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Upregulation of the Renin-Angiotensin System Pathways and SARS-CoV-2 Infection: Molecular...
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Upregulation of the Renin-Angiotensin System Pathways and SARS-CoV-2 Infection: Molecular and Cellular Insights and Possible Therapeutic Strategies

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 15669

Special Issue Editor

Dr. Loris Zamai

E-Mail Website1 Website2
Guest Editor
1. Department of Biomolecular Science, University of Urbino Carlo Bo, 61029 Urbino, Italy
2. National Institute for Nuclear Physics (INFN)-Gran Sasso National Laboratory (LNGS), Assergi, L’Aquila, Italy
Interests: immunity; natural killer cell biology; infectious diseases; haematopoiesis; evolution; ionising radiation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The interest of the scientific community regarding the effect of SARS-CoV-2 on the renin-angiotensin system (RAS) is highlighted by the increasing number of reviews and articles about this topic. In the present Special Issue of Cells, experts in the field will describe the state-of-the-art of the RAS activity in COVID-19 patients. Particular attention should be given to ACE2 activity based on a recent and surprising evidence describing that circulating ACE2 (and not only ACE) activity is remarkably upregulated; an observation that is opening new horizons for our understanding on COVID-19 pathophysiology. Indeed, excessive upregulation of ACE2 has been associated to some pathological conditions such as inflammation of the renal and gastrointestinal tract, cardiac dysfunction, human cirrhosis and lung fibrosis, and ACE2 expression in brain tissues suggests its implication in determining anosmia and neurological disorders in COVID-19 patients. Notably, ACE2 and ACE, but also ADAM17 (responsible for ACE2 membrane shedding and circulating ACE2) are all zinc metalloproteases that need zinc for their function and structure. In this regard, plasma albumin is an important zinc transporter that, by binding free zinc, reduces its availability.  Therefore, hypoalbuminemia, a marker of liver dysfunction that occurs during SARS-CoV-2 infection (and SARS-CoV-1, ARDS and MERS syndromes) can lead to an increase of bioavailable (and toxic) forms of zinc, finally providing “fuel” for the upregulation of ACE2, ACE and ADAM17 activities. A convergent downstream hepatic target stemming from distinct aetiological pathways in SARS-CoVs, ARDS and MERS pathologies is further highlighted by the common increase of procoagulant factors (e.g. C-reactive protein), which can lead to disseminated intravascular coagulopathy, a systemic underlying dysfunction that may culminate with severe interstitial pneumonia and a common acute respiratory distress syndrome. All aspects that warrant further investigation.

Another intriguing observation that deserves further consideration is that, among the key cytokines downstream RAS pathways and triggered by severe SARS-CoV-2 infection, only IL-10 has tolerogenic, anti-inflammatory and anti-proliferative activities that, differently from pro-inflammatory cytokines, can be associated with eosinopaenia and lymphopaenia; both common and early features of COVID-19 that impair immune responses and reduce the ability to counter SARS-CoV-2 infection.

The aim of this Special Issue is to shed light into the involvement of the RAS in COVID-19 and to pave the way for new therapeutics that target RAS pathways possibly encouraging clinical trials and the compassionate use of drugs against the SARS-CoV-2 infection.

We are looking forward to your contributions to this Special Issue.

Prof. Loris Zamai
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • severe acute respiratory syndrome coronavirus-2
  • renin-angiotensin system
  • ACE2
  • Zinc metalloprotesases
  • IL-10
  • convalescent plasma
  • zinc chelating agents
  • auto-immunity
  • albumin
  • hepatic dysfunction

Published Papers (5 papers)

