Cellular and Molecular Life Sciences

, Volume 75, Issue 19, pp 3625–3634 | Cite as

Depletion of angiotensin-converting enzyme 2 reduces brain serotonin and impairs the running-induced neurogenic response

  • Friederike KlempinEmail author
  • Valentina Mosienko
  • Susann Matthes
  • Daniel C. Villela
  • Mihail Todiras
  • Josef M. Penninger
  • Michael Bader
  • Robson A. S. Santos
  • Natalia Alenina
Original Article


Physical exercise induces cell proliferation in the adult hippocampus in rodents. Serotonin (5-HT) and angiotensin (Ang) II are important mediators of the pro-mitotic effect of physical activity. Here, we examine precursor cells in the adult brain of mice lacking angiotensin-converting enzyme (ACE) 2, and explore the effect of an acute running stimulus on neurogenesis. ACE2 metabolizes Ang II to Ang-(1–7) and is essential for the intestinal uptake of tryptophan (Trp), the 5-HT precursor. In ACE2-deficient mice, we observed a decrease in brain 5-HT levels and no increase in the number of BrdU-positive cells following exercise. Targeting the Ang II/AT1 axis by blocking the receptor, or experimentally increasing Trp/5-HT levels in the brain of ACE2-deficient mice, did not rescue the running-induced effect. Furthermore, mice lacking the Ang-(1–7) receptor, Mas, presented a normal neurogenic response to exercise. Our results identify ACE2 as a novel factor required for exercise-dependent modulation of adult neurogenesis and essential for 5-HT metabolism.


5-HT BrdU Hippocampus Physical exercise Neurobiology 



This work was supported by Deutsche Forschungsgemeinschaft (DFG) award KL 2805/1-1 to F.K., the Brazilian fellowship BJT 407352/2013-9 to N.A., the German Academic Exchange Service (DAAD)/the Brazilian National Council for Scientific and Technological Development (CNPq) program PROBRAL to N.A. and R.A.S.S, and RSF Grant 14-50-00069 to N.A. The authors thank Susanne da Costa Goncalves, Sabine Grüger, Charlene Memler, and Thorsten Riepenhausen for their excellent technical assistance.

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interests.


