Cell-Type-Specific Expression of Renin-Angiotensin-System Components in the Human Body and Its Relevance to SARS-CoV-2 Infection

Abstract

We have analyzed the cell-type-specific expression of the renin-angiotensin system (RAS) components across 141 cell types or subtypes as defined by single-cell RNA-seq (scRNAseq) analysis. ACE2, one of the components of RAS, also facilitates SARS-CoV-2 entry into cells in cooperation with its associated protease TMPRSS2. Therefore, our analysis also contributes to the understanding of SARS-CoV-2 infection, spreading of the virus throughout the body, and potential viral interference with RAS in COVID-19 patients.The COVID-19 pandemic caused by SARS coronavirus 2 (SARS-CoV-2) has created a global health emergency with more than a million confirmed cases as of April 4, 2020 1 . For cellular entry, SARS-CoV-2 relies on the interaction of its glycosylated viral spike (S) protein with the host membrane-bound aminopeptidase angiotensin-converting enzyme 2 (ACE2). Subsequently, transmembrane protease serine 2 (TMPRSS2) cleaves S and/or ACE2 protein, which facilitates the fusion of viral and cellular membranes 2 . ACE2 is also a crucial component of RAS, which regulates several key physiological processes such as blood pressure and electrolyte balance and viral infection of ACE2-expressing cells may impair RAS function 3 .The secreted and systemically distributed protease renin (REN) activates RAS by proteolytically cleaving plasma angiotensinogen (AGT) to produce the 10-amino-acid (aa) hormonal peptide, angiotensin I (Ang I). Subsequently, Ang I is processed to the 8-aa Ang II by the metallopeptidase angiotensin-converting enzyme (ACE) present on the surface of pulmonary and kidney endothelial cells. Ang II is the active peptide in RAS triggering vasoconstriction, sodium retention, and fibrosis and signals by binding to its receptor AGTR1 or AT1R. ACE2, a metallopeptidase paralogous to ACE, counters the activity of ACE by digesting Ang II to the 7 aa Ang-(1-7) form, thereby attenuating the effects of Ang II 3 . Ang-(1-7) signals through binding to the G-protein coupled receptor MAS1 as well as the receptor AGTR2 or AT2R. Activation of MAS1 protein is coupled with several downstream pathways including activation of phospholipase A2 was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

ACE2, TMPRSS2 distribution and extrapulmonary organ injury in patients with COVID-19

“…ACE2 and TMPRSS2 could help SARS-CoV-2 entry into the human cells, and it has been showed that ACE2 and TMPRSS2 expressions are widely distributed across human tissues including lung, liver, kidney, heart, brain and multiple digestive tract organs [ 28 , 33 , 147 , 148 ]. The co-expression of ACE2 and TMPRSS2 in the intestinal enterocytes may explain the disruption of intestinal absorption that leads to diarrhea [ 38 , 149 ]. Moreover, ACE2 and TMPRSS2 are highly expressed in renal tubular cells, implying that SARS-CoV-2 may directly bind to ACE2-positive cells in the kidney and destroy the function of renal tubules [ 32 , 38 ].…”

“…The co-expression of ACE2 and TMPRSS2 in the intestinal enterocytes may explain the disruption of intestinal absorption that leads to diarrhea [ 38 , 149 ]. Moreover, ACE2 and TMPRSS2 are highly expressed in renal tubular cells, implying that SARS-CoV-2 may directly bind to ACE2-positive cells in the kidney and destroy the function of renal tubules [ 32 , 38 ]. Furthermore, ACE2 and TMPRSS2 were co-expressed in heart, which may be related with the attack of SARS-CoV-2 in heart and lead to cardiac injury in patients with COVID-19 [ 29 , 35 , 38 ].…”

“…Moreover, ACE2 and TMPRSS2 are highly expressed in renal tubular cells, implying that SARS-CoV-2 may directly bind to ACE2-positive cells in the kidney and destroy the function of renal tubules [ 32 , 38 ]. Furthermore, ACE2 and TMPRSS2 were co-expressed in heart, which may be related with the attack of SARS-CoV-2 in heart and lead to cardiac injury in patients with COVID-19 [ 29 , 35 , 38 ]. Besides, the expression of ACE2 in the heart tissue of patients with underlying heart disease was higher than that of normal people, which may explain that COVID-19 patients with basic cardiovascular disease are more likely to progress to heat injury [ 35 , 36 ].…”

“…RNA and protein expression data of ACE2 in different human tissues and cancer cell lines were obtained from three online datasets including the Cancer Cell Line Encyclopedia (CCLE), GTEx database, and the Human Protein Atlas dataset, and the results indicated that both mRNA and protein expression levels of ACE2 were relatively high in kidney cells especially in renal tubular cells [ 37 ]. Meanwhile, Suryawanshi et al analyzed the data of kidney tissues in scRNA-Seq datasets, and found that either proximal tubular cells or tubular progenitor cells in the kidney co-expressed ACE2 and TMPRSS2 [ 38 ]. The data of the scRNA-seq from GEO dataset (GSE134355) showed that ACE2 and TMPRSS2 expression levels were high in nephron epithelial cells, epithelial cells, endothelial cells, and mesangial cells of the kidney [ 27 ].…”

“…There is a potential pathogenicity of SARS−COV-2 to testis, pancreas, breast, prostate and thyroid, and functional changes in these organs should also be monitored in the management of COVID-19 patients [ 26 , 27 , 38 ]. For example, due to the potential pathogenicity of SARS−COV-2 to testicular tissues, the possible testicular damage caused by the virus may exist as a late complication [ 27 , 137 ].…”