Association of age distribution with the expression of angiotensin-converting enzyme 2 in lung tissues in severe acute respiratory syndrome coronavirus 2 infection: reflections from the study of RAS pathway expression in mice
LOU Li-Li, XIE Liang, HU Yu, CHEN Li-Na, LIANG Ping, SHI Fang, LIU Cai-Jun, LIU Han-Min
Department of Pediatric Respiratory Immunology, West China Second University Hospital, Sichuan University, Chengdu 610041, China
Abstract：Objective To study the expression of angiotensin-converting enzyme 2 (ACE2) and other key molecules of the RAS pathway in normal mice at different developmental stages, and to provide ideas for understanding the infection mechanism of coronavirus disease 2019 (COVID-19) as well as the diagnosis and treatment of children with COVID-19. Methods The mice at different developmental stages were enrolled, including fetal mice (embryonic days 14.5 and 18.5), neonatal mice (0, 3, 7, 14, and 21 days old), young mice (28 and 42 days old), and adult mice (84 days old). The lung tissues of all fetal mice from 4 pregnant mice were collected at each time point in the fetal group. Four mice were sampled in other age groups at each time point. Whole transcriptome resequencing was used to measure the mRNA expression of AGT, ACE, ACE2, Renin, Agtr1a, Agtr1b, Agtr2, and Mas1 in mouse lung tissue. Results The expression of ACE2 in the lungs showed changes from embryonic stage to adult stage. It increased gradually after birth, reached a peak on day 3 after birth, and reached a nadir on day 14 after birth (P < 0.05). The expression of AGT reached a peak on days 0 and 7 after birth and reached a nadir on day 21 after birth (P < 0.05). The expression of ACE increased rapidly after birth and reached a peak on day 21 after birth (P < 0.05). Agtr1a expression reached a peak on day 21 after birth (P < 0.05). Agtr2 expression gradually decreased to a low level after birth. Renin, Agtr1b, and Mas1 showed low expression in lung tissues at all developmental stages. Conclusions At different developmental stages of mice, ACE2 has dynamic expression changes, with high expression in early neonatal and adult mice. The other key molecules of the RAS pathway have their own expression patterns. These suggest that the difference in clinical features between children and adults with COVID-19 might be associated with the different expression levels of ACE2 in the different stages, and further studies are needed for the mechanism.
LOU Li-Li,XIE Liang,HU Yu et al. Association of age distribution with the expression of angiotensin-converting enzyme 2 in lung tissues in severe acute respiratory syndrome coronavirus 2 infection: reflections from the study of RAS pathway expression in mice[J]. CJCP, 2020, 22(10): 1119-1124.
COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU)[EB/OL].[2020-09-15]. https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6.
Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 among children in China[J]. Pediatrics, 2020, 145(6):e20200702.
[6]
She J, Liu L, Liu W. COVID-19 epidemic:disease characteris-tics in children[J]. J Med Virol, 2020, 92(7):747-754.
[7]
Xu H, Zhong L, Deng J, et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa[J]. Int J Oral Sci, 2020, 12(1):8.
[8]
Baig AM, Khaleeq A, Ali U, et al. Evidence of the COVID-19 virus targeting the CNS:tissue distribution, host-virus interaction, and proposed neurotropic mechanisms[J]. ACS Chem Neurosci, 2020, 11(7):995-998.
[9]
Kruse RL. Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China[J]. F1000Res, 2020, 9:72.
Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome[J]. Lancet Respir Med, 2020, 8(4):420-422.
Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019[J]. N Engl J Med, 2020, 382(8):727-733.
[14]
Wan Y, Shang J, Graham R, et al. Receptor recognition by the novel coronavirus from Wuhan:an analysis based on decade-long structural studies of SARS coronavirus[J]. J Virol, 2020, 94(7):e00127-20.
[15]
Guo YR, Cao QD, Hong ZS, et al. The origin, transmission and clinical therapies on coronavirus disease 2019(COVID-19) outbreak-an update on the status[J]. Mil Med Res, 2020, 7(1):11.
Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9[J]. Circ Res, 2000, 87(5):E1-E9.
[18]
Tipnis SR, Hooper NM, Hyde R, et al. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase[J]. J Biol Chem, 2000, 275(43):33238-33243.
[19]
Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure[J]. Nature, 2005, 436(7047):112-116.
[20]
Boskabadi J, Askari VR, Hosseini M, et al. Immunomodulatory properties of captopril, an ACE inhibitor, on LPS-induced lung inflammation and fibrosis as well as oxidative stress[J]. Inflammopharmacology, 2019, 27(3):639-647.
Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor[J]. Cell, 2020, 181(2):271-280.e8.
[25]
Zhang H, Kang ZJ, Gong HY, et al. Digestive system is a potential route of COVID-19:an analysis of single-cell coexpression pattern of key proteins in viral entry process[J]. Gut, 2020, 69(6):1010-1018.
[26]
Chen W, Lan Y, Yuan X, et al. Detectable 2019-nCoV viral RNA in blood is a strong indicator for the further clinical severity[J]. Emerg Microbes Infect, 2020, 9(1):469-473.
