SARS-CoV-2感染的年龄分布与肺部ACE2表达的关系——源自小鼠不同发育阶段RAS通路表达情况的思考

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

摘要:

目的 探讨正常小鼠在发育不同时期血管紧张素转换酶2（ACE2）及RAS通路其他关键分子的表达情况，为儿童2019冠状病毒病（COVID-19）的感染机制及诊治提供思路。方法 将不同发育阶段的小鼠按日龄分为胎鼠（孕14.5 d、孕18.5 d）、新生鼠（生后第0、3、7、14、21天）、幼鼠（生后第28、42天）、成年鼠（生后第84天）10个组，胎鼠组每个时间点取4只孕鼠的所有胎鼠肺组织，其余时间点每组取4只小鼠，采用全转录组测序法检测小鼠肺组织中AGT、ACE、ACE2、Renin、Agtr1a、Agtr1b、Agtr2、Mas1基因的表达情况。结果 ACE2在小鼠胚胎期到成年期肺部表达有一定变化趋势，于生后逐渐上升并在第3天达峰，随后下降（P < 0.05），第14天到达表达低点后又上升；AGT表达水平在小鼠生后第0天及生后第7天呈双峰表达，于出生后第21天降至低值（P < 0.05）；ACE表达量在小鼠生后迅速升高，至生后第21天达峰（P < 0.05）；Agtr1a表达量于小鼠生后第21天达峰（P < 0.05）；Agtr2在小鼠出生后逐渐下降呈低水平表达；Renin、Agtr1b、Mas1在不同时期小鼠肺组织中均呈低水平表达。结论 在小鼠不同发育阶段，ACE2存在动态表达变化，其在早期新生鼠及成年鼠肺部表达量较高，同时RAS通路中其他关键分子也各有其表达趋势。提示COVID-19儿童患者临床特点不同于成人患者这一现象与不同时期ACE2表达水平可能存在一定的相关性，具体作用机制需进一步研究。

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.