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Research

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22 pages, 6875 KiB  
Article
Modulations of Homeostatic ACE2, CD147, GRP78 Pathways Correlate with Vascular and Endothelial Performance Markers during Pulmonary SARS-CoV-2 Infection
by Annuurun Nisa, Ranjeet Kumar, Santhamani Ramasamy, Afsal Kolloli, Judith Olejnik, Sallieu Jalloh, Suryaram Gummuluru, Selvakumar Subbian and Yuri Bushkin
Cells 2024, 13(5), 432; https://doi.org/10.3390/cells13050432 - 29 Feb 2024
Viewed by 1084
Abstract
The pathologic consequences of Coronavirus Disease-2019 (COVID-19) include elevated inflammation and dysregulated vascular functions associated with thrombosis. In general, disruption of vascular homeostasis and ensuing prothrombotic events are driven by activated platelets, monocytes, and macrophages, which form aggregates (thrombi) attached to the endothelium [...] Read more.
The pathologic consequences of Coronavirus Disease-2019 (COVID-19) include elevated inflammation and dysregulated vascular functions associated with thrombosis. In general, disruption of vascular homeostasis and ensuing prothrombotic events are driven by activated platelets, monocytes, and macrophages, which form aggregates (thrombi) attached to the endothelium lining of vessel walls. However, molecular pathways underpinning the pathological interactions between myeloid cells and endothelium during COVID-19 remain undefined. Here, we tested the hypothesis that modulations in the expression of cellular receptors angiotensin-converting enzyme 2 (ACE2), CD147, and glucose-regulated protein 78 (GRP78), which are involved in homeostasis and endothelial performance, are the hallmark responses induced by SARS-CoV-2 infection. Cultured macrophages and lungs of hamster model systems were used to test this hypothesis. The results indicate that while macrophages and endothelial cells are less likely to support SARS-CoV-2 proliferation, these cells may readily respond to inflammatory stimuli generated by the infected lung epithelium. SARS-CoV-2 induced modulations of tested cellular receptors correlated with corresponding changes in the mRNA expression of coagulation cascade regulators and endothelial integrity components in infected hamster lungs. Among these markers, tissue factor (TF) had the best correlation for prothrombotic events during SARS-CoV-2 infection. Furthermore, the single-molecule fluorescence in situ hybridization (smFISH) method alone was sufficient to determine the peak and resolution phases of SARS-CoV-2 infection and enabled screening for cellular markers co-expressed with the virus. These findings suggest possible molecular pathways for exploration of novel drugs capable of blocking the prothrombotic shift events that exacerbate COVID-19 pathophysiology and control the disease. Full article
(This article belongs to the Special Issue Upregulation of the Renin-Angiotensin System Pathways and SARS-CoV-2 Infection: Molecular and Cellular Insights and Possible Therapeutic Strategies)
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14 pages, 1952 KiB  
Article
Long-Term Subjective and Objective Assessment of Smell and Taste in COVID-19
by Andrea Ciofalo, Carlo Cavaliere, Simonetta Masieri, Alessandra Di Chicco, Irene Fatuzzo, Federica Lo Re, Silvia Baroncelli, Elona Begvarfaj, Andrea Adduci, Ivano Mezzaroma, Claudio Maria Mastroianni, Marco de Vincentiis, Antonio Greco, Loris Zamai and Marco Artico
Cells 2022, 11(5), 788; https://doi.org/10.3390/cells11050788 - 24 Feb 2022
Cited by 11 | Viewed by 2536
Abstract
Among the first clinical symptoms of the SARS-CoV-2 infection is olfactory–gustatory deficit; this continues for weeks and, in some cases, can be persistent. We prospectively evaluated 162 patients affected by COVID-19 using a visual analogue scale (VAS) for nasal and olfactory–gustatory symptoms. Patients [...] Read more.
Among the first clinical symptoms of the SARS-CoV-2 infection is olfactory–gustatory deficit; this continues for weeks and, in some cases, can be persistent. We prospectively evaluated 162 patients affected by COVID-19 using a visual analogue scale (VAS) for nasal and olfactory–gustatory symptoms. Patients were checked after 7, 14, 21, 28, 90, and 180 days. A total of 118 patients (72.8%) reported an olfactory VAS < 7 at baseline (group B), and 44 (27.2%) reported anosmia (VAS ≥ 7) (group A) and underwent the Brief Smell Identification Test (B-SIT) and Burghart Taste Strips (BTS) to quantify the deficit objectively and repeated the tests to confirm the sense recovery. Group A patients showed B-SIT anosmia and hyposmia in 44.2% and 55.8% of cases, respectively. A total of 88.6% of group A patients reported ageusia with VAS ≥ 7, and BTS confirmed 81.8% of ageusia and 18.2% of hypogeusia. VAS smell recovery was recorded starting from 14 days, with normalization at 28 days. The 28-day B-SIT score showed normosmia in 90.6% of group A patients. The mean time for full recovery (VAS = 0) was shorter in group B (22.9 days) than in group A (31.9 days). Chemosensory deficit is frequently the first symptom in patients with COVID-19, and, in most cases, recovery occurs after four weeks. Full article
(This article belongs to the Special Issue Upregulation of the Renin-Angiotensin System Pathways and SARS-CoV-2 Infection: Molecular and Cellular Insights and Possible Therapeutic Strategies)
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16 pages, 4287 KiB  
Article
Quantifying Renin-Angiotensin-System Alterations in COVID-19
by Fabrizio Pucci, Filippo Annoni, Robson Augusto Souza dos Santos, Fabio Silvio Taccone and Marianne Rooman
Cells 2021, 10(10), 2755; https://doi.org/10.3390/cells10102755 - 14 Oct 2021
Cited by 22 | Viewed by 3863
Abstract
The renin-angiotensin system (RAS) plays a pivotal role in a wide series of physiological processes, among which inflammation and blood pressure regulation. One of its key components, the angiotensin-converting enzyme 2, has been identified as the entry point of the SARS-CoV-2 virus into [...] Read more.
The renin-angiotensin system (RAS) plays a pivotal role in a wide series of physiological processes, among which inflammation and blood pressure regulation. One of its key components, the angiotensin-converting enzyme 2, has been identified as the entry point of the SARS-CoV-2 virus into the host cells, and therefore a lot of research has been devoted to study RAS dysregulation in COVID-19. Here we discuss the alterations of the regulatory RAS axes due to SARS-CoV-2 infection on the basis of a series of recent clinical investigations and experimental analyzes quantifying, e.g., the levels and activity of RAS components. We performed a comprehensive meta-analysis of these data in view of disentangling the links between the impaired RAS functioning and the pathophysiological characteristics of COVID-19. We also review the effects of several RAS-targeting drugs and how they could potentially help restore the normal RAS functionality and minimize the COVID-19 severity. Finally, we discuss the conflicting evidence found in the literature and the open questions on RAS dysregulation in SARS-CoV-2 infection whose resolution would improve our understanding of COVID-19. Full article
(This article belongs to the Special Issue Upregulation of the Renin-Angiotensin System Pathways and SARS-CoV-2 Infection: Molecular and Cellular Insights and Possible Therapeutic Strategies)
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Review

