Neurochemical Research

, Volume 44, Issue 6, pp 1323–1329 | Cite as

ACE2 in Brain Physiology and Pathophysiology: Evidence from Transgenic Animal Models

  • Natalia Alenina
  • Michael BaderEmail author
Original Paper


Angiotensin-converting enzyme 2 (ACE2) is a protein consisting of two domains, the N-terminus is a carboxypeptidase homologous to ACE and the C-terminus is homologous to collectrin and responsible for the trafficking of the neutral amino acid transporter B(0)AT1 to the plasma membrane of gut epithelial cells. The carboxypeptidase domain not only metabolizes angiotensin II to angiotensin-(1–7), but also other peptide substrates, such as apelin, kinins and morphins. In addition, the collectrin domain regulates the levels of some amino acids in the blood, in particular of tryptophan. Therefore it is of no surprise that animals with genetic alterations in the expression of ACE2 develop a diverse pattern of phenotypes ranging from hypertension, metabolic and behavioural dysfunctions, to impairments in serotonin synthesis and neurogenesis. This review summarizes the phenotypes of such animals with a particular focus on the central nervous system.


Angiotensin Serotonin Hypertension SARS Transgenic mice Knockout mice 


  1. 1.
    Bader M (2010) Tissue renin-angiotensin-aldosterone systems: targets for pharmacological therapy. Ann Rev Pharmacol Toxicol 50:439–465CrossRefGoogle Scholar
  2. 2.
    Santos RA, Simoes e Silva AC, Maric C, Silva DMR, Machado RP, de Buhr I, Heringer-Walther S, Pinheiro SVB, Lopes MT, Bader M, Mendes EP, Lemos VS, Campagnole-Santos MJ, Schultheiss HP, Speth R, Walther T (2003) Angiotensin-(1–7) is an endogenous ligand for the G-protein coupled receptor Mas. Proc Natl Acad Sci USA 100:8258–8263CrossRefGoogle Scholar
  3. 3.
    Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ (2000) A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 275:33238–33243CrossRefGoogle Scholar
  4. 4.
    Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S (2000) A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res 87:E1–E9CrossRefGoogle Scholar
  5. 5.
    Danilczyk U, Sarao R, Remy C, Benabbas C, Stange G, Richter A, Arya S, Pospisilik JA, Singer D, Camargo SM, Makrides V, Ramadan T, Verrey F, Wagner CA, Penninger JM (2006) Essential role for collectrin in renal amino acid transport. Nature 444:1088–1091CrossRefGoogle Scholar
  6. 6.
    Zhang H, Wada J, Hida K, Tsuchiyama Y, Hiragushi K, Shikata K, Wang H, Lin S, Kanwar YS, Makino H (2001) Collectrin, a collecting duct-specific transmembrane glycoprotein, is a novel homolog of ACE2 and is developmentally regulated in embryonic kidneys. J Biol Chem 276:17132–17139CrossRefGoogle Scholar
  7. 7.
    Turner AJ, Hooper NM (2002) The angiotensin-converting enzyme gene family: genomics and pharmacology. Trends Pharmacol Sci 23:177–183CrossRefGoogle Scholar
  8. 8.
    Fournier D, Luft FC, Bader M, Ganten D, Andrade-Navarro MA (2012) Emergence and evolution of the renin-angiotensin-aldosterone system. J Mol Med 90:495–508CrossRefGoogle Scholar
  9. 9.
    Warner FJ, Lew RA, Smith AI, Lambert DW, Hooper NM, Turner AJ (2005) Angiotensin-converting enzyme 2 (ACE2), but not ACE, is preferentially localized to the apical surface of polarized kidney cells. J Biol Chem 280:39353–39362CrossRefGoogle Scholar
  10. 10.
    Turner AJ (2003) Exploring the structure and function of zinc metallopeptidases: old enzymes and new discoveries. Biochem Soc Trans 31:723–727CrossRefGoogle Scholar
  11. 11.
    Lambert DW, Yarski M, Warner FJ, Thornhill P, Parkin ET, Smith AI, Hooper NM, Turner AJ (2005) Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2). J Biol Chem 280:30113–30119CrossRefGoogle Scholar
  12. 12.
