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CORD-19:02d18b4f484a0420c21595a95b8765125d4a484c JSONTXT 9 Projects

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Id Subject Object Predicate Lexical cue
T1 0-16 Sentence denotes Trilogy of ACE2:
T2 17-120 Sentence denotes A peptidase in the renin-angiotensin system, a SARS receptor, and a partner for amino acid transporters
T3 122-130 Sentence denotes Abstract
T4 131-416 Sentence denotes Keywords: ACE2 Amino acid transporter Acute respiratory distress syndrome Collectrin Renin-angiotensin system SARS Angiotensin-converting enzyme (ACE) 2 is a homolog to the carboxypeptidase ACE, which generates angiotensin II, the main active peptide of renin-angiotensin system (RAS).
T5 417-506 Sentence denotes After the cloning of ACE2 in 2000, three major ACE2 functions have been described so far.
T6 507-619 Sentence denotes First ACE2 has emerged as a potent negative regulator of the RAS counterbalancing the multiple functions of ACE.
T7 620-731 Sentence denotes By targeting angiotensin II ACE2 exhibits a protective role in the cardiovascular system and many other organs.
T8 732-847 Sentence denotes Second ACE2 was identified as an essential receptor for the SARS coronavirus that causes severe acute lung failure.
T9 848-935 Sentence denotes Downregulation of ACE2 strongly contributes to the pathogenesis of severe lung failure.
T10 936-1104 Sentence denotes Third, both ACE2 and its homologue Collectrin can associate with amino acid transporters and play essential role in the absorption of amino acids in the kidney and gut.
T11 1105-1179 Sentence denotes In this review, we will discuss the multiple biological functions of ACE2.
T12 1181-1407 Sentence denotes The renin-angiotensin system (RAS) plays a key role in maintaining blood pressure homeostasis, as well as fluid and salt balance in mammals (Skeggs et al., 1980; Inagami, 1994; Weinberg et al., 2000; Turner and Hooper, 2002) .
T13 1408-1643 Sentence denotes Abnormal activation of the RAS has been associated with the pathogenesis of cardiovascular and renal diseases such as hypertension, myocardial infarction and heart failure (Ferrario, 1990; Nicholls et al., 1998; Fleming et al., 2006) .
T14 1644-1719 Sentence denotes The protease renin cleaves angiotensinogen to generate angiotensin (Ang) I.
T15 1720-2062 Sentence denotes The angiotensin-converting enzyme (ACE) is the critical protease the cleaves Ang I to generate Ang II, which is a key regulator of the RAS and exerts biological functions through two G-protein-coupled receptors, the Ang II receptor type 1 receptor (AT1R) and Ang II receptor type 2 receptor (AT2R) (Skeggs et al., 1980; Corvol et al., 1995) .
T16 2063-2361 Sentence denotes Although there exist alternative Ang II-generating enzymes (such as cathepsins and chymase) (Belova, 2000; Miyazaki and Takai, 2006) , it has been thought that ACE is the key and possibly sole enzyme in the regulation of Ang II production in the RAS (Skeggs et al., 1980; Turner and Hooper, 2002) .
T17 2362-2497 Sentence denotes In 2000, a homologue of ACE, angiotensin-converting enzyme 2 (ACE2), has been discovered (Donoghue et al., 2000; Tipnis et al., 2000) .
T18 2498-2647 Sentence denotes Accumulated evidences indicate that ACE2 negatively regulates the activated renin-angiotensin system by degrading Ang II to the heptapeptide Ang 1-7.
T19 2648-2855 Sentence denotes Several studies support a counter-regulatory role for Ang 1-7 by opposing many AT1 receptor-mediated actions, especially in vasoconstriction and cellular proliferation (Santos et al., 2005; Ferrario, 2006) .
T20 2856-2974 Sentence denotes Thus, Ang 1-7 has become a key component of the RAS system due to its beneficial effects in the cardiovascular system.
T21 2975-3177 Sentence denotes In addition to its capacity to generate Ang-(1-7), ACE2 is a multifunctional enzyme and its beneficial effects may be a result of its ability to act on other vasoactive peptides (Vickers et al., 2002) .
T22 3178-3260 Sentence denotes Intriguingly, peptidase-independent actions of ACE2 have been recently elucidated.
T23 3261-3465 Sentence denotes In particular, ACE2 has been identified as an essential receptor for SARS coronavirus infections as well as a protective molecule against lethal lung failure in SARS (Li et al., 2003; Kuba et al., 2005) .
T24 3466-3683 Sentence denotes Interestingly, SARS receptor function of ACE2 is independent of its catalytic activities for Ang II degradation, whereas ACE2-mediated Ang II degradation is still important for lung protection from SARS pathogenesis .
T25 3684-3872 Sentence denotes Furthermore, ACE2 and its homolog Collectrin have been identified as essential molecules required for expression of neutral amino acid transporters on the cell surface of epithelial cells.
T26 3873-3979 Sentence denotes Collectrin might also have a role in insulin secretion in pancreatic β-cells and/or growth of islet cells.
T27 3980-4163 Sentence denotes In this review we will discuss the 'classical' functions of ACE2 in regulating the reninangiotensin system through its peptidase activity and its new, peptidase-independent functions.
T28 4164-4275 Sentence denotes ACE was termed a 'hypertensin-converting enzyme' when it was initially isolated in 1956 (Skeggs et al., 1980) .
T29 4276-4376 Sentence denotes The human ACE gene, located on chromosome 17, encodes a 180 kDa protein with two homologous domains.
T30 4377-4543 Sentence denotes Each domain has an active zinc-binding motif, His-Glu-X-X-His (HEXXH motif), which is found in many peptidases (Skeggs et al., 1980; Soubrier et al., 1988) (Fig. 1 ).
T31 4544-4681 Sentence denotes ACE is a type-I transmembrane glycoprotein, which anchored to the plasma membrane through a single carboxy-terminal transmembrane domain.
T32 4682-4976 Sentence denotes In humans, two distinct ACE isoenzymes have been described, an abundant somatic form found on the endothelial surface of the lungs and on brush-border membranes of kidneys, intestine, placenta and choroid plexus, and the germinal form of ACE found only in the testis (Turner and Hooper, 2002) .
T33 4977-5113 Sentence denotes Both ACE isoforms are membranebound protein and, at the cell surface, they function as ectoenzymes which hydrolyze circulating peptides.
T34 5114-5191 Sentence denotes ACE can be cleaved from the cell surface and thereby act as a soluble enzyme.
T35 5192-5260 Sentence denotes However, the biological significance of soluble ACE remains unclear.
