart, and plasma, and upregulation of hypoxia-induced genes in the heart. Conversely, Gurley et al[57] reported that ACE2 deletion enhanced susceptibility to Ang II-induced hypertension but had no effect on cardiac structure or function. Huentelman et al[71] showed that ACE2 overexpression protects the heart from Ang II-induced hypertrophy and fibrosis. Another study on SHR hypertensive rats also showed that ACE2 overexpression exerted protective effects against high blood pressure and cardiac pathophysiology induced by hypertension[72]. Similarly, in a rabbit atherosclerosis model, local overexpression of ACE2 significantly inhibited the development of early atherosclerotic lesions[73].

In humans, increased circulating ACE2 activity is associated with coronary heart disease and HF, and a large proportion of the variation in plasma ACE2 levels is attributed to hereditary factors. One study showed that ACE2 activity was significantly increased in HF patients with reduced ejection fraction (HFrEF). Serum ACE2 activity was negatively correlated with left ventricular systolic function in HfrEF[74]. In addition, one study measured soluble ACE2 (sACE2) activity in 113 patients with chronic systolic HF and showed that elevated plasma sACE2 activity was associated with greater severity of myocardial dysfunction, which indicated that plasma sACE2 activity might be an independent predictor of adverse clinical events[75]. A recent study published in Lancet presented one of the largest epidemiological datasets on plasma ACE2 concentration in the general population[76]. They performed a case-cohort study involving 10753 participants from the multinational Prospective Urban Rural Epidemiology study, including 5084 patients randomly selected as the sub-cohort and 5669 with an incident event of interest. They reported that ACE2 concentration was the highest-ranked independent predictor of death compared with standard cardiovascular risk markers (smoking, diabetes, SBP, non-high density lipoprotein cholesterol, and body mass index). An increased concentration of plasma ACE2 was associated with an increased risk of all-cause mortality [hazard ratio (HR): 1.35 per 1 standard deviation (SD) increase; 95% confidence interval (CI): 1.29-1.43], incident HF (HR: 1.27 per 1 SD increase; 95%CI: 1.10-1.46), stroke (HR: 1.21 per 1 SD increase; 95%CI: 1.10-1.32), myocardial infarction (HR: 1.23 per 1 SD increase; 95%CI: 1.13-1.33), and incident diabetes (HR: 1.44 per 1 SD increase; 95%CI: 1.36-1.52). Other studies have investigated whether the ACE2 gene is associated with left ventricular hypertrophy and coronary artery disease. The ACE2 SNPs most frequently used in association studies are rs2285666 and rs1978124[77]. Recently, Liu et al[55] found that the ACE2 SNPs rs2074192 and rs879922 were associated with carotid arteriosclerosis stenosis and that the ACE2 SNPs rs2048683, rs4240157, rs4646156, rs4646188, and rs879922 were linked to more substantial left heart remodeling. Furthermore, one study assessed ACE2 expression by performing bulk and single nucleus RNA-Seq on the left ventricles of 11 individuals with dilated cardiomyopathy, 15 individuals with hypertrophic cardiomyopathy, and 16 controls with nonfailing hearts from the Penn Human Heart Tissue Biobank. They found that cardiac ACE2 expression was down-regulated in fibroblasts, pericytes, and vascular smooth muscle but upregulated in cardiomyocytes[69].

Investigations of ACE2 as well as its role in cardiac function and HF will undoubtedly provide greater insight into the roles of this enzyme. However, carefully conducted large-scale clinical studies are urgently needed to clarify the potential role of ACE2 in cardiovascular diseases more precisely.

ACE2 and acute lung injury

Like many other organ lung cells also have a local RAS[78], which influences the pathogenesis of lung injury via cellular effects, including changes in vascular permeability, vascular tone, fibroblast activity, or alveolar epithelial cell apoptosis[79,80]. ACE2 plays a pivotal role in Ang II degradation in the RAS cascade and thus limits inflammation and fibrosis in the lung[81]. Imai et al[82] investigated the role of ACE2 in acute respiratory distress syndrome (ARDS) by using ACE2 knockout mice. In three different ARDS models (acid-aspiration-induced, endotoxin-induced, and peritoneal sepsis-induced ARDS), it was shown that a loss of ACE2 expression in mutant mice resulted in enhanced vascular permeability, increased lung edema, engendered neutrophil accumulation, and worsened lung function. Importantly, treatment with catalytically active recombinant ACE2 protein improved the symptoms of acute lung injury in both wild-type mice and ACE2 knockout mice. Thus, ACE2 plays a protective role in acute lung injury. Mechanically, the finding that reduced ACE2 on lung cell surfaces is correlated with lung damage due to an uncontrolled RAS cascade is supported by data about the effects of long-lasting hyperoxia on pulmonary tissue[82-86]. In addition, a study revealed that ACE2 activation can reduce the severity of lipopolysaccharide-induced acute lung injury via the activated serine/threonine protein kinase/mammalian target of rapamycin pathway[87].

In the current pandemic of COVID-19, both bioinformatics modeling and in vitro experiments indicate that SARS-CoV-2 likely utilizes ACE2 as a receptor to gain entry into human cells[88-90]. A recent study evaluated lung function in a mouse model of SARS-CoV-2 infection. They used transgenic mice expressing the human ACE2 (hACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2) and found that intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice resulted in high levels of viral infection in the lungs, with spread to other organs[91]. Similarly, one study also used a model of mice expressing hACE2 in the lung. In this study, the mice were transduced by oropharyngeal delivery of recombinant human adenovirus type 5 expressing hACE2[92]. They found that mice were infected with SARS-CoV-2 at day 4 post-transduction and developed interstitial pneumonia related to perivascular inflammation. On the other hand, as described above, a similar decrease in ACE2 has also been seen in cases of COVID-19 with severe lung injury, which might be attributable to the negative consequences that arise from insufficient Ang II degradation[93]. In human trials, GSK2586881, a rhACE2, was well tolerated in 44 patients with ARDS and has been found to reduce Ang II levels and increase Ang 1-7 levels, although it failed to improve the physiological and clinical indicators of ARDS in patients[94]. This study likely represents the first clinical application of rhACE2 in the field of ARDS, so we speculate that rhACE2 may become one of the most promising approaches for protecting against lung injury in patients with COVID-19.

Based on the above description, ACE2 plays a complex role in COVID-19-induced acute lung injury. On the one hand, high levels of ACE2 receptors on the cell surface may accelerate the invasion of SARS-CoV-2 during the very early phase of infection. On the other hand, low levels of ACE2 can ultimately worsen the disease course due to insufficient Ang II conversion in cases of severe COVID-19 with pulmonary complications.

CONCLUSION

As a vital component of the RAS, ACE2 is closely related to the occurrence and development of RAS-associated diseases. A better understanding of the biological functions of ACE2 will be beneficial to the treatment. Previous studies show that a high-salt diet can decrease the expression of ACE2 and cause RAS disorders. Recent reports have not yet indicated that ARBs or ACEIs will increase the level of ACE2, thereby aggravating SARS-CoV-2 infection. Therefore, the mechanisms involved need to be further improved. As ACE2 is an important receptor through which SARS-CoV-2 can invade cells, further studies on ACE2 should focus on the development of drugs that inhibit the virus from entering cells and impede the binding of the S protein to ACE2 for COVID-19 treatment. More research on ACE2 should be conducted in the future to carry out targeted and effective treatment at a higher level.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Medicine, research and experimental

Country/Territory of origin: China

Peer-review report’s scientific quality classification

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P-Reviewer: Manenti A S-Editor: Yan JP L-Editor: Wang TQ P-Editor: Ma YJ

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