    Xia H, Sriramula S, Chhabra KH, Lazartigues E (2013) Brain angiotensin-converting enzyme type 2 shedding contributes to the development of neurogenic hypertension. Circ Res 113:1087–1096CrossRefGoogle Scholar
  13. 13.
    Xu J, Sriramula S, Xia H, Moreno-Walton L, Culicchia F, Domenig O, Poglitsch M, Lazartigues E (2017) Clinical relevance and role of neuronal AT1 receptors in ADAM17-mediated ACE2 shedding in neurogenic hypertension. Circ Res 121:43–55CrossRefGoogle Scholar
  14. 14.
    Xu J, Sriramula S, Lazartigues E (2018) Excessive glutamate stimulation impairs ACE2 activity through ADAM17-mediated shedding in cultured cortical neurons. Cell Mol Neurobiol. Google Scholar
  15. 15.
    Komatsu T, Suzuki Y, Imai J, Sugano S, Hida M, Tanigami A, Muroi S, Yamada Y, Hanaoka K (2002) Molecular cloning, mRNA expression and chromosomal localization of mouse angiotensin-converting enzyme-related carboxypeptidase (mACE2). DNA Seq 13:217–220CrossRefGoogle Scholar
  16. 16.
    Rice GI, Thomas DA, Grant PJ, Turner AJ, Hooper NM (2004) Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J 383:45–51CrossRefGoogle Scholar
  17. 17.
    Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J, Godbout K, Parsons T, Baronas E, Hsieh F, Acton S, Patane M, Nichols A, Tummino P (2002) Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem 277:14838–14843CrossRefGoogle Scholar
  18. 18.
    Lambert DW, Hooper NM, Turner AJ (2008) Angiotensin-converting enzyme 2 and new insights into the renin-angiotensin system. Biochem Pharmacol 75:781–786CrossRefGoogle Scholar
  19. 19.
    Santos RAS, Sampaio WO, Alzamora AC, Motta-Santos D, Alenina N, Bader M, Campagnole-Santos MJ (2018) The ACE2/angiotensin-(1–7)/MAS axis of the renin-angiotensin system: focus on angiotensin-(1–7). Physiol Rev 98:505–553CrossRefGoogle Scholar
  20. 20.
    Hashimoto T, Perlot T, Rehman A, Trichereau J, Ishiguro H, Paolino M, Sigl V, Hanada T, Hanada R, Lipinski S, Wild B, Camargo SM, Singer D, Richter A, Kuba K, Fukamizu A, Schreiber S, Clevers H, Verrey F, Rosenstiel P, Penninger JM (2012) ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature 487:477–481CrossRefGoogle Scholar
  21. 21.
    Singer D, Camargo SM, Ramadan T, Schafer M, Mariotta L, Herzog B, Huggel K, Wolfer D, Werner S, Penninger JM, Verrey F (2012) Defective intestinal amino acid absorption in Ace2 null mice. Am J Physiol Gastrointest Liver Physiol 303:G686–G695CrossRefGoogle Scholar
  22. 22.
    Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M (2003) Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 426:450–454CrossRefGoogle Scholar
  23. 23.
    Turner AJ, Hiscox JA, Hooper NM (2004) ACE2: from vasopeptidase to SARS virus receptor. Trends Pharmacol Sci 25:291–294CrossRefGoogle Scholar
  24. 24.
    Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE, Oliveira-dos-Santos AJ, da Costa J, Zhang L, Pei Y, Scholey J, Ferrario CM, Manoukian AS, Chappell MC, Backx PH, Yagil Y, Penninger JM (2002) Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 417:822–828CrossRefGoogle Scholar
  25. 25.
    Yagil Y, Yagil C (2003) Hypothesis: ACE2 modulates blood pressure in the mammalian organism. Hypertension 41:871–873CrossRefGoogle Scholar
  26. 26.
    Bader M, Bohnemeier H, Zollmann FS, Lockley-Jones OE, Ganten D (2000) Transgenic animals in cardiovascular disease research. Exp Physiol 85:713–731CrossRefGoogle Scholar
  27. 27.
