Functional ACE2 deficiency leading to angiotensin imbalance in the pathophysiology of COVID-19

Cook, Joshua R.; Ausiello, John

doi:10.1007/s11154-021-09663-z

Cited by 23 publications

(15 citation statements)

References 197 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ACE2 is a key enzyme in the counter-regulatory pathway of the renin-angiotensin system that regulates blood pressure and fluid and electrolyte balance, as well as systemic vascular resistance ( Donoghue et al, 2000 ; Tikellis and Thomas, 2012 ; Cook and Ausiello, 2021 ). Considering these important functions, possible side effects of ACE2-targeted siRNAs must be taken into account, possibly hampering the use of ACE2 as an RNAi-based therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

“…Possible side effects, however, may be affected by the parallel treatment with drugs blocking the renin-angiotensin pathway ( Kuba et al, 2005 ). In addition, data derived from animal models suggest that infection with SARS-CoV-2 by itself already leads to an impaired ACE2 enzyme function ( Kuba et al, 2005 ; Cook and Ausiello, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…A high knockdown efficiency is a prerequisite for a successful blockage of the viral entry into the host cell, since even low levels of ACE2 are sufficient to allow for SARS-CoV-2 infection (Nawijn and Timens, 2020). ACE2 is a key enzyme in the counter-regulatory pathway of the renin-angiotensin system that regulates blood pressure and fluid and electrolyte balance, as well as systemic vascular resistance (Donoghue et al, 2000;Tikellis and Thomas, 2012;Cook and Ausiello, 2021). Considering these important functions, possible side effects of ACE2-targeted siRNAs must be taken into account, possibly hampering the use of ACE2 as an RNAi-based therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Selection and Validation of siRNAs Preventing Uptake and Replication of SARS-CoV-2

Friedrich

Pfeifer

Binder

et al. 2022

Front. Bioeng. Biotechnol.

View full text Add to dashboard Cite

In 2019, the novel highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak rapidly led to a global pandemic with more than 346 million confirmed cases worldwide, resulting in 5.5 million associated deaths (January 2022). Entry of all SARS-CoV-2 variants is mediated by the cellular angisin-converting enzyme 2 (ACE2). The virus abundantly replicates in the epithelia of the upper respiratory tract. Beyond vaccines for immunization, there is an imminent need for novel treatment options in COVID-19 patients. So far, only a few drugs have found their way into the clinics, often with modest success. Specific gene silencing based on small interfering RNA (siRNA) has emerged as a promising strategy for therapeutic intervention, preventing/limiting SARS-CoV-2 entry into host cells or interfering with viral replication. Here, we pursued both strategies. We designed and screened nine siRNAs (siA1-9) targeting the viral entry receptor ACE2. SiA1, (siRNA against exon1 of ACE2 mRNA) was most efficient, with up to 90% knockdown of the ACE2 mRNA and protein for at least six days. In vitro, siA1 application was found to protect Vero E6 and Huh-7 cells from infection with SARS-CoV-2 with an up to ∼92% reduction of the viral burden indicating that the treatment targets both the endosomal and the viral entry at the cytoplasmic membrane. Since the RNA-encoded genome makes SARS-CoV-2 vulnerable to RNA interference (RNAi), we designed and analysed eight siRNAs (siV1-8) directly targeting the Orf1a/b region of the SARS-CoV-2 RNA genome, encoding for non-structural proteins (nsp). As a significant hallmark of this study, we identified siV1 (siRNA against leader protein of SARS-CoV-2), which targets the nsp1-encoding sequence (a.k.a. ‘host shutoff factor’) as particularly efficient. SiV1 inhibited SARS-CoV-2 replication in Vero E6 or Huh-7 cells by more than 99% or 97%, respectively. It neither led to toxic effects nor induced type I or III interferon production. Of note, sequence analyses revealed the target sequence of siV1 to be highly conserved in SARS-CoV-2 variants. Thus, our results identify the direct targeting of the viral RNA genome (ORF1a/b) by siRNAs as highly efficient and introduce siV1 as a particularly promising drug candidate for therapeutic intervention.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Selection and Validation of siRNAs Preventing Uptake and Replication of SARS-CoV-2

Friedrich

Pfeifer

Binder

et al. 2022

Front. Bioeng. Biotechnol.