T36 5261-5380 Sentence denotes ACE2 consists of 805 amino acids and is type I transmembrane glycoprotein with a single extracellular catalytic domain.
T37 5381-5474 Sentence denotes The human ACE2 gene has been cloned and mapped to the X chromosome (Crackower et al., 2002) .
T38 5475-5584 Sentence denotes Like ACE, ACE2 has two domains: the aminoterminal catalytic domain and the carboxy-terminal domain (Fig. 1) .
T39 5585-5791 Sentence denotes The catalytic domain has one active sitethe zinc metallopeptidase domainand shows 41.8% sequence identity with the amino domain of ACE (Donoghue et al., 2000; Tipnis et al., 2000; Turner and Hooper, 2002) .
T40 5792-6170 Sentence denotes ACE2's carboxy-terminal domain shows 48% sequence identity with Collectrin (Fig. 1) , a noncatalytic protein recently shown to have a critical role in amino acid re-absorption in the kidney (Danilczyk et al., 2006; Malakauskas et al., 2007; Verrey et al., 2009) , pancreatic beta cell proliferation (Akpinar et al., 2005) , and possibly insulin exocytosis (Fukui et al., 2005) .
T41 6171-6525 Sentence denotes Early studies observed tissue localization of ACE2 predominantly in the heart, kidneys and testes, and at a lower level in a wide variety of tissues, particularly the colon and lung (Tipnis et al., 2000) , while later studies also indicated the significance of ACE2 in other organs like liver and intestines (Komatsu et al., 2002; Hamming et al., 2004) .
T42 6526-6627 Sentence denotes In the heart, ACE2 is expressed in the endothelium (Tipnis et al., 2000) as wells as cardiomyocytes .
T43 6628-6818 Sentence denotes In kidney ACE2 distributes to the luminal surface of tubular epithelial cells (Donoghue et al., 2000; Tipnis et al., 2000) , and in testes, to the adult Leydig cells (Douglas et al., 2004) .
T44 6819-7024 Sentence denotes ACE2 localization was mapped to the apical surface of epithelial cells, which is in contrast to ACE, which appears to be evenly distributed between the apical and basolateral membranes in polarized cells .
T45 7025-7199 Sentence denotes Moreover, the efficacy of a SARS-CoV infection was 10-fold increased when the virus was applied at the apical surface of ACE2-expressing cells in vitro (Tseng et al., 2005) .
T46 7200-7398 Sentence denotes ACE and ACE2 both belong to the M2 family (clan MA) of metalloproteases, and have their active site domains exposed to the extracellular surface, facilitating the metabolism of circulating peptides.
T47 7399-7651 Sentence denotes Both ACE and ACE2 catalyze reactions by utilizing zinc, coordinated by conserved histidines within the active site, to facilitate nucleophilic attack on the carbonyl bond of the substrate by a water molecule, forming a noncovalently bound intermediate.
T48 7652-7920 Sentence denotes In addition to the two histidines (located within the HEXXH motif), a further glutamate residue is involved in coordinating the zinc ion; this is located 23 amino acids C-terminally to the HEXXH motif in both ACE and ACE2 (Donoghue et al., 2000; Tipnis et al., 2000) .
T49 7921-8176 Sentence denotes Structural analyses for native ACE2 compared with inhibitor (MLN 4760)-bound ACE2 (Dales et al., 2002) revealed a large 'hinge-bending' motion, in which the catalytic subdomains I and II of the peptidase domain exhibit open-to-close transitions (Fig. 2) .
T50 8177-8296 Sentence denotes This movement is induced by binding of the inhibitor and repositions key residues for catalysis (Towler et al., 2004) .
T51 8297-8546 Sentence denotes Despite the similarities, ACE and ACE2 function differently; ACE releases a C-terminal dipeptide from its substrate (dipeptidylpeptidase), whereas ACE2 cleaves a single amino acid (monocarboxypeptidase) (Donoghue et al., 2000; Tipnis et al., 2000) .
T52 8547-8700 Sentence denotes ACE2 catalyzes peptides with a substrate preference for hydrolysis between proline and a hydrophobic or basic C-terminal residue (Vickers et al., 2002) .
T53 8701-9020 Sentence denotes While ACE converts Ang I to the potent vasoconstrictor Ang II (Corvol et al., 1995) , ACE2 cleaves Ang I to generate the presumably inactive Ang 1-9 peptide (Donoghue et al., 2000; Tipnis et al., 2000) , which then can be converted to the vasodilator peptide Ang 1-7 by ACE or other peptidases (Donoghue et al., 2000) .
T54 9021-9240 Sentence denotes Importantly, ACE2 directly metabolizes Ang II to generate Ang 1-7 with higher efficiency than Each protein is a type I integral protein with a signal peptide, depicted in gray, and a transmembrane domain shown in black.
T55 9241-9383 Sentence denotes The zinc-binding motif (HEMGH) repeats two times in ACE and once in ACE2, and is located within the homology region denoted by the yellow box.
T56 9384-9453 Sentence denotes Regions of homology between ACE2 and Collectrin are denoted in green.
T57 9454-9513 Sentence denotes The numbers refer to the amino acids in each human protein.
T58 9514-9566 Sentence denotes converting Ang I to Ang 1-9 (Vickers et al., 2002) .
T59 9567-9893 Sentence denotes The resolution of the ACE2 crystal structure revealed that these substrate specificity differences are a result of the smaller binding pocket in ACE2 due to arginine-273 making a salt-bridge with the C-terminus of the substrate, whereas in ACE this residue is substituted by a smaller glutamine residue (Towler et al., 2004) .
T60 9894-10268 Sentence denotes Although there were already known Ang 1-7-forming enzymes, such as neprilysin (Yamamoto et al., 1992) , prolyl endopeptidase 24.26 (Nozaki et al., 1992) , and thimet oligopeptidase (Chappell et al., 2000) , the identification of ACE2 has added further support to the biological significance of the Ang 1-7 (Donoghue et al., 2000; Tipnis et al., 2000; Vickers et al., 2002) .
T61 10269-10481 Sentence denotes This peptide has been shown to interact with the G-protein-coupled receptor Mas to mediate its vasoprotective effects (Santos et al., 2003; Keidar et al., 2007; Raizada and Ferreira, 2007; Alenina et al., 2008) .
T62 10482-10659 Sentence denotes ACE2 also acts on the C-terminus of the peptides Apelin-13 and Apelin-36 and cleaves an amino acid out from them with high catalytic efficiency in vitro (Vickers et al., 2002) .
T63 10660-10867 Sentence denotes Apelin is synthesized as 77 amino-acid preprohormone, which is processed into the 36 amino acid peptide apelin-36; further proteolytic cleavage generates Apelin-13 (Tatemoto et al., 1998; Lee et al., 2006) .
