ACE2: Angiotensin II/Angiotensin-(1–7) Balance in Cardiac and Renal Injury

  • Jasmina Varagic
  • Sarfaraz Ahmad
  • Sayaka Nagata
  • Carlos M. Ferrario
Mediators, Mechanisms, and Pathways in Tissue Injury (T Fujita, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Hypertension and Metabolic Syndrome


Our current recognition of the renin-angiotensin system is more convoluted than originally thought due to the discovery of multiple novel enzymes, peptides, and receptors inherent in this interactive biochemical cascade. Over the last decade, angiotensin-converting enzyme 2 (ACE2) has emerged as a key player in the pathophysiology of hypertension and cardiovascular and renal disease due to its pivotal role in metabolizing vasoconstrictive/hypertrophic/proliferative angiotensin II into favorable angiotensin-(1–7). This review addresses the considerable advancement in research on the role of tissue ACE2 in the development and progression of hypertension and cardiac and renal injury. We summarize the results from recent clinical and experimental studies suggesting that serum or urine soluble ACE2 may serve as a novel biomarker or independent risk factor relevant for diagnosis and prognosis of cardiorenal disease. We also review recent proceedings on novel therapeutic approaches to enhance ACE2/angiotensin-(1–7) axis.


Angiotensin-converting enzyme 2 Angiotensin II Angiotensin-(1–7) Heart Kidney Hypertension Left ventricular remodeling Heart failure Diabetes Renal disease 


Compliance with Ethics Guidelines

Conflict of Interest

Jasmina Varagic, Sarfaraz Ahmad, Sayaka Nagata, and Carlos M. Ferrario declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

With regard to the authors’ research cited in this paper, all procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000 and 2008, and all institutional and national guidelines for the care and use of laboratory animals were followed.


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.•
    Ahmad S, Simmons T, Varagic J, Moniwa N, Chappell MC, Ferrario CM. Chymase-dependent generation of angiotensin II from angiotensin-(1-12) in human atrial tissue. PLoS One. 2011;6(12):e28501. The first paper to show the chymase-dependent generation of Ang II from the novel intermediate precursor Ang-(1-12) in atrial tissue from patients undergoing cardiac surgery for primary control of atrial fibrillation.Google Scholar
  2. 2.
    Ahmad S, Wei CC, Tallaj J, Dell'Italia LJ, Moniwa N, Varagic J, et al. Chymase mediates angiotensin-(1-12) metabolism in normal human hearts. J Am Soc Hypertens. 2013;7(2):128–36.Google Scholar
  3. 3.
    Ferrario CM, Ahmad S, Nagata S, Simington S, Varagic J, Kon N, et al. An evolving story of angiotensin II-forming pathways in rodents and humans. Clin Sci. 2013;156(7):461–9.Google Scholar
  4. 4.
    Ferrario CM, Varagic J. The ANG-(1-7)/ACE2/mas axis in the regulation of nephron function. Am J Physiol Renal Physiol. 2010;298(6):F1297–305.Google Scholar
  5. 5.
    Varagic J, Trask AJ, Jessup JA, Chappell MC, Ferrario CM. New angiotensins. J Mol Med (Berl). 2008;86(6):663–71.Google Scholar
  6. 6.
    Epelman S, Shrestha K, Troughton RW, Francis GS, Sen S, Klein AL, et al. Soluble angiotensin-converting enzyme 2 in human heart failure: relation with myocardial function and clinical outcomes. J Card Fail. 2009;15(7):565–71.Google Scholar
  7. 7.•
    Wysocki J, Garcia-Halpin L, Ye M, Maier C, Sowers K, Burns KD, et al. Regulation of urinary ACE2 in diabetic mice. Am J Physiol Renal Physiol. 2013;305(4):F600–11. In db/db mice and STZ-induced diabetes serum, urinary, and renal cortex ACE2 were increased. This study suggests that urinary ACE2 reflected renal rather than systemic source.Google Scholar
  8. 8.
    Lambert DW, Yarski M, Warner FJ, Thornhill P, Parkin ET, Smith AI, et al. 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. 2005;280(34):30113–9.Google Scholar
  9. 9.
    Rice GI, Thomas DA, Grant PJ, Turner AJ, Hooper NM. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J. 2004;383(Pt 1):45–51.PubMedCentralPubMedGoogle Scholar
  10. 10.
    Kazemi-Bajestani SM, Patel VB, Wang W, Oudit GY. Targeting the ACE2 and Apelin Pathways Are Novel Therapies for Heart Failure: Opportunities and Challenges. Cardiol Res Pract. 2012;2012:823193.PubMedCentralPubMedGoogle Scholar
  11. 11.
    Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000;87(5):E1–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000;275(43):33238–43.PubMedCrossRefGoogle Scholar
  13. 13.
    Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE, et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature. 2002;417(6891):822–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Trask AJ, Averill DB, Ganten D, Chappell MC, Ferrario CM. Primary role of angiotensin-converting enzyme-2 in cardiac production of angiotensin-(1-7) in transgenic Ren-2 hypertensive rats. Am J Physiol Heart Circ Physiol. 2007;292(6):H3019–24.PubMedCrossRefGoogle Scholar
  15. 15.
    Trask AJ, Groban L, Westwood BM, Varagic J, Ganten D, Gallagher PE, et al. Inhibition of angiotensin-converting enzyme 2 exacerbates cardiac hypertrophy and fibrosis in Ren-2 hypertensive rats. Am J Hypertens. 2010;23(6):687–93.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Kassiri Z, Zhong J, Guo D, Basu R, Wang X, Liu PP, et al. Loss of angiotensin-converting enzyme 2 accelerates maladaptive left ventricular remodeling in response to myocardial infarction. Circ Heart Fail. 2009;2(5):446–55.PubMedCrossRefGoogle Scholar
  17. 17.
    Kim MA, Yang D, Kida K, Molotkova N, Yeo SJ, Varki N, et al. Effects of ACE2 inhibition in the post-myocardial infarction heart. J Card Fail. 2010;16(9):777–85.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.•
    Patel VB, Bodiga S, Basu R, Das SK, Wang W, Wang Z, et al. Loss of angiotensin-converting enzyme-2 exacerbates diabetic cardiovascular complications and leads to systolic and vascular dysfunction: a critical role of the angiotensin II/AT1 receptor axis. Circ Res. 2012;110(10):1322–35. This study pinpoints the crucial role of ACE2 in development of diabetic cardiomyopathy through Ang II-dependent mechanisms.Google Scholar
  19. 19.
    Oudit GY, Kassiri Z, Patel MP, Chappell M, Butany J, Backx PH, et al. Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE2 null mice. Cardiovasc Res. 2007;75(1):29–39.PubMedCrossRefGoogle Scholar
  20. 20.•
    Zhong J, Basu R, Guo D, Chow FL, Byrns S, Schuster M, et al. Angiotensin-converting enzyme 2 suppresses pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction. Circulation. 2010;122(7):717–28. This comprehensive study provides critical evidence for beneficial effects of hrACE2 in Ang II- and pressure overload-induced cardiac remodeling and dysfunction. The cardioprotection was associated with attenuation of signaling pathways and molecules relevant for hypertrophy, fibrosis, and oxidative stress and correlated with reduction in Ang II and elevation in Ang-(1-7).Google Scholar
  21. 21.
    Bodiga S, Zhong JC, Wang W, Basu R, Lo J, Liu GC, et al. Enhanced susceptibility to biomechanical stress in ACE2 null mice is prevented by loss of the p47(phox) NADPH oxidase subunit. Cardiovasc Res. 2011;91(1):151–61.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Yamamoto K, Ohishi M, Katsuya T, Ito N, Ikushima M, Kaibe M, et al. Deletion of angiotensin-converting enzyme 2 accelerates pressure overload-induced cardiac dysfunction by increasing local angiotensin II. Hypertension. 2006;47(4):718–26.PubMedCrossRefGoogle Scholar
  23. 23.•
    Patel VB, Bodiga S, Fan D, Das SK, Wang Z, Wang W, et al. Cardioprotective effects mediated by angiotensin II type 1 receptor blockade and enhancing angiotensin 1-7 in experimental heart failure in angiotensin-converting enzyme 2-null mice. Hypertension. 2012;59(6):1195–203. When ACE2 is absent, a blockade of Ang II action or Ang-(1-7) supplementation provides comparable cardioprotection in an experimental model of heart failure due to pressure overload revealing striking redundancy of these two counterregulatory mechanisms.Google Scholar
  24. 24.
    Zisman LS, Keller RS, Weaver B, Lin Q, Speth R, Bristow MR, et al. Increased angiotensin-(1-7)-forming activity in failing human heart ventricles: evidence for upregulation of the angiotensin-converting enzyme Homologue ACE2. Circulation. 2003;108(14):1707–12.PubMedCrossRefGoogle Scholar
  25. 25.
    Burrell LM, Risvanis J, Kubota E, Dean RG, MacDonald PS, Lu S, et al. Myocardial infarction increases ACE2 expression in rat and humans. Eur Heart J. 2005;26(4):369–75.PubMedCrossRefGoogle Scholar
  26. 26.
