ACE2 was observed as the cell surface receptor of the SARS-CoV-2 virus. Interestingly, we also found ACE2 positivity inside the cell nucleus. The ACE2 levels changed during cell differentiation and aging and varied in distinct cell types. We observed ACE2 depletion in the aortas of aging female mice, similarly, the aging caused ACE2 decrease in the kidneys. Compared with that in the heart, brain and kidneys, the ACE2 level was the lowest in the mouse lungs. In mice exposed to nicotine, ACE2 was not changed in olfactory bulbs but in the lungs, ACE2 was upregulated in females and downregulated in males. These observations indicate the distinct gender-dependent properties of ACE2. Differentiation into enterocytes, and cardiomyocytes, caused ACE2 depletion. The cardiomyogenesis was accompanied by renin upregulation, delayed in HDAC1-depleted cells. In contrast, vitamin D2 decreased the renin level while ACE2 was upregulated. Together, the ACE2 level is high in non-differentiated cells. This protein is more abundant in the tissues of mouse embryos and young mice in comparison with older animals. Mostly, downregulation of ACE2 is accompanied by renin upregulation. Thus, the pathophysiology of COVID-19 disease should be further studied not only by considering the ACE2 level but also the whole renin-angiotensin system.

Institute of Biophysics Academy of Sciences of the Czech Republic 612 65 Brno Czech Republic

Zobrazit více v PubMed

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; 383:45–51. 10.1042/BJ20040634 PubMed DOI PMC

Chung CM, Wang RY, Fann CS, Chen JW, Jong YS, Jou YS, Yang HC, Kang CS, Chen CC, Chang HC, Pan WH. Fine-mapping angiotensin-converting enzyme gene: separate QTLs identified for hypertension and for ACE activity. PLoS One. 2013; 8:e56119. 10.1371/journal.pone.0056119 PubMed DOI PMC

Burrell LM, Johnston CI, Tikellis C, Cooper ME. ACE2, a new regulator of the renin-angiotensin system. Trends Endocrinol Metab. 2004; 15:166–69. 10.1016/j.tem.2004.03.001 PubMed DOI PMC

Danilczyk U, Penninger JM. Angiotensin-converting enzyme II in the heart and the kidney. Circ Res. 2006; 98:463–71. 10.1161/01.RES.0000205761.22353.5f PubMed DOI

Wang W, Bodiga S, Das SK, Lo J, Patel V, Oudit GY. Role of ACE2 in diastolic and systolic heart failure. Heart Fail Rev. 2012; 17:683–91. 10.1007/s10741-011-9259-x PubMed DOI

Koitka A, Cooper ME, Thomas MC, Tikellis C. Angiotensin converting enzyme 2 in the kidney. Clin Exp Pharmacol Physiol. 2008; 35:420–25. 10.1111/j.1440-1681.2008.04889.x PubMed DOI PMC

Fang Y, Guo Z, Chai Y, Zhang H, Wang Z. [2019 novel coronavirus, renin-angiotension system imbalance and coronavirus disease 2019]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2020; 32:613–17. 10.3760/cma.j.cn121430-20200312-00159 PubMed DOI

Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003; 426:450–54. 10.1038/nature02145 PubMed DOI PMC

Feng Y, Ling Y, Bai T, Xie Y, Huang J, Li J, Xiong W, Yang D, Chen R, Lu F, Lu Y, Liu X, Chen Y, et al.. COVID-19 with different severities: a multicenter study of clinical features. Am J Respir Crit Care Med. 2020; 201:1380–88. 10.1164/rccm.202002-0445OC PubMed DOI PMC

Peng YD, Meng K, Guan HQ, Leng L, Zhu RR, Wang BY, He MA, Cheng LX, Huang K, Zeng QT. [Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV]. Zhonghua Xin Xue Guan Bing Za Zhi. 2020; 48:450–455. 10.3760/cma.j.cn112148-20200220-00105 PubMed DOI

Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J Virol. 2020; 94:e00127–20. 10.1128/JVI.00127-20 PubMed DOI PMC

Li F. Structure, function, and evolution of coronavirus spike proteins. Annu Rev Virol. 2016; 3:237–61. 10.1146/annurev-virology-110615-042301 PubMed DOI PMC

Bártová E, Pacherník J, Harnicarová A, Kovarík A, Kovaríková M, Hofmanová J, Skalníková M, Kozubek M, Kozubek S. Nuclear levels and patterns of histone H3 modification and HP1 proteins after inhibition of histone deacetylases. J Cell Sci. 2005; 118:5035–46. 10.1242/jcs.02621 PubMed DOI

Shaw G, Morse S, Ararat M, Graham FL. Preferential transformation of human neuronal cells by human adenoviruses and the origin of HEK 293 cells. FASEB J. 2002; 16:869–71. 10.1096/fj.01-0995fje PubMed DOI

Ilie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin Exp Res. 2020; 32:1195–98. 10.1007/s40520-020-01570-8 PubMed DOI PMC