    Mori MAS, Bader M, Pesquero JB (2008) Genetically altered animals in the study of the metabolic functions of peptide hormone systems. Curr Opin Nephrol Hypertens 17:11–17CrossRefGoogle Scholar
  28. 28.
    Bader M (2010) Rat models of cardiovascular diseases. Methods Mol Biol 597:403–414CrossRefGoogle Scholar
  29. 29.
    Alenina N, Xu P, Rentzsch B, Patkin EL, Bader M (2008) Genetically altered animal models for Mas and angiotensin-(1–7). Exp Physiol 93:528–537CrossRefGoogle Scholar
  30. 30.
    Donoghue M, Wakimoto H, Maguire CT, Acton S, Hales P, Stagliano N, Fairchild-Huntress V, Xu J, Lorenz JN, Kadambi V, Berul CI, Breitbart RE (2003) Heart block, ventricular tachycardia, and sudden death in ACE2 transgenic mice with downregulated connexins. J Mol Cell Cardiol 35:1043–1053CrossRefGoogle Scholar
  31. 31.
    Patel VB, Mori J, McLean BA, Basu R, Das SK, Ramprasath T, Parajuli N, Penninger JM, Grant MB, Lopaschuk GD, Oudit GY (2016) ACE2 deficiency worsens epicardial adipose tissue inflammation and cardiac dysfunction in response to diet-induced obesity. Diabetes 65:85–95CrossRefGoogle Scholar
  32. 32.
    Motta-Santos D, Dos Santos RA, Oliveira M, Qadri F, Poglitsch M, Mosienko V, Kappes BL, Campagnole-Santos MJ, Penninger M, Alenina N, Bader M (2016) Effects of ACE2 deficiency on physical performance and physiological adaptations of cardiac and skeletal muscle to exercise. Hypertens Res 39:506–512CrossRefGoogle Scholar
  33. 33.
    Rentzsch B, Todiras M, Iliescu R, Popova E, Campos LA, Oliveira ML, Baltatu OC, Santos RA, Bader M (2008) Transgenic ACE2 overexpression in vessels of SHRSP rats reduces blood pressure and improves endothelial function. Hypertension 52:967–973CrossRefGoogle Scholar
  34. 34.
    Lovren F, Pan Y, Quan A, Teoh H, Wang G, Shukla PC, Levitt KS, Oudit GY, Al-Omran M, Stewart DJ, Slutsky AS, Peterson MD, Backx PH, Penninger JM, Verma S (2008) Angiotensin converting enzyme-2 confers endothelial protection and attenuates atherosclerosis. Am J Physiol Heart Circ Physiol 295:H1377–H1384CrossRefGoogle Scholar
  35. 35.
    Rabelo LA, Todiras M, Nunes-Souza V, Qadri F, Szijarto IA, Gollasch M, Penninger JM, Bader M, Santos RA, Alenina N (2016) Genetic deletion of ACE2 induces vascular dysfunction in C57BL/6 mice: role of nitric oxide imbalance and oxidative stress. PLoS ONE 11:e0150255CrossRefGoogle Scholar
  36. 36.
    Thomas MC, Pickering RJ, Tsorotes D, Koitka A, Sheehy K, Bernardi S, Toffoli B, Nguyen-Huu TP, Head GA, Fu Y, Chin-Dusting J, Cooper ME, Tikellis C (2010) Genetic Ace2 deficiency accentuates vascular inflammation and atherosclerosis in the ApoE knockout mouse. Circ Res 107:888–897CrossRefGoogle Scholar
  37. 37.
    Niu MJ, Yang JK, Lin SS, Ji XJ, Guo LM (2008) Loss of angiotensin-converting enzyme 2 leads to impaired glucose homeostasis in mice. Endocrine 34:56–61CrossRefGoogle Scholar
  38. 38.
    Sahara M, Ikutomi M, Morita T, Minami Y, Nakajima T, Hirata Y, Nagai R, Sata M (2014) Deletion of angiotensin-converting enzyme 2 promotes the development of atherosclerosis and arterial neointima formation. Cardiovasc Res 101:236–246CrossRefGoogle Scholar
  39. 39.