T64 10868-10988 Sentence denotes Systemic administration of Apelin-13 prompts hypotension in rats and mice (Tatemoto et al., 2001; Ishida et al., 2004) .
T65 10989-11238 Sentence denotes Interestingly, modification of the C-terminal residue of Apelin-13 (F13A) lost its hypotensive action and further antagonized the effect of wild type Apelin-13 (Lee et al., 2005) , implicating putative roles of ACE2 in metabolism of Apelin peptides.
T66 11239-11355 Sentence denotes The requirement of chloride ions for the hydrolysis of Ang I by ACE has long been recognized (Skeggs et al., 1956) .
T67 11356-11440 Sentence denotes Similarly, ACE2 activity is also regulated by chloride ions (Vickers et al., 2002) .
T68 11441-11595 Sentence denotes However, the presence of chloride ions increases the hydrolysis of Ang I by ACE2, but inhibits cleavage of the vasoconstrictor Ang II (Guy et al., 2003) .
T69 11596-11782 Sentence denotes It has been proposed that chloride binding induces subtle changes in the conformation of the active site, which either facilitate or hinder substrate binding (Ehlers and Riordan, 1991) .
T70 11783-11992 Sentence denotes An increase in [Cl − ] above 100 mM which is the physiological concentration in human plasma increases Ang I and decreases Ang II cleavage by ACE2 and increases Ang I cleavage by ACE (Rushworth et al., 2008) .
T71 11993-12210 Sentence denotes This would have the effect of increasing the localized concentration of the vasoconstrictor Ang II in the kidney, where both ACE and ACE2 have high levels of expression and extracellular chloride ion levels fluctuate.
T72 12211-12682 Sentence denotes A broad range of ACE inhibitors, such as captopril and lisinopril does not affect the activity of ACE2 (Donoghue et al., 2000; Tipnis et al., 2000) , whereas ACE2 activity is inhibited by the dipeptide Pro-Phe (Guy et al., 2003) , and specific ACE2 inhibitors, such as the peptide analogues DX600 (Huang et al., 2003) and MLN 4760 ((S,S)-2-[1-carboxy-2-[3-(3,5-dichlorobenzyl)-3H-imidazol4-yl]-ethylamino]-4-methylpentanoicacid) have been developed (Dales et al., 2002) .
T73 12683-12852 Sentence denotes MLN 4760 was the first rationally designed inhibitor of ACE2, based on the C-terminal dipeptide of Ang I (His-Leu), and has high potency (K i = 0.44 nM) and specificity.
T74 12853-13031 Sentence denotes A counter-regulatory axis of the RAS by ACE2 prompted researchers to investigate the impact of ACE2 delivery on cardiovascular diseases in animal models (Katovich et al., 2005) .
T75 13032-13250 Sentence denotes ACE2 treatment by means of gene therapy or recombinant protein indeed improved hypertension, atherosclerosis, and kidney diseases (Diez-Freire et al., 2006; Dong et al., 2008; Lovren et al., 2008; Oudit et al., 2010) .
T76 13251-13449 Sentence denotes In silico conformation-based drug screening identified two compounds of ACE2 activator (a xanthenone and resorcinolnaphthalein) that moderately enhance ACE2 activity (Hernandez Prada et al., 2008) .
T77 13450-13508 Sentence denotes However, it is not clear how specific these compounds are.
T78 13509-13668 Sentence denotes Although ACE2 functions as a peptidase to catalyze Ang II cleavage, recent studies demonstrate that transmembrane domain of ACE2 has also biological functions.
T79 13669-13866 Sentence denotes In 2003, the epidemics of SARS threatened the world, and ACE2 was identified as a functional receptor for a causative pathogen, the SARS coronavirus ( Fig. 4) (Li et al., 2003; Kuba et al., 2005) .
T80 13867-14059 Sentence denotes Cells expressing catalytic inactive mutants of ACE2 are still permissive for SARS-CoV infection, indicating that the peptidase actions of ACE2 are not necessary for SARS entry into host cells.
T81 14060-14322 Sentence denotes Consistent with the biological result, structural analyses demonstrated that SARS Spike protein contacts the tip of subdomain I of the ACE2 catalytic domain but does not affect the subdomain II nor occludes the peptidase active site ( Fig. 2) (Li et al., 2005) .
T82 14323-14554 Sentence denotes Upon ligation of SARS-CoV to ACE2, the ectodomain of ACE2 is cleaved while the transmembrane domain is internalized for further virus particle-host cell fusions ( Fig. 3) (Inoue et al., 2007; Haga et al., 2008; Wang et al., 2008) .
T83 14555-14653 Sentence denotes Thus, although detailed mechanisms are still elusive, the transmembrane domain of ACE2 is Fig. 2 .
T84 14654-14724 Sentence denotes Schematic diagram of the role of ACE2 in the renin-angiotensin system.
T85 14725-14921 Sentence denotes Angiotensin I (Ang I; DRVYIHPFHL) serves as a substrate for ACE, a dipeptidyl carboxypeptidase, and is converted to Angiotensin II (Ang II; DRVYIHPF), the main active peptide of the classical RAS.
T86 14922-15111 Sentence denotes ACE2 catalyzes and inactivates Angiotensin II and produces the vasodilator peptide Angiotensin 1-7 (Ang 1-7; DRVYIHPF), which binds the Mas receptor and/or is degraded to inactive peptides.
T87 15112-15204 Sentence denotes Red arrowheads indicate the ACE cleavage site; blue arrowheads show the ACE2 cleavage sites.
T88 15205-15321 Sentence denotes It should be noted that ACE2 is an unspecific protease and can cleave multiple additional substrates such as Apelin.
T89 15322-15436 Sentence denotes implicated to the traffic of SARS-CoV-receptor complex from cell membrane to the cytoplasm in SARS-CoV infections.
T90 15437-15549 Sentence denotes Expression analyses for rat kidneys isolated Collectrin as an upregulated gene in regenerating collecting ducts.
T91 15550-15705 Sentence denotes Collectrin shares 47.8% identity with C-terminal end of ACE2; however, unlike ACE2, Collectrin lacks active carboxypeptidase catalytic domains ( Fig. 1 ) .
T92 15706-15973 Sentence denotes The initial report documented that Collectrin localized in the cytoplasm of collecting duct epithelial cells, but further studies indicated the predominant localization of Collectrin in brush borders of the proximal tubular epithelial cells (Danilczyk et al., 2006) .
T93 15974-16128 Sentence denotes Danilczyk et al. also serendipitously identified Collectrin as an essential regulator of neutral amino acid transporters by genetargeting studies in mice.