  1. 1.
    Altman J, Das GD (1965) Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124(3):319–335CrossRefPubMedGoogle Scholar
  2. 2.
    Kempermann G, Kuhn HG, Gage FH (1997) More hippocampal neurons in adult mice living in an enriched environment. Nature 386(6624):493–495CrossRefPubMedGoogle Scholar
  3. 3.
    van Praag H, Kempermann G, Gage FH (1999) Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 2(3):266–270CrossRefPubMedGoogle Scholar
  4. 4.
    Kronenberg G, Reuter K, Steiner B et al (2003) Subpopulations of proliferating cells of the adult hippocampus respond differently to physiologic neurogenic stimuli. J Comp Neurol 467(4):455–463CrossRefPubMedGoogle Scholar
  5. 5.
    Klempin F, Beis D, Mosienko V et al (2013) Serotonin is required for exercise-induced adult hippocampal neurogenesis. J Neurosci 33(19):8270–8275CrossRefPubMedGoogle Scholar
  6. 6.
    Chieffi S, Messina G, Villano I et al (2017) Exercise influence on hippocampal function: possible involvement of orexin-A. Front Physiol 8:85PubMedPubMedCentralGoogle Scholar
  7. 7.
    Fabel K, Fabel K, Tam B et al (2003) VEGF is necessary for exercise-induced adult hippocampal neurogenesis. Eur J Neurosci 18(10):2803–2812CrossRefPubMedGoogle Scholar
  8. 8.
    Trejo JL, Carro E, Torres-Aleman I (2001) Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J Neurosci 21(5):1628–1634CrossRefPubMedGoogle Scholar
  9. 9.
    Turner AJ, Hooper NM (2002) The angiotensin-converting enzyme gene family: genomics and pharmacology. Trends Pharmacol Sci 23(4):177–183CrossRefPubMedGoogle Scholar
  10. 10.
    Santos RA, Simoes e Silva AC, Maric C et al (2003) Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci USA 100(14):8258–8263CrossRefPubMedGoogle Scholar
  11. 11.
    Rabelo LA, Alenina N, Bader M (2011) ACE2-angiotensin-(1–7)-Mas axis and oxidative stress in cardiovascular disease. Hypertens Res 34(2):154–160CrossRefPubMedGoogle Scholar
  12. 12.
    Santos RA, Ferreira AJ, Verano-Braga T et al (2013) Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system. J Endocrinol 216(2):R1–R17CrossRefPubMedGoogle Scholar
  13. 13.
    Gironacci MM, Cerniello FM, Longo Carbajosa NA et al (2014) Protective axis of the renin–angiotensin system in the brain. Clin Sci (Lond) 127(5):295–306CrossRefGoogle Scholar
  14. 14.
    Xu P, Sriramula S, Lazartigues E (2011) ACE2/ANG-(1–7)/Mas pathway in the brain: the axis of good. Am J Physiol Regul Integr Comp Physiol 300(4):R804–R817CrossRefPubMedGoogle Scholar
  15. 15.
    Bunnemann B, Fuxe K, Metzger R et al (1990) Autoradiographic localization of mas proto-oncogene mRNA in adult rat brain using in situ hybridization. Neurosci Lett 114(2):147–153CrossRefPubMedGoogle Scholar
  16. 16.
    Doobay MF, Talman LS, Obr TD et al (2007) Differential expression of neuronal ACE2 in transgenic mice with overexpression of the brain renin–angiotensin system. Am J Physiol Regul Integr Comp Physiol 292(1):R373–R381CrossRefPubMedGoogle Scholar
  17. 17.
    Freund M, Walther T, von und Halbach BO (2012) Immunohistochemical localization of the angiotensin-(1–7) receptor Mas in the murine forebrain. Cell Tissue Res 348(1):29–35CrossRefPubMedGoogle Scholar
  18. 18.
    Kuba K, Imai Y, Rao S et al (2005) A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 11(8):875–879CrossRefPubMedGoogle Scholar
  19. 19.
    Camargo SM, Singer D, Makrides V et al (2009) Tissue-specific amino acid transporter partners ACE2 and collectrin differentially interact with Hartnup mutations. Gastroenterology 136(3):872–882CrossRefPubMedGoogle Scholar
  20. 20.
    Kowalczuk S, Broer A, Tietze N et al (2008) A protein complex in the brush-border membrane explains a Hartnup disorder allele. FASEB J 22(8):2880–2887CrossRefPubMedGoogle Scholar
  21. 21.
    Hashimoto T, Perlot T, Rehman A et al (2012) ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature 487(7408):477–481CrossRefPubMedGoogle Scholar
  22. 22.
    Singer D, Camargo SM, Ramadan T et al (2012) Defective intestinal amino acid absorption in Ace2 null mice. Am J Physiol Gastrointest Liver Physiol 303(6):G686–G695CrossRefPubMedGoogle Scholar
  23. 23.
    Duelli R, Enerson BE, Gerhart DZ et al (2000) Expression of large amino acid transporter LAT1 in rat brain endothelium. J Cereb Blood Flow Metab 20(11):1557–1562CrossRefPubMedGoogle Scholar
  24. 24.
    Alenina N, Klempin F (2015) The role of serotonin in adult hippocampal neurogenesis. Behav Brain Res 277:49–57CrossRefPubMedGoogle Scholar
  25. 25.
    Crackower MA, Sarao R, Oudit GY et al (2002) Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 417(6891):822–828CrossRefPubMedGoogle Scholar
  26. 26.
    Walther T, Balschun D, Voigt JP et al (1998) Sustained long term potentiation and anxiety in mice lacking the Mas protooncogene. J Biol Chem 273(19):11867–11873CrossRefPubMedGoogle Scholar
  27. 27.
    Marlatt MW, Lucassen PJ, van Praag H (2010) Comparison of neurogenic effects of fluoxetine, duloxetine and running in mice. Brain Res 1341:93–99CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Yamaguchi T, Sawada M, Kato T et al (1981) Demonstration of tryptophan 5-monooxygenase activity in human brain by high sensitive high-performance liquid chromatography with fluorometric detection. Biochem Int 2:295–303Google Scholar
  29. 29.