    Thatcher SE, Zhang X, Howatt DA, Yiannikouris F, Gurley SB, Ennis T, Curci JA, Daugherty A, Cassis LA (2014) Angiotensin-Converting enzyme 2 decreases formation and severity of angiotensin II-induced abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 34:2617–2623CrossRefGoogle Scholar
  40. 40.
    Cao X, Yang FY, Xin Z, Xie RR, Yang JK (2014) The ACE2/Ang-(1–7)/Mas axis can inhibit hepatic insulin resistance. Mol Cell Endocrinol 393:30–38CrossRefGoogle Scholar
  41. 41.
    Oudit GY, Herzenberg AM, Kassiri Z, Wong D, Reich H, Khokha R, Crackower MA, Backx PH, Penninger JM, Scholey JW (2006) Loss of angiotensin-converting enzyme-2 leads to the late development of angiotensin II-dependent glomerulosclerosis. Am J Pathol 168:1808–1820CrossRefGoogle Scholar
  42. 42.
    Yang XH, Wang YH, Wang JJ, Liu YC, Deng W, Qin C, Gao JL, Zhang LY (2012) Role of angiotensin-converting enzyme (ACE and ACE2) imbalance on tourniquet-induced remote kidney injury in a mouse hindlimb ischemia-reperfusion model. Peptides 36:60–70CrossRefGoogle Scholar
  43. 43.
    Fang F, Liu GC, Zhou X, Yang S, Reich HN, Williams V, Hu A, Pan J, Konvalinka A, Oudit GY, Scholey JW, John R (2013) Loss of ACE2 exacerbates murine renal ischemia-reperfusion injury. PLoS ONE 8:e71433CrossRefGoogle Scholar
  44. 44.
    Nadarajah R, Milagres R, Dilauro M, Gutsol A, Xiao F, Zimpelmann J, Kennedy C, Wysocki J, Batlle D, Burns KD (2012) Podocyte-specific overexpression of human angiotensin-converting enzyme 2 attenuates diabetic nephropathy in mice. Kidney Int 82:292–303CrossRefGoogle Scholar
  45. 45.
    Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, Yang P, Sarao R, Wada T, Leong-Poi H, Crackower MA, Fukamizu A, Hui CC, Hein L, Uhlig S, Slutsky AS, Jiang C, Penninger JM (2005) Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 436:112–116CrossRefGoogle Scholar
  46. 46.
    Zhang J, Dong J, Martin M, He M, Gongol B, Marin TL, Chen L, Shi X, Yin Y, Shang F, Wu Y, Huang HY, Zhang J, Zhang Y, Kang J, Moya EA, Huang HD, Powell FL, Chen Z, Thistlethwaite PA, Yuan ZY, Shyy JY (2018) AMPK phosphorylation of ACE2 in endothelium mitigates pulmonary hypertension. Am J Respir Crit Care Med 198:509–520CrossRefGoogle Scholar
  47. 47.
    Santos RA, Ferreira AJ, Verano-Braga T, Bader M (2013) Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin-angiotensin system. J Endocrinol 216:R1–R17CrossRefGoogle Scholar
  48. 48.
    Patel VB, Zhong JC, Grant MB, Oudit GY (2016) Role of the ACE2/angiotensin 1–7 axis of the renin-angiotensin system in heart failure. Circ Res 118:1313–1326CrossRefGoogle Scholar
  49. 49.
    Williams VR, Scholey JW (2018) Angiotensin-converting enzyme 2 and renal disease. Curr Opin Nephrol Hypertens 27:35–41CrossRefGoogle Scholar
  50. 50.
    Danilczyk U, Penninger JM (2006) Angiotensin-converting enzyme II in the heart and the kidney. Circ Res 98:463–471CrossRefGoogle Scholar
  51. 51.
    Gurley SB, Allred A, Le TH, Griffiths R, Mao L, Philip N, Haystead TA, Donoghue M, Breitbart RE, Acton SL, Rockman HA, Coffman TM (2006) Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice. J Clin Investig 116:2218–2225CrossRefGoogle Scholar
  52. 52.
