Abstract
Human angiotensin-converting enzyme 2 (hACE2) has recently received a great attention due to it play a critical role as SARS-CoV receptor in the infection of human body. However, no further analysis for gene regulation has been performed in target tissues of model mice during hACE2 overproduction. To characterize changes in global gene expression in the hearts and kidneys of rtTA/hACE2 double transgenic (dTg) mice in response to hACE2 overexpression, total RNA extracted from these tissues from dTg mice after doxycycline (Dox) treatment was hybridized to oligonucleotide microarrays. Briefly, dTg mice were generated by cross-mating pα-MHC/rtTA Tg mice with pTRE/hACE2 Tg mice. The expression level of hACE2 protein was determined to be high in hearts, kidneys, and brains of dTg mice, whereas lung, liver, and testis tissues expressed low levels. The level of hACE2 was significantly enhanced in hearts and kidneys of the Dox+dTg group compared to that in Vehicle+dTg mice although consistent levels of mouse ACE2 (mACE2) remained in the same tissues. Based on the microarray analysis of heart tissue, 385 genes were differentially expressed, including 168 upregulated and 217 downregulated, when comparing non-Tg and Vehicle+dTg mice, whereas 216 genes were differentially expressed, including 136 upregulated and 80 downregulated, between Vehicle+dTg and Dox+dTg mice. In the kidneys, 402 genes were differentially expressed, including 159 upregulated and 243 downregulated, between non-Tg and Vehicle+dTg mice. Dox-treated dTg mice exhibited the differential expression of 4735 genes including 1636 upregulated and 3109 downregulated. Taken together, these findings suggested that several functional groups and individual genes can be considered biomarkers that respond to hACE2 overexpression in dTg mice. Moreover, our results provided a lot of useful information to predict physiological responses when these dTg mice are applied as a susceptible model for novel coronavirus (SARS-CoV, COVID-19) in both vaccine and drug development.
Highlights
Angiotensin-converting enzyme 2 (ACE2) is the first known human homolog of ACE and was cloned from a human heart failure and human lymphoma cDNA library [1, 2]
Α-Myosin heavy chain (MHC)/reverse tTA (rtTA) and tet response element (TRE)/Human angiotensin-converting enzyme 2 (hACE2) constructs were transmitted into the genomes of their offspring of both sexes at a rate of approximately 50% hemizygous animals based on Mendelian inheritance
Tissue-specific expression of hACE2 during dox treatment To test whether the hACE2 transgene was expressed under the control of rtTA in a tissue-specific manner, its expression level was detected in various tissues including the brain, heart, lung, liver, kidney, and testis of double transgenic (dTg) mice treated with 2 mg/mL Dox for 4 weeks
Summary
Angiotensin-converting enzyme 2 (ACE2) is the first known human homolog of ACE and was cloned from a human heart failure and human lymphoma cDNA library [1, 2]. ACE2 might play a pivotal role as a new element of the renin angiotensin system (RAS) by reducing Ang II and increasing levels of Ang1–7 [3,4,5,6] and is distributed in a wide variety of tissues, including the brain, lung, heart, liver, kidney, and testis, as well as most cardiovascular-relevant tissues [7,8,9,10,11]. It has been reported that ACE2 gene expression is upregulated in humans with heart failure [13]. It is predominantly expressed in the proximal tubular brush border, distal tubules, and glomerular epithelial cells in the kidneys of humans, rats, and mice [14,15,16,17]. More recently, ACE2 has aroused considerable attention as a receptor for the coronavirus that causes severe acute respiratory syndrome and a protector against severe lung failure [23, 24]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