T94 16129-16246 Sentence denotes Excess amounts of neutral amino acids (tyrosine and phenylalanine) appeared in the urine of Collectrin knockout mice.
T95 16247-16551 Sentence denotes Biochemical studies indicated that Collectrin binds to B 0 AT1 neutral amino acid transporters and plays critical roles for proper expression of these transporters on cell surface required for amino acid re-absorption in proximal tubules of the kidney (Danilczyk et al., 2006; Malakauskas et al., 2007) .
T96 16552-16724 Sentence denotes Despite its structural similarity, ACE2 does not bind to amino acid transporters in kidneys, but in intestines, where ACE2 is highly expressed and amino acids are absorbed.
T97 16725-16844 Sentence denotes In the gut, ACE2 does bind to the B 0 AT1 amino acid transporter and contributes to absorption of neutral amino acids .
T98 16845-16950 Sentence denotes Importantly, the peptidase activity of ACE2 is not necessary for pairing with the amino acid transporter.
T99 16951-17242 Sentence denotes ACE2 was originally cloned using a cDNA library of human failing heart ventricle (Donoghue et al., 2000) , and ACE2 mRNA levels changing dynamically depending on the physiological and pathological conditions (Zisman et al., 2003; Kuba et al., 2006; Koitka et al., 2008; Oudit et al., 2009) .
T100 17243-17490 Sentence denotes Although transcriptional regulation of ACE2 is still elusive, accumulating evidences have indicated that inhibition of RAS by ACE inhibitors or AT1 receptor blockers upregulates ACE2 mRNA expression (Ishiyama et al., 2004; Ferrario et al., 2005) .
T101 17491-17747 Sentence denotes For instance, downregulation of ACE2 mRNA levels in rat proteinuric renal injury model was reversed by pharmacological inhibition of the NF-κB transcription factor, which operates downstream of Ang II receptor and cytokine signaling (Takase et al., 2005) .
T102 17748-17958 Sentence denotes Inhibition of mineralcorticoids (or aldosterone) increased ACE2 mRNA in macrophages likely through suppression of oxidative stress, which is associated with Ang II and/or NF-κB signaling (Keidar et al., 2005) .
T103 17959-18092 Sentence denotes Consistently, Interferon-γ and interleukin-4 downregulate expression of ACE2 mRNA levels in epithelial cells (de Lang et al., 2006) .
T104 18093-18203 Sentence denotes Thus, inflammatory signals, including Ang II, cytokines, and NF-κB, are likely to suppress ACE2 transcription.
T105 18204-18337 Sentence denotes Our early studies observed the upregulation of hypoxia-inducible genes in the hearts of Ace2 knockout mice (Crackower et al., 2002) .
T106 18338-18576 Sentence denotes Tissue local hypoxia increases ACE2 expression in human and rat myocardial infarction (Burrell et al., 2005) , although in another model of rat, myocardial infarction changes in ACE2 mRNA levels were not observed (Ishiyama et al., 2004) .
T107 18577-18703 Sentence denotes ACE2 overexpression counteracts and inhibits hypoxia-induced collagen production by cardiac fibroblasts (Grobe et al., 2007) .
T108 18704-18927 Sentence denotes In pulmonary smooth muscle cells subjected to hypoxia, ACE2 mRNA levels increased during the early stages of hypoxia and decreased to near-baseline levels at the later stages after HIF-1α accumulation (Zhang et al., 2009) .
T109 18928-19040 Sentence denotes Thus, the regulation ACE2 expression under hypoxia is still elusive and may be context or cells/organ-dependent.
T110 19041-19170 Sentence denotes All-trans retinoic acid has also been shown to elevate ACE2 mRNA levels in spontaneously hypertensive rats (Zhong et al., 2004) .
T111 19171-19393 Sentence denotes Hepatocyte nuclear factor 1β (HNF-1β, TCF2) is a tissue-specific transcription factor whose mutation in humans leads to renal cysts, genital malformations, pancreas atrophy and maturity onset diabetes of the young (MODY5).
T112 19394-19580 Sentence denotes In cell lines, ACE2 was identified as a direct target gene for HNF-1β, but not HNF-1α (TCF1), and there are multiple HNF-1β binding sites in ACE2 promoter regions (Senkel et al., 2005) .
T113 19581-19805 Sentence denotes The ACE2 homologue Collectrin, located close to ACE2 locus on the X chromosome, is also a target gene for HNF-1 transcription factors; HNF-1α in pancreatic β cells (Fukui et al., 2005) and HNF-1β in kidney epithelial cells .
T114 19806-19928 Sentence denotes Thus, one can speculate that ACE2 and Collectrin gene expression is coordinately regulated by HNF-1 transcription factors.
T115 19929-20244 Sentence denotes ACE2 was identified as a SARS receptor (Li et al., 2003) and is has been reported that ACE2 as an intact molecule and/or its transmembrane domain are internalized together with SARS-CoV upon infection, since endocytosis is essential for establishment of the virus entry (Blau and Holmes, 2001; Inoue et al., 2007) .
T116 20245-20288 Sentence denotes The internalization can take place Fig. 3 .
T117 20289-20360 Sentence denotes Post-translational modifications of ACE2; internalization and shedding.
T118 20361-20479 Sentence denotes SARS coronavirus (SARS-CoV) binds to and internalizes with ACE2 for its cellular entry in a Clathrin-dependent manner.
T119 20480-20644 Sentence denotes Membrane fusion is mediated via activation of Spike by proteases, such as trypsin or furin, and viral RNAs are released into cytoplasm, establishing SARS infection.
T120 20645-20815 Sentence denotes The transmembrane proteinase (ADAM17) cleaves the extracellular juxtamembrane region of ACE2, releasing the catalytically active ectodomain into the extracellular milieu.
T121 20816-20893 Sentence denotes Whether such ACE2 cleavage contributes to SARS pathogenesis is not known yet.
T122 20894-20902 Sentence denotes Fig. 4 .
T123 20903-20963 Sentence denotes Interaction of ACE2 with the B 0 AT1 amino acid transporter.
T124 20964-21123 Sentence denotes ACE2 interacts with the B 0 AT1 amino acid transporter (SLC6A19) which is required for polarized surface expression of the transporter in gut epithelial cells.
T125 21124-21357 Sentence denotes Whether ACE2 cleavage contributes to supplying neutral amino acids for the B 0 AT1 is not known yet. even when recombinant SARS Spike protein, the SARS-CoV surface ligand for receptor binding, interacts with ACE2 Wang et al., 2008) .
T126 21358-21489 Sentence denotes Clathrin-dependent and -independent entry of SARS-CoV into target cells has been proposed (Inoue et al., 2007; Wang et al., 2008) .