    Yamamoto K, Ohishi M, Katsuya T, Ito N, Ikushima M, Kaibe M, Tatara Y, Shiota A, Sugano S, Takeda S, Rakugi H, Ogihara T (2006) Deletion of angiotensin-converting enzyme 2 accelerates pressure overload-induced cardiac dysfunction by increasing local angiotensin II. Hypertension 47:718–726CrossRefGoogle Scholar
  53. 53.
    Liu C, Xiao L, Li F, Zhang H, Li Q, Liu H, Fu S, Li C, Zhang X, Wang J, Staunstrup NH, Li Y, Yang H (2015) Generation of outbred Ace2 knockout mice by RNA transfection of TALENs displaying colitis reminiscent pathophysiology and inflammation. Transgenic Res 24:433–446CrossRefGoogle Scholar
  54. 54.
    Zhang ZZ, Cheng YW, Jin HY, Chang Q, Shang QH, Xu YL, Chen LX, Xu R, Song B, Zhong JC (2017) The sirtuin 6 prevents angiotensin II-mediated myocardial fibrosis and injury by targeting AMPK-ACE2 signaling. Oncotarget 8:72302–72314Google Scholar
  55. 55.
    Homberg JR, Wohr M, Alenina N (2017) Comeback of the rat in biomedical research. ACS Chem Neurosci 8:900–903CrossRefGoogle Scholar
  56. 56.
    Feng Y, Xia H, Cai Y, Halabi CM, Becker LK, Santos RA, Speth RC, Sigmund CD, Lazartigues E (2010) Brain-selective overexpression of human angiotensin-converting enzyme type 2 attenuates neurogenic hypertension. Circ Res 106:373–382CrossRefGoogle Scholar
  57. 57.
    Xia H, de Queiroz TM, Sriramula S, Feng Y, Johnson T, Mungrue IN, Lazartigues E (2015) Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress. Am J Physiol Regul Integr Comp Physiol 308:R370–R378CrossRefGoogle Scholar
  58. 58.
    Qi YF, Zhang J, Wang L, Shenoy V, Krause E, Oh SP, Pepine CJ, Katovich MJ, Raizada MK (2016) Angiotensin-converting enzyme 2 inhibits high-mobility group box 1 and attenuates cardiac dysfunction post-myocardial ischemia. J Mol Med (Berlin) 94:37–49CrossRefGoogle Scholar
  59. 59.
    Wang L, de Kloet AD, Pati D, Hiller H, Smith JA, Pioquinto DJ, Ludin JA, Oh SP, Katovich MJ, Frazier CJ, Raizada MK, Krause EG (2016) Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors. Neuropharmacology 105:114–123CrossRefGoogle Scholar
  60. 60.
    Feng Y, Hans C, McIlwain E, Varner KJ, Lazartigues E (2012) Angiotensin-converting enzyme 2 over-expression in the central nervous system reduces angiotensin-II-mediated cardiac hypertrophy. PLoS ONE 7:e48910CrossRefGoogle Scholar
  61. 61.
    Baltatu O, Silva JA Jr, Ganten D, Bader M (2000) The brain renin-angiotensin system modulates angiotensin II-induced hypertension and cardiac hypertrophy. Hypertension 35:409–412CrossRefGoogle Scholar
  62. 62.
    Sriramula S, Xia H, Xu P, Lazartigues E (2015) Brain-targeted angiotensin-converting enzyme 2 overexpression attenuates neurogenic hypertension by inhibiting cyclooxygenase-mediated inflammation. Hypertension 65:577–586CrossRefGoogle Scholar
  63. 63.
    Xiao L, Gao L, Lazartigues E, Zucker IH (2011) Brain-selective overexpression of angiotensin-converting enzyme 2 attenuates sympathetic nerve activity and enhances baroreflex function in chronic heart failure. Hypertension 58:1057–1065CrossRefGoogle Scholar
  64. 64.
    Xia H, Suda S, Bindom S, Feng Y, Gurley SB, Seth D, Navar LG, Lazartigues E (2011) ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function. PLoS ONE 6:e22682CrossRefGoogle Scholar
  65. 65.