    Goulter AB, Goddard MJ, Allen JC, Clark KL. ACE2 gene expression is up-regulated in the human failing heart. BMC Med. 2004;2:19.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Ohtsuki M, Morimoto S, Izawa H, Ismail TF, Ishibashi-Ueda H, Kato Y, et al. Angiotensin converting enzyme 2 gene expression increased compensatory for left ventricular remodeling in patients with end-stage heart failure. Int J Cardiol. 2010;145(2):333–4.PubMedCrossRefGoogle Scholar
  28. 28.•
    Wang Y, Moreira MC, Heringer-Walther S, Ebermann L, Schultheiss HP, Wessel N, et al. Plasma ACE2 activity is an independent prognostic marker in Chagas' disease and equally potent as BNP. J Card Fail. 2010;16(2):157–63. This study suggests that measurements of both ACE2 activity and BNP may be of greater value in prediction morbidity and mortality in patients with heart failure.Google Scholar
  29. 29.
    Zhao YX, Yin HQ, Yu QT, Qiao Y, Dai HY, Zhang MX, et al. ACE2 overexpression ameliorates left ventricular remodeling and dysfunction in a rat model of myocardial infarction. Hum Gene Ther. 2010;21(11):1545–54.PubMedCrossRefGoogle Scholar
  30. 30.
    Ishiyama Y, Gallagher PE, Averill DB, Tallant EA, Brosnihan KB, Ferrario CM. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension. 2004;43(5):970–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Inaba S, Iwai M, Furuno M, Kanno H, Senba I, Okayama H, et al. Role of angiotensin-converting enzyme 2 in cardiac hypertrophy induced by nitric oxide synthase inhibition. J Hypertens. 2011;29(11):2236–45.PubMedCrossRefGoogle Scholar
  32. 32.
    Sukumaran V, Veeraveedu PT, Gurusamy N, Yamaguchi K, Lakshmanan AP, Ma M, et al. Cardioprotective effects of telmisartan against heart failure in rats induced by experimental autoimmune myocarditis through the modulation of angiotensin-converting enzyme-2/angiotensin 1-7/mas receptor axis. Int J Biol Sci. 2011;7(8):1077–92.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Ferrario CM, Jessup J, Gallagher PE, Averill DB, Brosnihan KB, Ann TE, et al. Effects of renin-angiotensin system blockade on renal angiotensin-(1-7) forming enzymes and receptors. Kidney Int. 2005;68(5):2189–96.PubMedCrossRefGoogle Scholar
  34. 34.
    Ferrario CM, Jessup J, Chappell MC, Averill DB, Brosnihan KB, Tallant EA, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005;111(20):2605–10.PubMedCrossRefGoogle Scholar
  35. 35.
    Gallagher PE, Chappell MC, Ferrario CM, Tallant EA. Distinct roles for ANG II and ANG-(1-7) in the regulation of angiotensin-converting enzyme 2 in rat astrocytes. Am J Physiol Cell Physiol. 2006;290(2):C420–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Gallagher PE, Ferrario CM, Tallant EA. MAP kinase/phosphatase pathway mediates the regulation of ACE2 by angiotensin peptides. Am J Physiol Cell Physiol. 2008;295(5):C1169–74.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Jessup JA, Gallagher PE, Averill DB, Brosnihan KB, Tallant EA, Chappell MC, et al. Effect of angiotensin II blockade on a new congenic model of hypertension derived from transgenic Ren-2 rats. Am J Physiol Heart Circ Physiol. 2006;291(5):H2166–72.PubMedCrossRefGoogle Scholar
  38. 38.
    Gallagher PE, Ferrario CM, Tallant EA. Regulation of ACE2 in cardiac myocytes and fibroblasts. Am J Physiol Heart Circ Physiol. 2008;295(6):H2373–9.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Qi Y, Shenoy V, Wong F, Li H, Afzal A, Mocco J, et al. Lentivirus-mediated overexpression of angiotensin-(1-7) attenuated ischaemia-induced cardiac pathophysiology. Exp Physiol. 2011;96(9):863–74.PubMedCentralPubMedGoogle Scholar
  40. 40.
    Lin CS, Pan CH, Wen CH, Yang TH, Kuan TC. Regulation of angiotensin converting enzyme II by angiotensin peptides in human cardiofibroblasts. Peptides. 2010;31(7):1334–40.PubMedCrossRefGoogle Scholar
  41. 41.