T127 21490-21741 Sentence denotes However, the role of the cytoplasmic tail of ACE2 is controversial; for instance, deletion of the cytoplasmic tail of ACE2 did not affect SARS-CoV entry (Inoue et al., 2007) , whereas it attenuated SARS-CoV entry in another study (Haga et al., 2008) .
T128 21742-21895 Sentence denotes Similar to ACE (Parkin et al., 2004) , ACE2 is subject to a juxtamembrane cleavage events (shedding) which releases the catalytically active ectodomain .
T129 21896-21980 Sentence denotes The process can be stimulated by phorbol ester, ionomycin, endotoxin, IL-1β or TNFα.
T130 21981-22174 Sentence denotes Shedding is mediated by a promiscuous 'sheddase', ADAM17 (or TACE, TNF-α converting enzyme; Fig. 3 ) Jia et al., 2009 ) and ADAM17-null cells are reduced in ACE2 shedding (Iwata et al., 2009) .
T131 22175-22426 Sentence denotes Moreover, calmodulinbinding sites were identified in the cytoplasmic tail of ACE2 (Lambert et al., 2008) , and inhibition of calmodulin increased the release of the ACE2 ectodomain to the culture supernatants (Lambert et al., 2008; Lai et al., 2009) .
T132 22427-22771 Sentence denotes Although the physiological role of ACE2 ectodomain shedding remains elusive as roles for circulating ACE2 and remnant Cterminal domain have yet to be identified, shedding seems to be involved in SARS-CoV cellular entry and replication and an ADAM17 inhibitor suppresses SARS-CoV replication in vitro (Glowacka et al., 2010; Haga et al., 2008) .
T133 22772-22774 Sentence denotes 5.
T134 22775-22839 Sentence denotes ACE2 as a negative regulator of RAS in the cardiovascular system
T135 22840-22967 Sentence denotes The ace2 gene was mapped to a quantitative trait locus (QTL) on the X chromosome in three different rat models of hypertension.
T136 22968-23091 Sentence denotes These hypertensive rats show reduced ACE2 transcripts and protein expression in heart and kidney (Crackower et al., 2002) .
T137 23092-23330 Sentence denotes Consistently, transgenic ACE2 overexpression in vessels of SHRSP rats reduces blood pressure and improves endothelial function , and neuronal overexpression of ACE2 also attenuates hypertension (Yamazato et al., 2007; Feng et al., 2008) .
T138 23331-23581 Sentence denotes In humans, several studies have shown a strong association of ACE2 polymorphisms to hypertension in female Chinese patients with metabolic syndrome (Zhong et al., 2006) or essential hypertension (Yi et al., 2006; Fan et al., 2007; Niu et al., 2007) .
T139 23582-23723 Sentence denotes Thus, together with biochemical data that ACE2 degrades Ang II to generate Ang 1-7, ACE2 plays a profound role in controlling blood pressure.
T140 23724-23888 Sentence denotes However, genetic inactivation of ACE2 using homologous recombination results in no apparent alterations in blood pressure in basal levels (Crackower et al., 2002) .
T141 23889-23996 Sentence denotes In another ACE2 knockout mouse line blood pressure was significantly increased following Ang II infusions .
T142 23997-24252 Sentence denotes This is a sharp contrast to spontaneous hypotension observed in ACE knockout mice (Krege et al., 1995) , suggesting that, in addition to the Ang II system, ACE2 might regulate blood pressure through other peptide systems, such as bradykinin and/or Apelin.
T143 24253-24477 Sentence denotes Nevertheless, exogenous supplementation of ACE2 by gene transfer decreased blood pressure in SHR hypertensive rats , and recombinant ACE2 treatment attenuated Ang II-induced hypertension specifically (Wysocki et al., 2010) .
T144 24478-24546 Sentence denotes Thus, ACE2 is a negative regulator of RAS in blood pressure control.
T145 24547-24760 Sentence denotes In addition to hypertension, ACE2 gene delivery has also shown beneficial effects on atherosclerosis in animal models, suggesting that ACE2 confers endothelial protection (Dong et al., 2008; Lovren et al., 2008) .
T146 24761-24886 Sentence denotes The heart is a major organ, which abundantly expresses ACE2, and many literatures have shown its importance in heart failure.
T147 24887-25126 Sentence denotes ACE2 null mice displayed impaired cardiac contractility which is associated with aging and/or cardiac pressure overload in several different ACE2 knockout mouse lines (Crackower et al., 2002; Yamamoto et al., 2006; Nakamura et al., 2008) .
T148 25127-25433 Sentence denotes Heart contractility impairment was correlated with elevated cardiac and plasma Ang II levels, and double knockout mice of ACE and ACE2 genes or treatment with AT1 receptor blockers reversed the cardiac phenotype in ACE2 knockout mice (Crackower et al., 2002; Yamamoto et al., 2006; Nakamura et al., 2008) .
T149 25434-25559 Sentence denotes Similarly, in myocardial infarction loss of ACE2 accelerates maladaptive left ventricular remodeling (Kassiri et al., 2009) .
T150 25560-25782 Sentence denotes Mechanistically, the agedependent cardiomyopathy in ACE2 knockout mice is likely mediated by Ang II-induced oxidative stress and inflammation through AT1 receptor downstream PI3K (phosphatidylinositol-3-kinase) signaling .
T151 25783-26008 Sentence denotes Of note, one study reported that their knockout mouse line did not show alterations in cardiac function, although these mice were not investigated under conditions of cardiac like pressure overload Gurley and Coffman, 2008) .
T152 26009-26126 Sentence denotes However, these differences were resolved and appear to be dependent on modifier genes in different mouse background .
T153 26127-26235 Sentence denotes Thus, ACE and ACE2 balance Ang II levels and contribute to maintaining heart functions through AT1 receptor.
T154 26236-26396 Sentence denotes In addition to counterbalancing Ang II with ACE, the involvement of Ang 1-7 and Apelin in the actions of ACE2 on controlling heart function has been postulated.
T155 26397-26519 Sentence denotes Increasing evidences have shown the beneficial effects of Ang 1-7/Mas receptor axis in pathological settings of the heart.
T156 26520-26815 Sentence denotes Treatment with Ang 1-7 peptide has been shown to improve myocardial performance, cardiac remodeling, and even survival in rodent heart failure models, including ischemia/reperfusion injury, myocardial infarction, hypertension-induced cardiomyopathy (Ferreira et al., 2001; Santos et al., 2004) .