    Chen J, Zhao Y, Chen S, Wang J, Xiao X, Ma X, Penchikala M, Xia H, Lazartigues E, Zhao B, Chen Y (2014) Neuronal over-expression of ACE2 protects brain from ischemia-induced damage. Neuropharmacology 79:550–558CrossRefGoogle Scholar
  66. 66.
    Zheng JL, Li GZ, Chen SZ, Wang JJ, Olson JE, Xia HJ, Lazartigues E, Zhu YL, Chen YF (2014) Angiotensin converting enzyme 2/Ang-(1–7)/mas axis protects brain from ischemic injury with a tendency of age-dependence. CNS Neurosci Ther 20:452–459CrossRefGoogle Scholar
  67. 67.
    Zheng J, Li G, Chen S, Bihl J, Buck J, Zhu Y, Xia H, Lazartigues E, Chen Y, Olson JE (2014) Activation of the ACE2/Ang-(1–7)/Mas pathway reduces oxygen-glucose deprivation-induced tissue swelling, ROS production, and cell death in mouse brain with angiotensin II overproduction. Neuroscience 273:39–51CrossRefGoogle Scholar
  68. 68.
    Bennion DM, Jones CH, Donnangelo LL, Graham JT, Isenberg JD, Dang AN, Rodriguez V, Sinisterra RDM, Sousa FB, Santos RAS, Sumners C (2018) Neuroprotection by post-stroke administration of an oral formulation of angiotensin-(1–7) in ischaemic stroke. Exp Physiol 103:916–923CrossRefGoogle Scholar
  69. 69.
    Bennion DM, Haltigan E, Regenhardt RW, Steckelings UM, Sumners C (2015) Neuroprotective mechanisms of the ACE2-angiotensin-(1–7)-Mas axis in stroke. Curr Hypertens Rep 17:3CrossRefGoogle Scholar
  70. 70.
    Regenhardt RW, Desland F, Mecca AP, Pioquinto DJ, Afzal A, Mocco J, Sumners C (2013) Anti-inflammatory effects of angiotensin-(1–7) in ischemic stroke. Neuropharmacology 71:154–163CrossRefGoogle Scholar
  71. 71.
    Mecca AP, Regenhardt RW, O’Connor TE, Joseph JP, Raizada MK, Katovich MJ, Sumners C (2011) Cerebroprotection by angiotensin-(1–7) in endothelin-1-induced ischaemic stroke. Exp Physiol 96:1084–1096CrossRefGoogle Scholar
  72. 72.
    Regenhardt RW, Mecca AP, Desland F, Ritucci-Chinni PF, Ludin JA, Greenstein D, Banuelos C, Bizon JL, Reinhard MK, Sumners C (2014) Centrally administered angiotensin-(1–7) increases the survival of stroke prone spontaneously hypertensive rats. Exp Physiol 99:442–453CrossRefGoogle Scholar
  73. 73.
    Jiang T, Gao L, Guo J, Lu J, Wang Y, Zhang Y (2012) Suppressing inflammation by inhibiting the NF-kappaB pathway contributes to the neuroprotective effect of angiotensin-(1–7) in rats with permanent cerebral ischaemia. Br J Pharmacol 167:1520–1532CrossRefGoogle Scholar
  74. 74.
    Yang XH, Deng W, Tong Z, Liu YX, Zhang LF, Zhu H, Gao H, Huang L, Liu YL, Ma CM, Xu YF, Ding MX, Deng HK, Qin C (2007) Mice transgenic for human angiotensin-converting enzyme 2 provide a model for SARS coronavirus infection. Comp Med 57:450–459Google Scholar
  75. 75.
    McCray PB Jr, Pewe L, Wohlford-Lenane C, Hickey M, Manzel L, Shi L, Netland J, Jia HP, Halabi C, Sigmund CD, Meyerholz DK, Kirby P, Look DC, Perlman S (2007) Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus. J Virol 81:813–821CrossRefGoogle Scholar
  76. 76.
    Netland J, Meyerholz DK, Moore S, Cassell M, Perlman S (2008) Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J Virol 82:7264–7275CrossRefGoogle Scholar
  77. 77.