    Lieb W, Graf J, Gotz A, Konig IR, Mayer B, Fischer M, et al. Association of angiotensin-converting enzyme 2 (ACE2) gene polymorphisms with parameters of left ventricular hypertrophy in men. Results of the MONICA Augsburg echocardiographic substudy. J Mol Med (Berl). 2006;84(1):88–96.CrossRefGoogle Scholar
  42. 42.
    Patel SK, Wai B, Ord M, MacIsaac RJ, Grant S, Velkoska E, et al. Association of ACE2 genetic variants with blood pressure, left ventricular mass, and cardiac function in Caucasians with type 2 diabetes. Am J Hypertens. 2012;25(2):216–22.PubMedCrossRefGoogle Scholar
  43. 43.
    van der Merwe L, Cloete R, Revera M, Heradien M, Goosen A, Corfield VA, et al. Genetic variation in angiotensin-converting enzyme 2 gene is associated with extent of left ventricular hypertrophy in hypertrophic cardiomyopathy. Hum Genet. 2008;124(1):57–61.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Wang SX, Fu CY, Zou YB, Wang H, Shi Y, Xu XQ, et al. Polymorphisms of angiotensin-converting enzyme 2 gene associated with magnitude of left ventricular hypertrophy in male patients with hypertrophic cardiomyopathy. Chin Med J (Engl). 2008;121(1):27–31.Google Scholar
  45. 45.
    Yang W, Huang W, Su S, Li B, Zhao W, Chen S, et al. Association study of ACE2 (angiotensin I-converting enzyme 2) gene polymorphisms with coronary heart disease and myocardial infarction in a Chinese Han population. Clin Sci (Lond). 2006;111(5):333–40.CrossRefGoogle Scholar
  46. 46.
    Chaoxin J, Daili S, Yanxin H, Ruwei G, Chenlong W, Yaobin T. The influence of angiotensin-converting enzyme 2 gene polymorphisms on type 2 diabetes mellitus and coronary heart disease. Eur Rev Med Pharmacol Sci. 2013;17(19):2654–9.PubMedGoogle Scholar
  47. 47.
    Huang W, Yang W, Wang Y, Zhao Q, Gu D, Chen R. Association study of angiotensin-converting enzyme 2 gene (ACE2) polymorphisms and essential hypertension in northern Han Chinese. J Hum Hypertens. 2006;20(12):968–71.PubMedCrossRefGoogle Scholar
  48. 48.
    Zhong J, Yan Z, Liu D, Ni Y, Zhao Z, Zhu S, et al. Association of angiotensin-converting enzyme 2 gene A/G polymorphism and elevated blood pressure in Chinese patients with metabolic syndrome. J Lab Clin Med. 2006;147(2):91–5.PubMedCrossRefGoogle Scholar
  49. 49.
    Lu N, Yang Y, Wang Y, Liu Y, Fu G, Chen D, et al. ACE2 gene polymorphism and essential hypertension: an updated meta-analysis involving 11,051 subjects. Mol Biol Rep. 2012;39(6):6581–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Fan X, Wang Y, Sun K, Zhang W, Yang X, Wang S, et al. Polymorphisms of ACE2 gene are associated with essential hypertension and antihypertensive effects of Captopril in women. Clin Pharmacol Ther. 2007;82(2):187–96.PubMedCrossRefGoogle Scholar
  51. 51.
    Benjafield AV, Wang WY, Morris BJ. No association of angiotensin-converting enzyme 2 gene (ACE2) polymorphisms with essential hypertension. Am J Hypertens. 2004;17(7):624–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Zhou JB, Yang JK. Meta-analysis of association of ACE2 G8790A polymorphism with Chinese Han essential hypertension. J Renin Angiotensin Aldosterone Syst. 2009;10(1):31–4.PubMedCrossRefGoogle Scholar
  53. 53.
    Sotoodehnia N, Li G, Johnson CO, Lemaitre RN, Rice KM, Rea TD, et al. Genetic variation in angiotensin-converting enzyme-related pathways associated with sudden cardiac arrest risk. Heart Rhythm. 2009;6(9):1306–14.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Lely AT, Hamming I, van GH, Navis GJ. Renal ACE2 expression in human kidney disease. J Pathol. 2004;204(5):587–93.Google Scholar
  55. 55.
    Soler MJ, Ye M, Wysocki J, William J, Lloveras J, Batlle D. Localization of ACE2 in the renal vasculature: amplification by angiotensin II type 1 receptor blockade using telmisartan. Am J Physiol Renal Physiol. 2009;296(2):F398–405.PubMedCrossRefGoogle Scholar
  56. 56.
