Identification of the regulatory mechanism of ACE2 in COVID-19–induced kidney damage with systems genetics approach

Abstract

Studies showed that SARS-CoV-2 can directly target the kidney and induce renal damage. As the cell surface receptor for SARS-CoV-2 infection, the angiotensin-converting enzyme 2 (ACE2) plays a pivotal role for renal physiology and function. Thus, it is important to understand ACE2 through which pathway influences the pathogenesis of renal damage induced by COVID-19. In this study, we first performed an eQTL mapping for Ace2 in kidney tissues in 53 BXD mice strains. Results demonstrated that Ace2 is highly expressed and strongly controlled by a genetic locus on chromosome 16 in the kidney, with six genes ( Dnase1 , Vasn , Usp7 , Abat , Mgrn1 , and Rbfox1 ) dominated as the upstream modulator, as they are highly correlated with Ace2 expression. Gene co-expression analysis showed that Ace2 co-variates are significantly involved in the renin-angiotensin system (RAS) pathway which acts as a reno-protector. Importantly, we also found that Ace2 is positively correlated with Pdgf family members, particularly Pdgfc , which showed the most association among the 76 investigated growth factors. Mammalian Phenotype Ontology enrichment indicated that the cognate transcripts for both Ace2 and Pdgfc were mainly involved in regulating renal physiology and morphology. Among which, Cd44 , Egfr , Met , Smad3 , and Stat3 were identified as hub genes through protein–protein interaction analysis. Finally, in aligning with our systems genetics findings, we found ACE2 , pdgf family members, and RAS genes decreased significantly in the CAKI-1 kidney cancer cells treated with S protein and receptor binding domain structural protein. Collectively, our data suggested that ACE2 work with RAS, PDGFC, as well as their cognate hub genes to regulate renal function, which could guide for future clinical prevention and targeted treatment for COVID-19–induced renal damage outcomes. Key messages • Ace2 is highly expressed and strongly controlled by a genetic locus on chromosome 16 in the kidney. • Ace2 co-variates are enriched in the RAS pathway. • Ace2 is strongly correlated with the growth factor Pdgfc. • Ace2 and Pdgfc co-expressed genes involved in the regulation of renal physiology and morphology. • SARS-CoV-2 spike glycoprotein induces down-regulation of Ace2, RAS, and Pdgfc. Supplementary Information ...

Studying the Roles of the Renin–Angiotensin System in Accelerating the Disease of High-Fat-Diet-Induced Diabetic Nephropathy in a db/db and ACE2 Double-Gene-Knockout Mouse Model

“…The effects of RAS regulation, ACE2 and kidney diseases in the era of COVID-19 have also been discussed. However, no clear conclusion could be reached [ 52 , 53 ].…”

New Insights into the Link between SARS-CoV-2 Infection and Renal Cancer

“…The study by Niu and colleagues highlighted that ACE2 mRNA expression showed a positive link to the abundance of B cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells, while the copy number alteration of ACE2 could inhibit the number of infiltrating cells [45]. The inhibitory effect of ACE2 expression on human tumor proliferation in ccRCC was further confirmed by in vitro and in preclinical animal models showing that lower ACE2 expression was also associated with advanced tumor stage (T3/T4), higher histological grade (grade 3/4), pathological stage (III/IV) and metastasis (M1) [47,48].…”

“…Interestingly the authors mimed the mechanism of SARS-CoV-2/ACE2 binding and the invasion mechanism of host cells by using the CAKI-1 renal cancer cells. SARS-CoV-2 epitope S (spike glycoprotein) was reported to induce the repression of ACE2, PDGFC, and RAS pathway [48]. These interesting findings showed that knowledge of the ACE2 gene regulatory network is important in revealing potential genetic drivers in ACE2-dependent renal function, the results of which are useful for the diagnosis and treatment of renal cancer patients with COVID-19 complications.…”

“…However, recent research studies reported high ACE2 expression levels, in particular in papillary (94%) and clear cell (86%) renal carcinoma [28,[48][49][50]. The variability in ACE2 expression in renal cancer cells has raised questions about whether there could be differences in susceptibility to SARS-CoV-2 infection among individuals with RCC.…”

“…It has been reported that the Ace2 gene resides on chromosome 16 and in the kidney it is tightly controlled by an upstream genetic locus on the same chromosome consisting of six genes whose expression is highly correlated with that of ACE2 [48]. The expression of ACE2 and the co-variants are involved in the RAS signaling which has a renal protective function, in particular, ACE2 and PDGFC are co-expressed and play an important role in the renal physiology and morphology [48]. Interestingly the authors mimed the mechanism of SARS-CoV-2/ACE2 binding and the invasion mechanism of host cells by using the CAKI-1 renal cancer cells.…”