    Gu J, Gong E, Zhang B, Zheng J, Gao Z, Zhong Y, Zou W, Zhan J, Wang S, Xie Z, Zhuang H, Wu B, Zhong H, Shao H, Fang W, Gao D, Pei F, Li X, He Z, Xu D, Shi X, Anderson VM, Leong AS (2005) Multiple organ infection and the pathogenesis of SARS. J Exp Med 202:415–424CrossRefGoogle Scholar
  78. 78.
    Wang XL, Iwanami J, Min LJ, Tsukuda K, Nakaoka H, Bai HY, Shan BS, Kan-No H, Kukida M, Chisaka T, Yamauchi T, Higaki A, Mogi M, Horiuchi M (2016) Deficiency of angiotensin-converting enzyme 2 causes deterioration of cognitive function. NPJ Aging Mech Dis 2:16024CrossRefGoogle Scholar
  79. 79.
    Lazaroni TL, Raslan AC, Fontes WR, de Oliveira ML, Bader M, Alenina N, Moraes MF, Dos Santos RA, Pereira GS (2012) Angiotensin-(1–7)/Mas axis integrity is required for the expression of object recognition memory. Neurobiol Learn Mem 97:113–123CrossRefGoogle Scholar
  80. 80.
    Wang LA, de Kloet AD, Smeltzer MD, Cahill KM, Hiller H, Bruce EB, Pioquinto DJ, Ludin JA, Katovich MJ, Raizada MK, Krause EG (2018) Coupling corticotropin-releasing-hormone and angiotensin converting enzyme 2 dampens stress responsiveness in male mice. Neuropharmacology 133:85–93CrossRefGoogle Scholar
  81. 81.
    Walther T, Balschun D, Voigt JP, Fink H, Zuschratter W, Birchmeier C, Ganten D, Bader M (1998) Sustained long term potentiation and anxiety in mice lacking the Mas protooncogene. J Biol Chem 273:11867–11873CrossRefGoogle Scholar
  82. 82.
    Kangussu LM, Almeida-Santos AF, Bader M, Alenina N, Fontes MA, Santos RA, Aguiar DC, Campagnole-Santos MJ (2013) Angiotensin-(1–7) attenuates the anxiety and depression-like behaviors in transgenic rats with low brain angiotensinogen. Behav Brain Res 257:25–30CrossRefGoogle Scholar
  83. 83.
    Kangussu LM, Almeida-Santos AF, Moreira FA, Fontes MAP, Santos RAS, Aguiar DC, Campagnole-Santos MJ (2017) Reduced anxiety-like behavior in transgenic rats with chronically overproduction of angiotensin-(1–7): role of the Mas receptor. Behav Brain Res 331:193–198CrossRefGoogle Scholar
  84. 84.
    Moura SD, Ribeiro MF, Limborco-Filho M, de Oliveira ML, Hamamoto D, Xavier CH, Moreira FA, Santos RA, Campagnole-Santos MJ, Peliky Fontes MA (2017) Chronic overexpression of angiotensin-(1–7) in rats reduces cardiac reactivity to acute stress and dampens anxious behavior. Stress 20:189–196CrossRefGoogle Scholar
  85. 85.
    Klempin F, Mosienko V, Matthes S, Villela DC, Todiras M, Penninger JM, Bader M, Santos RAS, Alenina N (2018) Depletion of angiotensin-converting enzyme 2 reduces brain serotonin and impairs the running-induced neurogenic response. Cell Mol Life Sci 75:3625–3634CrossRefGoogle Scholar
  86. 86.
    Klempin F, Beis D, Mosienko V, Kempermann G, Bader M, Alenina N (2013) Serotonin is required for exercise-induced adult hippocampal neurogenesis. J Neurosci 33:8270–8275CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Max-Delbrück-Center for Molecular Medicine (MDC)BerlinGermany
  2. 2.DZHK (German Center for Cardiovascular Research), Partner Site BerlinBerlinGermany
  3. 3.Berlin Institute of Health (BIH)BerlinGermany
  4. 4.Charité - University MedicineBerlinGermany
  5. 5.Institute for BiologyUniversity of LübeckLübeckGermany

Personalised recommendations