Holmes KD, Mattar P, Marsh DR, Jordan V, Weaver LC, Dekaban GA. The C-terminal C1 cassette of the N-methyl-D-aspartate receptor 1 subunit contains a bi-partite nuclear localization sequence. J Neurochem. 2002; 81:1152–65. 10.1046/j.1471-4159.2002.00865.x PubMed DOI

Kesten D, Horovitz-Fried M, Brutman-Barazani T, Sampson SR. Insulin-induced translocation of IR to the nucleus in insulin responsive cells requires a nuclear translocation sequence. Biochim Biophys Acta Mol Cell Res. 2018; 1865:551–59. 10.1016/j.bbamcr.2018.01.004 PubMed DOI

Valyaeva AA, Zharikova AA, Kasianov AS, Vassetzky YS, Sheval EV. Expression of SARS-CoV-2 entry factors in lung epithelial stem cells and its potential implications for COVID-19. Sci Rep. 2020; 10:17772. 10.1038/s41598-020-74598-5 PubMed DOI PMC

Smith JC, Sausville EL, Girish V, Yuan ML, Vasudevan A, John KM, Sheltzer JM. Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract. Dev Cell. 2020; 53:514–29.e3. 10.1016/j.devcel.2020.05.012 PubMed DOI PMC

Klein SL. Sex influences immune responses to viruses, and efficacy of prophylaxis and treatments for viral diseases. Bioessays. 2012; 34:1050–59. 10.1002/bies.201200099 PubMed DOI PMC

Jin JM, Bai P, He W, Wu F, Liu XF, Han DM, Liu S, Yang JK. Gender Differences in Patients With COVID-19: Focus on Severity and Mortality. Front Public Health. 2020; 8:152. PubMed PMC

Jaggers GK, Watkins BA, Rodriguez RL. COVID-19: repositioning nutrition research for the next pandemic. Nutr Res. 2020; 81:1–6. 10.1016/j.nutres.2020.07.005 PubMed DOI PMC

Suchánková J, Legartová S, Ručková E, Vojtěšek B, Kozubek S, Bártová E. Mutations in the TP53 gene affected recruitment of 53BP1 protein to DNA lesions, but level of 53BP1 was stable after γ-irradiation that depleted MDC1 protein in specific TP53 mutants. Histochem Cell Biol. 2017; 148:239–55. 10.1007/s00418-017-1567-3 PubMed DOI

Feng XL, Fei HZ, Hu L. Dexamethasone induced apoptosis of A549 cells via the TGF-β1/Smad2 pathway. Oncol Lett. 2018; 15:2801–06. 10.3892/ol.2017.7696 PubMed DOI PMC

Zupkovitz G, Grausenburger R, Brunmeir R, Senese S, Tischler J, Jurkin J, Rembold M, Meunier D, Egger G, Lagger S, Chiocca S, Propst F, Weitzer G, Seiser C. The cyclin-dependent kinase inhibitor p21 is a crucial target for histone deacetylase 1 as a regulator of cellular proliferation. Mol Cell Biol. 2010; 30:1171–81. 10.1128/MCB.01500-09 PubMed DOI PMC

Arcidiacono OA, Krejčí J, Suchánková J, Bártová E. Deacetylation of histone H4 accompanying cardiomyogenesis is weakened in HDAC1-depleted ES cells. Int J Mol Sci. 2018; 19:2425. 10.3390/ijms19082425 PubMed DOI PMC

Kudová J, Vašíček O, Číž M, Kubala L. Melatonin promotes cardiomyogenesis of embryonic stem cells via inhibition of HIF-1α stabilization. J Pineal Res. 2016; 61:493–503. 10.1111/jpi.12366 PubMed DOI

Večeřa J, Bártová E, Krejčí J, Legartová S, Komůrková D, Rudá-Kučerová J, Štark T, Dražanová E, Kašpárek T, Šulcová A, Dekker FJ, Szymanski W, Seiser C, et al.. HDAC1 and HDAC3 underlie dynamic H3K9 acetylation during embryonic neurogenesis and in schizophrenia-like animals. J Cell Physiol. 2018; 233:530–48. 10.1002/jcp.25914 PubMed DOI PMC

Legartová S, Lochmanová G, Zdráhal Z, Kozubek S, Šponer J, Krepl M, Pokorná P, Bártová E. DNA damage changes distribution pattern and levels of HP1 protein isoforms in the nucleolus and increases phosphorylation of HP1β-Ser88. Cells. 2019; 8:1097. 10.3390/cells8091097 PubMed DOI PMC

Bártová E, Večeřa J, Krejčí J, Legartová S, Pacherník J, Kozubek S. The level and distribution pattern of HP1β in the embryonic brain correspond to those of H3K9me1/me2 but not of H3K9me3. Histochem Cell Biol. 2016; 145:447–61. 10.1007/s00418-015-1402-7 PubMed DOI

Jugová A, Sustáčková G, Legartová S, Stixová L, Kozubek S, Bártová E. Effects of epigenetic-based anti-cancer drugs in leukaemia and multiple myeloma cells. Cell Biol Int. 2011; 35:1195–203. 10.1042/CBI20100820 PubMed DOI

McKnight PE, Najab J. Mann-Whitney U Test. The Corsini encyclopedia of psychology. 2010:1–1.