    Mosienko V, Matthes S, Hirth N et al (2014) Adaptive changes in serotonin metabolism preserve normal behavior in mice with reduced TPH2 activity. Neuropharmacology 85:73–80CrossRefPubMedGoogle Scholar
  30. 30.
    Kempermann G (2004) Milestones of neuronal development in the adult hippocampus. Trends Neurosci 27(8):447–452CrossRefPubMedGoogle Scholar
  31. 31.
    Gohlke P, Weiss S, Jansen A et al (2001) AT1 receptor antagonist telmisartan administered peripherally inhibits central responses to angiotensin II in conscious rats. J Pharmacol Exp Ther 298(1):62–70PubMedGoogle Scholar
  32. 32.
    Alenina N, Kikic D, Todiras M et al (2009) Growth retardation and altered autonomic control in mice lacking brain serotonin. Proc Natl Acad Sci USA 106(25):10332–10337CrossRefPubMedGoogle Scholar
  33. 33.
    Holmes MM, Galea LA, Mistlberger RE et al (2004) Adult hippocampal neurogenesis and voluntary running activity: circadian and dose-dependent effects. J Neurosci Res 76(2):216–222CrossRefPubMedGoogle Scholar
  34. 34.
    Motta-Santos D, Dos Santos RA, Oliveira M et al (2016) Effects of ACE2 deficiency on physical performance and physiological adaptations of cardiac and skeletal muscle to exercise. Hypertens Res 39(7):506–512CrossRefPubMedGoogle Scholar
  35. 35.
    Moon HY, Becke A, Berron D et al (2016) Running-induced systemic cathepsin B secretion is associated with memory function. Cell Metab 24(2):332–340CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Bindom SM, Lazartigues E (2009) The sweeter side of ACE2: physiological evidence for a role in diabetes. Mol Cell Endocrinol 302(2):193–202CrossRefPubMedGoogle Scholar
  37. 37.
    Dias-Peixoto MF, Santos RA, Gomes ER et al (2008) Molecular mechanisms involved in the angiotensin-(1–7)/Mas signaling pathway in cardiomyocytes. Hypertension (Dallas, Tex: 1979) 52(3):542–548CrossRefGoogle Scholar
  38. 38.
    Morales MG, Abrigo J, Acuna MJ et al (2016) Angiotensin-(1–7) attenuates disuse skeletal muscle atrophy in mice via its receptor, Mas. Dis Models Mech 9(4):441–449CrossRefGoogle Scholar
  39. 39.
    Santos SH, Fernandes LR, Mario EG et al (2008) Mas deficiency in FVB/N mice produces marked changes in lipid and glycemic metabolism. Diabetes 57(2):340–347CrossRefPubMedGoogle Scholar
  40. 40.
    Leite LH, Santiago HP, de Almeida RS et al (2013) Implications of angiotensin II in central nervous system on exercise performance. Curr Protein Pept Sci 14(8):711–720PubMedGoogle Scholar
  41. 41.
    Mukuda T, Koyama Y, Hamasaki S et al (2014) Systemic angiotensin II and exercise-induced neurogenesis in adult rat hippocampus. Brain Res 1588:92–103CrossRefPubMedGoogle Scholar
  42. 42.
    Guimaraes GG, Santos SH, Oliveira ML et al (2012) Exercise induces renin–angiotensin system unbalance and high collagen expression in the heart of Mas-deficient mice. Peptides 38(1):54–61CrossRefPubMedGoogle Scholar
  43. 43.
    Merritt JR, Rhodes JS (2015) Mouse genetic differences in voluntary wheel running, adult hippocampal neurogenesis and learning on the multi-strain-adapted plus water maze. Behav Brain Res 280:62–71CrossRefPubMedGoogle Scholar
  44. 44.
    Umschweif G, Shabashov D, Alexandrovich AG et al (2014) Neuroprotection after traumatic brain injury in heat-acclimated mice involves induced neurogenesis and activation of angiotensin receptor type 2 signaling. J Cereb Blood Flow Metab 34(8):1381–1390CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Vickers C, Hales P, Kaushik V et al (2002) Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem 277(17):14838–14843CrossRefPubMedGoogle Scholar
  46. 46.
    Chieffi S, Messina G, Villano I et al (2017) Neuroprotective effects of physical activity: evidence from human and animal studies. Front Neurol 8:188CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Wright JW, Harding JW (2011) Brain renin–angiotensin—a new look at an old system. Prog Neurobiol 95(1):49–67CrossRefPubMedGoogle Scholar
  48. 48.
    Hernandez AF, Harrington RA (2008) Comparative effectiveness of angiotensin-converting-enzyme inhibitors: is an ACE always an ace? CMAJ 178(10):1316–1319CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Imai Y, Kuba K, Rao S et al (2005) Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 436(7047):112–116CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Friederike Klempin
    • 1
    • 2
    Email author return OK on get
  • Valentina Mosienko
    • 1
    • 8
  • Susann Matthes
    • 1
  • Daniel C. Villela
    • 3
    • 9
  • Mihail Todiras
    • 1
  • Josef M. Penninger
    • 4
  • Michael Bader
    • 1
    • 2
    • 5
    • 6
  • Robson A. S. Santos
    • 3
  • Natalia Alenina
    • 1
    • 6
    • 7
  1. 1.Max-Delbrück-Center for Molecular MedicineBerlinGermany
  2. 2.Charité, University Medicine BerlinBerlinGermany
  3. 3.Federal University of Minas Gerais (UFmG), ICBBelo HorizonteBrazil
  4. 4.Institute of Molecular Biotechnology of the Austrian Academy of SciencesViennaAustria
  5. 5.Institute of BiologyUniversity of LübeckLübeckGermany
  6. 6.DZHK (German Centre for Cardiovascular Research), Partner Site BerlinBerlinGermany
  7. 7.Institute of Translational Biomedicine, St. Petersburg State UniversitySaint PetersburgRussia
  8. 8.University of Exeter Medical SchoolExeterUK
  9. 9.Federal University of Jequitinhonha and Mucuri ValleysDiamantinaBrazil

Personalised recommendations