    Ye M, Wysocki J, William J, Soler MJ, Cokic I, Batlle D. Glomerular localization and expression of Angiotensin-converting enzyme 2 and Angiotensin-converting enzyme: implications for albuminuria in diabetes. J Am Soc Nephrol. 2006;17(11):3067–75.PubMedCrossRefGoogle Scholar
  57. 57.
    Mizuiri S, Hemmi H, Arita M, Ohashi Y, Tanaka Y, Miyagi M, et al. Expression of ACE and ACE2 in individuals with diabetic kidney disease and healthy controls. Am J Kidney Dis. 2008;51(4):613–23.PubMedCrossRefGoogle Scholar
  58. 58.
    Tikellis C, Johnston CI, Forbes JM, Burns WC, Burrell LM, Risvanis J, et al. Characterization of renal angiotensin-converting enzyme 2 in diabetic nephropathy. Hypertension. 2003;41(3):392–7.PubMedCrossRefGoogle Scholar
  59. 59.
    Wysocki J, Ye M, Soler MJ, Gurley SB, Xiao HD, Bernstein KE, et al. ACE and ACE2 activity in diabetic mice. Diabetes. 2006;55(7):2132–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Oudit GY, Herzenberg AM, Kassiri Z, Wong D, Reich H, Khokha R, et al. Loss of angiotensin-converting enzyme-2 leads to the late development of angiotensin II-dependent glomerulosclerosis. Am J Pathol. 2006;168(6):1808–20.PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Wong DW, Oudit GY, Reich H, Kassiri Z, Zhou J, Liu QC, et al. Loss of angiotensin-converting enzyme-2 (Ace2) accelerates diabetic kidney injury. Am J Pathol. 2007;171(2):438–51.PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Liu Z, Huang XR, Chen HY, Penninger JM, Lan HY. Loss of angiotensin-converting enzyme 2 enhances TGF-beta/Smad-mediated renal fibrosis and NF-kappaB-driven renal inflammation in a mouse model of obstructive nephropathy. Lab Invest. 2012;92(5):650–61.PubMedCrossRefGoogle Scholar
  63. 63.
    Gurley SB, Allred A, Le TH, Griffiths R, Mao L, Philip N, et al. Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice. J Clin Invest. 2006;116(8):2218–25.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Zhong J, Guo D, Chen CB, Wang W, Schuster M, Loibner H, et al. Prevention of angiotensin II-mediated renal oxidative stress, inflammation, and fibrosis by angiotensin-converting enzyme 2. Hypertension. 2011;57(2):314–22.PubMedCrossRefGoogle Scholar
  65. 65.
    Soler MJ, Wysocki J, Ye M, Lloveras J, Kanwar Y, Batlle D. ACE2 inhibition worsens glomerular injury in association with increased ACE expression in streptozotocin-induced diabetic mice. Kidney Int. 2007;72(5):614–23.PubMedCrossRefGoogle Scholar
  66. 66.
    Prieto MC, Gonzalez-Villalobos RA, Botros FT, Martin VL, Pagan J, Satou R, et al. Reciprocal changes in renal ACE/ANG II and ACE2/ANG 1-7 are associated with enhanced collecting duct renin in Goldblatt hypertensive rats. Am J Physiol Renal Physiol. 2011;300(3):F749–55.PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Zhong JC, Huang DY, Yang YM, Li YF, Liu GF, Song XH, et al. Upregulation of angiotensin-converting enzyme 2 by all-trans retinoic acid in spontaneously hypertensive rats. Hypertension. 2004;44(6):907–12.PubMedCrossRefGoogle Scholar
  68. 68.
    Tikellis C, Cooper ME, Bialkowski K, Johnston CI, Burns WC, Lew RA, et al. Developmental expression of ACE2 in the SHR kidney: a role in hypertension? Kidney Int. 2006;70(1):34–41.PubMedCrossRefGoogle Scholar
  69. 69.
    Samuel P, Ali Q, Sabuhi R, Wu Y, Hussain T. High Na intake increases renal angiotensin II levels and reduces expression of the ACE2-AT(2)R-MasR axis in obese Zucker rats. Am J Physiol Renal Physiol. 2012;303(3):F412–9.PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Bernardi S, Toffoli B, Zennaro C, Tikellis C, Monticone S, Losurdo P, et al. High-salt diet increases glomerular ACE/ACE2 ratio leading to oxidative stress and kidney damage. Nephrol Dial Transplant. 2012;27(5):1793–800.PubMedCrossRefGoogle Scholar
  71. 71.