T157 26816-27049 Sentence denotes The nonpeptide AVE-0991, a selective ligand for Mas receptor, has actions similar to the cardioprotective effects of Ang 1-7 peptide , and knockout mice of Mas receptor displayed a reduced heart contractility (Alenina et al., 2008) .
T158 27050-27203 Sentence denotes Although there are accumulating literatures on ACE2-Ang 1-7-Mas axis, most of them are correlative studies on ACE2 relationships with Ang 1-7-Mas system.
T159 27204-27310 Sentence denotes We still miss direct evidence linking functional causal relationships between ACE2 and Ang 1-7-Mas system.
T160 27311-27435 Sentence denotes For instance, whether Ang 1-7 peptide or Mas agonist can rescue ACE2 knockout mouse heart phenotypes is not even challenged.
T161 27436-27497 Sentence denotes A connection of ACE2 and Ang 1-7-Mas system is still elusive.
T162 27498-27640 Sentence denotes In addition to Ang II, ACE2 also acts on the peptides Apelin-13 and Apelin-36 with high catalytic efficiency in vitro (Vickers et al., 2002) .
T163 27641-27832 Sentence denotes Apelin-13 and Apelin-36 are overlapped C-terminus fragments of 77 amino-acid Apelin preprohormone and are generated from it by proteolytic cleavage (Tatemoto et al., 1998; Lee et al., 2006) .
T164 27833-28091 Sentence denotes Although systemic administration of Apelin peptides prompts hypotension in rats and mice (Tatemoto et al., 2001; Ishida et al., 2004) , Apelin knockout mice and APJ (Apelin receptor) knockout mice both showed little alterations in blood pressure at baseline.
T165 28092-28332 Sentence denotes Interestingly, Apelin knockout mice showed aging-or stress-associated cardiac contractility defects, similar to the heart phenotype of ACE2 knockout mice, implicating a potential in vivo interaction of ACE2 with Apelin (Kuba et al., 2007) .
T166 28333-28458 Sentence denotes Nevertheless, there are no direct evidences of in vivo catalysis of Apelin peptides by ACE2, and further studies are awaited.
T167 28459-28774 Sentence denotes In humans, ACE2 gene polymorphisms associate with parameters of left ventricular hypertrophy in men (Lieb et al., 2006) , and soluble ACE2 activity is increased in patients with myocardial dysfunction and correlates with disease severity (Epelman et al., 2008) , implicating physiological roles of ACE2 in patients.
T168 28775-29200 Sentence denotes For therapeutic applications of ACE2 using transgenic overexpression of ACE2 in the hearts, the phenotypes are controversial; one study showed that cardiac overexpression of ACE2 protects the heart from ischemia-induced heart failure (Der Sarkissian et al., 2008) , whereas in the others overexpression of ACE2 was not beneficial, leading to fatal arrhythmia and severe fibrosis (Donoghue et al., 2003; Masson et al., 2009) .
T169 29201-29486 Sentence denotes The latter harmful effects may be due to the artifacts of transgenic gene overexpression, since utilizing recombinant ACE2 protein for therapeutic models has been recently shown to be beneficial in various disease models (Oudit et al., 2010; Treml et al., 2010; Wysocki et al., 2010) .
T170 29487-29567 Sentence denotes Neuronal control of heart function by ACE2 in brains has also been demonstrated.
T171 29568-29825 Sentence denotes Injections of the ACE2 inhibitor MLN4760 into the nucleus tractus solitarii reduced the baroreceptor reflex for reflex bradycardia in rats (Diz et al., 2008; Xia and Lazartigues, 2008) , suggesting a role for ACE2 and RAS in controlling baroreceptor reflex.
T172 29826-29976 Sentence denotes In kidney, ACE2 is abundantly expressed (Crackower et al., 2002) , and the activity of ACE2 is even higher in the kidney cortex than in heart tissue .
T173 29977-30134 Sentence denotes ACE2 has emerged as a protective molecule against kidney diseases in the context of negative regulation of the RAS (Soler et al., 2008; Oudit et al., 2009) .
T174 30135-30375 Sentence denotes For instance, deletion of ACE2 leads to late-onset nephrotic glomerulosclerosis spontaneously (Oudit et al., 2006) and accelerates diabetic kidney injury in Akita diabetic mice (Wong et al., 2007) and in streptozocin-induced diabetic mice .
T175 30376-30605 Sentence denotes In line with these results, pharmacological ablation of ACE2 by MLN-4760 resulted in increased albuminuria and glomerular pathology in the kidneys of db/db diabetic mice and streptozocininduced diabetic mice Soler et al., 2007) .
T176 30606-30739 Sentence denotes These phenotypes are at least in part dependent on Ang II signaling and can be rescued by AT1 receptor blockade Soler et al., 2007) .
T177 30740-30821 Sentence denotes Thus, these data definitely indicate that ACE2 is physiologically renoprotective.
T178 30822-30968 Sentence denotes In hypertensive SHR rats, with the onset of hypertension, the tubular expression of ACE2 in the kidneys is downregulated compared to control rats.
T179 30969-31085 Sentence denotes Diabetic nephropathy in experimental models has been shown to alter both glomerular and tubular expressions of ACE2.
T180 31086-31357 Sentence denotes In a long-term diabetic rat model, renal ACE2 expression is decreased (Tikellis et al., 2003) , whereas there is an early increase in ACE2 expression and activity in the kidneys of diabetic db/db (Ye et al., 2004; Wysocki et al., 2006) and Akita (Wong et al., 2007) mice.
T181 31358-31515 Sentence denotes The highest expression of the ACE2 mRNA found in renal proximal tubules was significantly reduced in the tubules from diabetic rats (Tikellis et al., 2003) .
T182 31516-31685 Sentence denotes Thus, reduced ACE2 expression might contribute to the pathogenesis and progression of kidney diseases (Tikellis et al., 2003; Mizuiri et al., 2008; Reich et al., 2008) .
T183 31686-31813 Sentence denotes Renal expression of ACE2 may play a more profound role in controlling local RAS rather than regulating systemic blood pressure.
T184 31814-31941 Sentence denotes Therefore, ACE2 counterbalances ACE function, negatively regulates Ang II levels and thereby controls local kidney homeostasis.
T185 31942-31944 Sentence denotes 6.
T186 31945-32000 Sentence denotes ACE2 is a SARS receptor -ACE2 in the respiratory system
T187 32001-32236 Sentence denotes Acute respiratory distress syndrome (ARDS) is the most severe form of acute lung injury, which affects approximately one million individuals worldwide/year and has a mortality rate of at least 30-50% (Hudson et al., 1995; Ware, 2006) .
T188 32237-32430 Sentence denotes ARDS can be triggered by multiple diseases such as sepsis, aspiration, trauma, acute pancreatitis, or pneumonias following infections with SARS coronavirus or avian and human influenza viruses.