View full text Add to dashboard Cite

show abstract

“…Conversely, due to the anti-inflammatory effects of Ang (1-7), increased ACE2 expression might also induce beneficial effects in COVID-19 ( Dilauro et al., 2010 ). While the impact of RAS inhibitor-induced ACE2 upregulation on clinical outcomes in COVID-19 remains unclear, there has emerged an overwhelming consensus that despite possible ACE2 upregulation, the use of ACEIs and ARBs did not lead to poor prognostic outcomes ( Cook and Ausiello, 2021 ).…”

Section: Indirect Kidney Injury Caused By Sars-cov-2 Infectionmentioning

confidence: 99%

Mechanisms of SARS-CoV-2 Infection-Induced Kidney Injury: A Literature Review

Liu

et al. 2022

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

The severe acute respiratory coronavirus 2 (SARS-CoV-2) has become a life-threatening pandemic. Clinical evidence suggests that kidney involvement is common and might lead to mild proteinuria and even advanced acute kidney injury (AKI). Moreover, AKI caused by coronavirus disease 2019 (COVID-19) has been reported in several countries and regions, resulting in high patient mortality. COVID-19‐induced kidney injury is affected by several factors including direct kidney injury mediated by the combination of virus and angiotensin-converting enzyme 2, immune response dysregulation, cytokine storm driven by SARS-CoV-2 infection, organ interactions, hypercoagulable state, and endothelial dysfunction. In this review, we summarized the mechanism of AKI caused by SARS-CoV-2 infection through literature search and analysis.

show abstract

“…If ACE2 endocytosis is the mechanism by which SARS-CoV-2 infiltrates host cells then by definition, high viral loads will lead to a reduction in ACE2 on the surface of cells [27,28]. There is strong evidence to support SARS-CoV-1 downregulation of ACE2 and/or shedding of ACE2 from the cell surface [12,13,29,30]. Given the fact that SARS-CoV-1 and SARS-CoV-2 both rely on the binding of the viral S glycoprotein to ACE2 for viral entry into cells it was therefore highly likely that ACE2 would also be downregulated by SARS-CoV-2 in COVID-19.…”

Section: The Role Of Ace2 In the Raas And Kksmentioning

confidence: 99%

Role of the Renin–Angiotensin–Aldosterone and Kinin–Kallikrein Systems in the Cardiovascular Complications of COVID-19 and Long COVID

Cooper

Boyle

Jefferson

et al. 2021

IJMS

View full text Add to dashboard Cite

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the virus responsible for the COVID-19 pandemic. Patients may present as asymptomatic or demonstrate mild to severe and life-threatening symptoms. Although COVID-19 has a respiratory focus, there are major cardiovascular complications (CVCs) associated with infection. The reported CVCs include myocarditis, heart failure, arrhythmias, thromboembolism and blood pressure abnormalities. These occur, in part, because of dysregulation of the Renin–Angiotensin–Aldosterone System (RAAS) and Kinin–Kallikrein System (KKS). A major route by which SARS-CoV-2 gains cellular entry is via the docking of the viral spike (S) protein to the membrane-bound angiotensin converting enzyme 2 (ACE2). The roles of ACE2 within the cardiovascular and immune systems are vital to ensure homeostasis. The key routes for the development of CVCs and the recently described long COVID have been hypothesised as the direct consequences of the viral S protein/ACE2 axis, downregulation of ACE2 and the resulting damage inflicted by the immune response. Here, we review the impact of COVID-19 on the cardiovascular system, the mechanisms by which dysregulation of the RAAS and KKS can occur following virus infection and the future implications for pharmacological therapies.

show abstract

Functional ACE2 deficiency leading to angiotensin imbalance in the pathophysiology of COVID-19

Cited by 23 publications

References 197 publications

Selection and Validation of siRNAs Preventing Uptake and Replication of SARS-CoV-2

Selection and Validation of siRNAs Preventing Uptake and Replication of SARS-CoV-2

Mechanisms of SARS-CoV-2 Infection-Induced Kidney Injury: A Literature Review

Role of the Renin–Angiotensin–Aldosterone and Kinin–Kallikrein Systems in the Cardiovascular Complications of COVID-19 and Long COVID

Contact Info

Product

Resources

About