    Wakahara S, Konoshita T, Mizuno S, Motomura M, Aoyama C, Makino Y, et al. Synergistic expression of angiotensin-converting enzyme (ACE) and ACE2 in human renal tissue and confounding effects of hypertension on the ACE to ACE2 ratio. Endocrinology. 2007;148(5):2453–7.PubMedCrossRefGoogle Scholar
  72. 72.
    Mizuiri S, Hemmi H, Arita M, Aoki T, Ohashi Y, Miyagi M, et al. Increased ACE and decreased ACE2 expression in kidneys from patients with IgA nephropathy. Nephron Clin Pract. 2011;117(1):c57–66.PubMedCrossRefGoogle Scholar
  73. 73.
    Reich HN, Oudit GY, Penninger JM, Scholey JW, Herzenberg AM. Decreased glomerular and tubular expression of ACE2 in patients with type 2 diabetes and kidney disease. Kidney Int. 2008;74(12):1610–6.PubMedCrossRefGoogle Scholar
  74. 74.•
    Nadarajah R, Milagres R, Dilauro M, Gutsol A, Xiao F, Zimpelmann J, et al. Podocyte-specific overexpression of human angiotensin-converting enzyme 2 attenuates diabetic nephropathy in mice. Kidney Int. 2012;82(3):292–303. This study provides critical evidence that podocyte-specific overexpression of hACE2 transiently attenuated the development of diabetic nephropathy.Google Scholar
  75. 75.
    Currie D, McKnight AJ, Patterson CC, Sadlier DM, Maxwell AP. Investigation of ACE, ACE2 and AGTR1 genes for association with nephropathy in Type 1 diabetes mellitus. Diabet Med. 2010;27(10):1188–94.PubMedCrossRefGoogle Scholar
  76. 76.
    Frojdo S, Sjolind L, Parkkonen M, Makinen VP, Kilpikari R, Pettersson-Fernholm K, et al. Polymorphisms in the gene encoding angiotensin I converting enzyme 2 and diabetic nephropathy. Diabetologia. 2005;48(11):2278–81.PubMedCrossRefGoogle Scholar
  77. 77.
    Dilauro M, Zimpelmann J, Robertson SJ, Genest D, Burns KD. Effect of ACE2 and angiotensin-(1-7) in a mouse model of early chronic kidney disease. Am J Physiol Renal Physiol. 2010;298(6):F1523–32.PubMedCrossRefGoogle Scholar
  78. 78.
    Velkoska E, Dean RG, Burchill L, Levidiotis V, Burrell LM. Reduction in renal ACE2 expression in subtotal nephrectomy in rats is ameliorated with ACE inhibition. Clin Sci (Lond). 2010;118(4):269–79.CrossRefGoogle Scholar
  79. 79.
    Velkoska E, Dean RG, Griggs K, Burchill L, Burrell LM. Angiotensin-(1-7) infusion is associated with increased blood pressure and adverse cardiac remodelling in rats with subtotal nephrectomy. Clin Sci (Lond). 2011;120(8):335–45.CrossRefGoogle Scholar
  80. 80.
    Zimpelmann J, Burns KD. Angiotensin-(1-7) activates growth-stimulatory pathways in human mesangial cells. Am J Physiol Renal Physiol. 2009;296(2):F337–46.PubMedCrossRefGoogle Scholar
  81. 81.
    Yang XH, Wang YH, Wang JJ, Liu YC, Deng W, Qin C, et al. Role of angiotensin-converting enzyme (ACE and ACE2) imbalance on tourniquet-induced remote kidney injury in a mouse hindlimb ischemia-reperfusion model. Peptides. 2012;36(1):60–70.PubMedCrossRefGoogle Scholar
  82. 82.•
    Ali Q, Wu Y, Hussain T. Chronic AT2 receptor activation increases renal ACE2 activity, attenuates AT1 receptor function and blood pressure in obese Zucker rats. Kidney Int. 2013;84(5):931–9. This is the first study to show a contribution of AT2 receptor in the regulation of renal ACE2 of obese Zuker rats. ACE2 and related Ang-(1-7) upregulation was associated with reduction of blood pressure and increased urinary sodium excretion. AT2 receptor agonist increased ACE2 activity in HK-2 cells confirming a direct effect of AT2 activation in enhancing ACE2/Ang-(1-7) axis.Google Scholar
  83. 83.
    Koka V, Huang XR, Chung AC, Wang W, Truong LD, Lan HY. Angiotensin II up-regulates angiotensin I-converting enzyme (ACE), but down-regulates ACE2 via the AT1-ERK/p38 MAP kinase pathway. Am J Pathol. 2008;172(5):1174–83.PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Varagic J, Ahmad S, VonCannon JL, Moniwa N, Brosnihan KB, Wysocki J, et al. Predominance of AT(1) blockade over mas-mediated angiotensin-(1-7) mechanisms in the regulation of blood pressure and renin-angiotensin system in mRen2.Lewis rats. Am J Hypertens. 2013;26(5):583–90.PubMedCrossRefGoogle Scholar
  85. 85.