T189 32431-32726 Sentence denotes Previous studies of ACE insertion/deletion (I/D) polymorphism correlation with severity of ARDS in humans (Marshall et al., 2002; Jerng et al., 2006) and ACE inhibitor treatments in rodent ARDS models (Raiden et al., 2002) have suggested that the RAS could have a role in ARDS/acute lung injury.
T190 32727-33013 Sentence denotes Intriguingly, despite its normal lung structures and functions, ace2 knockout mice exhibited very severe pathology of ARDS/acute lung injury compared with wild type control mice ; enhanced vascular permeability, increased lung edema, neutrophil accumulation, and worsened lung function.
T191 33014-33179 Sentence denotes AT1 blocker treatment or additional ace gene deficiency on an ace2 knockout background rescues the severe phenotype of ace2 single mutant mice in acute lung injury .
T192 33180-33382 Sentence denotes Importantly, treatment with catalytically active, but not enzymatically inactive, recombinant ACE2 protein improved the symptoms of acute lung injury in wild type mice as well as in ace2 knockout mice .
T193 33383-33596 Sentence denotes Furthermore, in a recent study of large animals in sepsis ARDS models, recombinant ACE2 protein significantly improved the respiratory failure and increased the oxygen levels of ARDS in pigs (Treml et al., 2010) .
T194 33597-33797 Sentence denotes Thus, in animal models of acute lung injury, ACE, Ang II, and AT1 receptor function as lung injury-promoting factors, while the negative regulation of Ang II levels by ACE2 protects from lung injury .
T195 33798-34056 Sentence denotes Moreover, in other lung injury models like bleomycin-induced lung fibrosis and monocrotaline-induced pulmonary hypertension, ACE2 has recently been shown to protect from chronic lung injuries, fibrosis, and pulmonary vasoconstriction Yamazato et al., 2009) .
T196 34057-34321 Sentence denotes These results suggest that ACE2 may serve as an entirely novel therapeutic for chronic lung diseases as well as acute lung injury, and the efficacy of recombinant ACE2 protein or AT1 receptor blockers on lung diseases should be further tested in clinical settings.
T197 34322-34461 Sentence denotes During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world.
T198 34462-34648 Sentence denotes International cooperative teams swiftly isolated a novel coronavirus as the SARS pathogen (SARS-CoV) and determined the SARS-CoV genome sequence (Marra et al., 2003; Rota et al., 2003) .
T199 34649-34937 Sentence denotes Surprisingly, ACE2 was identified as a functional receptor in vitro by using co-immunoprecipitation techniques (Li et al., 2003) , and subsequently, in a mouse SARS infection model with ace2 knockout mice, ACE2 was indeed identified as the essential receptor for SARS infections in vivo .
T200 34938-35107 Sentence denotes Interaction of SARS-CoV with ACE2 is initiated via trimers of the SARS Spike protein which extends into a hydrophobic pocket of ACE2 catalytic domain (Li et al., 2005) .
T201 35108-35290 Sentence denotes This ACE2-Spike interaction leads to endocytosis of virus particles through internalization with ACE2, induces the fusion of virus and host cells, and establishes SARS-CoV infection.
T202 35291-35574 Sentence denotes However, this process does not require nor affect the peptidase activity of ACE2, since cells expressing enzymatically inactive ACE2 can still be infected with the SARS-CoV and ACE2 substrates are still accessible to the catalytic pocket of ACE2 when the SARS Spike protein is bound.
T203 35575-35730 Sentence denotes Furthermore, in the structure of SARS Spike-bound ACE2, the catalytically active site of ACE2 was not blocked by the SARS Spike protein (Li et al., 2005) .
T204 35731-35816 Sentence denotes Therefore, ACE2 functions as a SARS receptor independently of its peptidase activity.
T205 35817-35958 Sentence denotes One mystery of SARS-CoV is why, in contrast to the other coronaviruses, such infections trigger severe lung disease with such high mortality.
T206 35959-36189 Sentence denotes Accumulating evidence indicates that severe SARS infections are dependent on the burden of viral replication as well as on the immunopathologic consequences of the host response (Lau and Peiris, 2005; Perlman and Dandekar, 2005) .
T207 36190-36333 Sentence denotes In addition to the aberrant activation of the immune system, our own studies have implicated a direct involvement of ACE2 in SARS pathogenesis.
T208 36334-36505 Sentence denotes Intriguingly, both SARS-CoV infection and challenge with recombinant SARS-Spike protein triggered a marked downregulation of ACE2 expression in lungs and in cell culture .
T209 36506-36588 Sentence denotes Thus, SARS-CoV-infected or Spike protein-treated mice resemble ace2 knockout mice.
T210 36589-36705 Sentence denotes Similar to ace2 mutant mice, Spike-treated wild type mice show markedly more severe pathology in acute lung injury .
T211 36706-36903 Sentence denotes Therefore, downregulation of the SARS receptor ACE2 expression by SARS-CoV infection activates the renin-angiotensin system and contributes to pathogenesis of severe ARDS/acute lung injury in SARS.
T212 36904-37112 Sentence denotes One of the clinical features of SARS patients is the progressive and rapid deterioration of lung function and the obvious loss of lung repair capacity after the viral load has declined (Peiris et al., 2003) .
T213 37113-37381 Sentence denotes Although many studies demonstrated that SARS receptor ACE2-expressing cells are alveolar type-1 or type-2 pneumocytes or vascular endothelial cells, a couple of recent studies suggested that lung epithelial stem/ progenitor cells are also important for SARS infection.
T214 37382-37678 Sentence denotes Mouse Oct-4+ lung epithelial progenitor cells, which arise from in vitro cultures of enzyme-released cells from neonatal lung tissues, express ACE2 and are the target cells for SARS-CoV infection in vitro and support active virus replication leading to their own destruction (Ling et al., 2006) .
T215 37679-37903 Sentence denotes Detailed expression analyses for mouse lungs revealed the highest expression of ACE2 in late embryonic days (E18.5) which declines after birth (Wiener et al., 2007) and further supporting a role for ACE2 in progenitor cells.
T216 37904-38114 Sentence denotes In SARS-infected human patient lungs, CD34+ Oct4+ lung progenitor cells are also positive for SARS-CoV antigens using immunohistochemistry, while mature pneumocytes appear to be negative for SARS-CoV antigens .
T217 38115-38280 Sentence denotes Interestingly, in rabbit atherosclerosis models, co-localization of ACE2 in CD34+ Oct4+ cells was also observed in the atherosclerotic plaques (Zulli et al., 2006) .