    Tikellis C, Bialkowski K, Pete J, Sheehy K, Su Q, Johnston C, et al. ACE2 deficiency modifies renoprotection afforded by ACE inhibition in experimental diabetes. Diabetes. 2008;57(4):1018–25.PubMedCrossRefGoogle Scholar
  86. 86.
    Lew RA, Warner FJ, Hanchapola I, Yarski MA, Manohar J, Burrell LM, et al. Angiotensin-converting enzyme 2 catalytic activity in human plasma is masked by an endogenous inhibitor. Exp Physiol. 2008;93(5):685–93.PubMedCrossRefGoogle Scholar
  87. 87.
    Roberts MA, Velkoska E, Ierino FL, Burrell LM. Angiotensin-converting enzyme 2 activity in patients with chronic kidney disease. Nephrol Dial Transplant. 2013;28(9):2287–94.PubMedCrossRefGoogle Scholar
  88. 88.
    Epelman S, Tang WH, Chen SY, Van LF, Francis GS, Sen S. Detection of soluble angiotensin-converting enzyme 2 in heart failure: insights into the endogenous counter-regulatory pathway of the renin-angiotensin-aldosterone system. J Am Coll Cardiol. 2008;52(9):750–4.PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Ortiz-Perez JT, Riera M, Bosch X, De Caralt TM, Perea RJ, Pascual J, et al. Role of circulating angiotensin converting enzyme 2 in left ventricular remodeling following myocardial infarction: a prospective controlled study. PLoS One. 2013;8(4):e61695.PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Shao Z, Shrestha K, Borowski AG, Kennedy DJ, Epelman S, Thomas JD, et al. Increasing serum soluble angiotensin-converting enzyme 2 activity after intensive medical therapy is associated with better prognosis in acute decompensated heart failure. J Card Fail. 2013;19(9):605–10.PubMedCrossRefGoogle Scholar
  91. 91.
    Soro-Paavonen A, Gordin D, Forsblom C, Rosengard-Barlund M, Waden J, Thorn L, et al. Circulating ACE2 activity is increased in patients with type 1 diabetes and vascular complications. J Hypertens. 2012;30(2):375–83.PubMedCrossRefGoogle Scholar
  92. 92.
    Wang G, Lai FM, Lai KB, Chow KM, Kwan CH, Li KT, et al. Urinary mRNA expression of ACE and ACE2 in human type 2 diabetic nephropathy. Diabetologia. 2008;51(6):1062–7.PubMedCrossRefGoogle Scholar
  93. 93.
    Park SE, Kim WJ, Park SW, Park JW, Lee N, Park CY, et al. High urinary ACE2 concentrations are associated with severity of glucose intolerance and microalbuminuria. Eur J Endocrinol. 2013;168(2):203–10.PubMedCrossRefGoogle Scholar
  94. 94.
    Yamaleyeva LM, Gilliam-Davis S, Almeida I, Brosnihan KB, Lindsey SH, Chappell MC. Differential regulation of circulating and renal ACE2 and ACE in hypertensive mRen2.Lewis rats with early-onset diabetes. Am J Physiol Renal Physiol. 2012;302(11):F1374–84.PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Soler MJ, Riera M, Crespo M, Mir M, Marquez E, Pascual MJ, et al. Circulating angiotensin-converting enzyme 2 activity in kidney transplantation: a longitudinal pilot study. Nephron Clin Pract. 2012;121(3–4):c144–50.PubMedCrossRefGoogle Scholar
  96. 96.
    Barretti DL, Magalhaes FC, Fernandes T, do Carmo EC, Rosa KT, Irigoyen MC, et al. Effects of aerobic exercise training on cardiac renin-angiotensin system in an obese Zucker rat strain. PLoS One. 2012;7(10):e46114.PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.•
    Fernandes T, Hashimoto NY, Magalhaes FC, Fernandes FB, Casarini DE, Carmona AK, et al. Aerobic exercise training-induced left ventricular hypertrophy involves regulatory MicroRNAs, decreased angiotensin-converting enzyme-angiotensin ii, and synergistic regulation of angiotensin-converting enzyme 2-angiotensin (1-7). Hypertension. 2011;58(2):182–9. This study suggests a regulatory role for specific microRNAs in reciprocal regulation of cardiac ACE and ACE2 as an underlying cardioprotective molecular mechanism for the development of non-pathological left ventricular hypertrophy in response to aerobic exercise.Google Scholar
  98. 98.
    Oudit GY, Liu GC, Zhong J, Basu R, Chow FL, Zhou J, et al. Human recombinant ACE2 reduces the progression of diabetic nephropathy. Diabetes. 2010;59(2):529–38.PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    Lo J, Patel VB, Wang Z, Levasseur J, Kaufman S, Penninger JM, et al. Angiotensin-converting enzyme 2 antagonizes angiotensin II-induced pressor response and NADPH oxidase activation in Wistar-Kyoto rats and spontaneously hypertensive rats. Exp Physiol. 2013;98(1):109–22.PubMedCrossRefGoogle Scholar
  100. 100.
    Wysocki J, Ye M, Rodriguez E, Gonzalez-Pacheco FR, Barrios C, Evora K, et al. Targeting the degradation of angiotensin II with recombinant angiotensin-converting enzyme 2: prevention of angiotensin II-dependent hypertension. Hypertension. 2010;55(1):90–8.PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    Ye M, Wysocki J, Gonzalez-Pacheco FR, Salem M, Evora K, Garcia-Halpin L, et al. Murine recombinant angiotensin-converting enzyme 2: effect on angiotensin II-dependent hypertension and distinctive angiotensin-converting enzyme 2 inhibitor characteristics on rodent and human angiotensin-converting enzyme 2. Hypertension. 2012;60(3):730–40.PubMedCentralPubMedCrossRefGoogle Scholar
  102. 102.
    Huentelman MJ, Grobe JL, Vazquez J, Stewart JM, Mecca AP, Katovich MJ, et al. Protection from angiotensin II-induced cardiac hypertrophy and fibrosis by systemic lentiviral delivery of ACE2 in rats. Exp Physiol. 2005;90(5):783–90.PubMedCrossRefGoogle Scholar
  103. 103.
    Dong B, Yu QT, Dai HY, Gao YY, Zhou ZL, Zhang L, et al. Angiotensin-converting enzyme-2 overexpression improves left ventricular remodeling and function in a rat model of diabetic cardiomyopathy. J Am Coll Cardiol. 2012;59(8):739–47.PubMedCrossRefGoogle Scholar
  104. 104.
    Liu CX, Hu Q, Wang Y, Zhang W, Ma ZY, Feng JB, et al. Angiotensin-converting enzyme (ACE) 2 overexpression ameliorates glomerular injury in a rat model of diabetic nephropathy: a comparison with ACE inhibition. Mol Med. 2011;17(1–2):59–69.PubMedCentralPubMedGoogle Scholar
  105. 105.
    Hernandez Prada JA, Ferreira AJ, Katovich MJ, Shenoy V, Qi Y, Santos RA, et al. Structure-based identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents. Hypertension. 2008;51(5):1312–7.PubMedCrossRefGoogle Scholar
  106. 106.
    Murca TM, Moraes PL, Capuruco CA, Santos SH, Melo MB, Santos RA, et al. Oral administration of an angiotensin-converting enzyme 2 activator ameliorates diabetes-induced cardiac dysfunction. Regul Pept. 2012;177(1–3):107–15.PubMedCentralPubMedCrossRefGoogle Scholar
  107. 107.
    Burchill LJ, Velkoska E, Dean RG, Griggs K, Patel SK, Burrell LM. Combination renin-angiotensin system blockade and angiotensin-converting enzyme 2 in experimental myocardial infarction: implications for future therapeutic directions. Clin Sci (Lond). 2012;123(11):649–58.CrossRefGoogle Scholar
  108. 108.
    Wei CC, Hase N, Inoue Y, Bradley EW, Yahiro E, Li M, et al. Mast cell chymase limits the cardiac efficacy of Ang I-converting enzyme inhibitor therapy in rodents. J Clin Invest. 2010;120(4):1229–39.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Jasmina Varagic
    • 1
    • 2
    • 3
  • Sarfaraz Ahmad
    • 2
  • Sayaka Nagata
    • 2
  • Carlos M. Ferrario
    • 2
    • 3
    • 4
  1. 1.Hypertension & Vascular Research Center, Division of Surgical SciencesWake Forest University School of MedicineWinston-SalemUSA
  2. 2.Division of Surgical SciencesWake Forest University School of MedicineWinston-SalemUSA
  3. 3.Department of Physiology and PharmacologyWake Forest University School of MedicineWinston-SalemUSA
  4. 4.Department of Internal Medicine and NephrologyWake Forest University School of MedicineWinston-SalemUSA

Personalised recommendations