T218 38281-38593 Sentence denotes However, it should be noted that ACE2 expression is downregulated by SARS infection at the transcriptional and posttranslational level (Glowacka et al., 2010; Inoue et al., 2007; Haga et al., 2008; Wang et al., 2008) , and therefore one would actually expect low ACE2-immunoreactivity in SARS-CoV infected cells.
T219 38594-38856 Sentence denotes Nevertheless, these observations suggest a potential role of ACE2 for lung stem/ progenitor cells, in addition to type-1/type-2 pneumocytes, in the continued destruction of lung tissues and apparent loss in the capacity for lung repair after SARS-CoV infections.
T220 38857-38896 Sentence denotes Further studies are, however, required.
T221 38897-39120 Sentence denotes Homology searches have shown that ACE2 is a chimeric protein that has emerged from the duplication of two genes: homology with ACE at the catalytic domain and homology with Collectrin in the transmembrane C-terminal domain.
T222 39121-39322 Sentence denotes The Collectrin gene (gene name transmembrane protein 27; Tmem27) is located in immediate proximity to the ACE2 locus on the X chromosome and both genes share similar transcription factor binding sites.
T223 39323-39582 Sentence denotes Collectrin was shown to be expressed in β-cells of the pancreas under the transcriptional control of hepatocyte nuclear factor 1 (HNF1), and its function was implicated as insulin exocytosis or β-cell proliferation (Akpinar et al., 2005; Fukui et al., 2005) .
T224 39583-39762 Sentence denotes Surprisingly, using gene-targeting studies of Collectrin, the physiological in vivo function of Collectrin turned out to be a critical binding partner for amino acid transporters.
T225 39763-39935 Sentence denotes Collectrin physically associates with numerous apical amino acid transporters in the kidney and controls their expression and transport functions (Danilczyk et al., 2006) .
T226 39936-40071 Sentence denotes As a consequence Collectrin mutant mice exhibit a marked defect in re-absorption of amino acids in the proximal tubules of the kidneys.
T227 40072-40274 Sentence denotes Biochemically, Collectrin binds to B 0 AT1-family amino acid transporters and controls polarized expression of these transporters on the cell surface (Danilczyk et al., 2006; Malakauskas et al., 2007) .
T228 40275-40418 Sentence denotes Due to the high homology at its transmembrane with Collectrin, ACE2 was also anticipated to play a role in amino acid re-absorption in kidneys.
T229 40419-40594 Sentence denotes However, this was not the case; rather ACE2 binds to the B 0 AT1 amino acid transporter in the intestine but not in the kidney (Kowalczuk et al., 2008; Camargo et al., 2009) .
T230 40595-40780 Sentence denotes In ACE2 knockout mice, luminal expression of B 0 AT1 in the intestine is completely lost, suggesting that ACE2 is essential for expression of B 0 AT1 in cell surface of the intestine ).
T231 40781-41027 Sentence denotes Thus, ACE2 and Collectrin are both binding partners for B 0 AT1 and contribute to absorption of neutral amino acids in intestine and kidney, respectively, although reasons for tissue-specific bindings of B 0 AT1 to ACE2 or Collectrin are unknown.
T232 41028-41217 Sentence denotes Hartnup disorder is a hereditary familial disease, characterized by a pellagra-like light-sensitive rash, cerebellar ataxia, emotional instability, and amino aciduria (Baron et al., 1956) .
T233 41218-41381 Sentence denotes Gene mutations in the B 0 AT1 (Slc6a19) neutral amino acid transporter were identified as one cause of Hartnup's disorder (Kleta et al., 2004; Seow et al., 2004) .
T234 41382-41557 Sentence denotes Despite crucial roles of ACE2 and Collectrin in expression of this amino acid transporter, gene mutations of ACE2 and Collectrin have not been identified in Hartnup's disease.
T235 41558-41730 Sentence denotes Among the human Hartnup mutations of B 0 AT1, the A69T and R240Q missense mutants were shown in vitro defective for activation of transport function by ACE2 and Collectrin.
T236 41731-41941 Sentence denotes In in vitro Xenopus oocyte expression system the B 0 AT1 mutants alone show similar levels of amino acid uptake to wild-type one, although the transport rates are low (Seow et al., 2004; Camargo et al., 2009) .
T237 41942-42145 Sentence denotes However, when the mutants were co-expressed with ACE2, transport function was not activated by the binding partners, while the coexpression of ACE2 and B 0 AT1 dramatically activates transport functions.
T238 42146-42293 Sentence denotes Thus, mutations in Hartnup disorder patients interfering with the interaction between B 0 AT1 and ACE2 may explain the disease in some individuals.
T239 42294-42401 Sentence denotes On the other hand, ACE2 knockout mice were not reported for any phenotypes recapitulating Hartnup disorder.
T240 42402-42595 Sentence denotes Also in Hartnup patients, for instance, a compound heterozygous for A69T and the original Hartnup mutation IVS8+2T-NG showed only seizures but not other symptoms like pellagra or ataxic gaits .
T241 42596-42772 Sentence denotes Therefore, the physiological significance of this impaired activation of the mutants by ACE2 is yet elusive, and further analyses for the role of the mutations would be needed.
T242 42773-43013 Sentence denotes Studies of ACE2 knockout mice and gene transfer or administration of recombinant ACE2 protein have demonstrated that ACE2 is an in vivo negative regulator of the both systemic and local effects of the RAS systems through peptidase activity.
T243 43014-43235 Sentence denotes The carboxypeptidase activity of ACE2 appears to limit the availability of Ang II, generates counter-regulatory vasodilator peptides such as Ang 1-7, and may even act on other peptide systems such as Apelin and dynorphin.
T244 43236-43347 Sentence denotes Importantly, ACE2 was also identified as a key SARS receptor and plays a protective role in SARS-mediated ARDS.
T245 43348-43597 Sentence denotes These findings are now providing the opportunity to develop a potential novel medicine for the treatment of ARDS, an often lethal condition that can develop in emerging infectious lung diseases such as avian influenza (H5N1) or the swine flu (H1N1).
T246 43598-43800 Sentence denotes During the course of studying ACE2 function, we also made an entirely unexpected finding: ACE2 and Collectrin are essential for expression of amino acid transporters in the gut and kidney, respectively.
T247 43801-44013 Sentence denotes The discovery and functional characterization of ACE2 have shown that the RAS system is far more complex and that this system is tightly connected to other peptide systems and even amino acid transport functions.
T248 44014-44267 Sentence denotes An understanding of such complexity and molecular crosstalks will not only broaden our knowledge on the evolution and biology of cardiovascular systems, but will also offer a chance to develop new and refined therapeutic strategies for various diseases.