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16 pages, 1060 KiB  
Review
Lock, Stock and Barrel: Role of Renin-Angiotensin-Aldosterone System in Coronavirus Disease 2019
by Christian Zanza, Michele Fidel Tassi, Tatsiana Romenskaya, Fabio Piccolella, Ludovico Abenavoli, Francesco Franceschi, Andrea Piccioni, Veronica Ojetti, Angela Saviano, Barbara Canonico, Mariele Montanari, Loris Zamai, Marco Artico, Chiara Robba, Fabrizio Racca and Yaroslava Longhitano
Cells 2021, 10(7), 1752; https://doi.org/10.3390/cells10071752 - 11 Jul 2021
Cited by 12 | Viewed by 3772
Abstract
Since the end of 2019, the medical-scientific community has been facing a terrible pandemic caused by a new airborne viral agent known as SARS-CoV2. Already in the early stages of the pandemic, following the discovery that the virus uses the ACE2 cell receptor [...] Read more.
Since the end of 2019, the medical-scientific community has been facing a terrible pandemic caused by a new airborne viral agent known as SARS-CoV2. Already in the early stages of the pandemic, following the discovery that the virus uses the ACE2 cell receptor as a molecular target to infect the cells of our body, it was hypothesized that the renin-angiotensin-aldosterone system was involved in the pathogenesis of the disease. Since then, numerous studies have been published on the subject, but the exact role of the renin-angiotensin-aldosterone system in the pathogenesis of COVID-19 is still a matter of debate. RAAS represents an important protagonist in the pathogenesis of COVID-19, providing the virus with the receptor of entry into host cells and determining its organotropism. Furthermore, following infection, the virus is able to cause an increase in plasma ACE2 activity, compromising the normal function of the RAAS. This dysfunction could contribute to the establishment of the thrombo-inflammatory state characteristic of severe forms of COVID-19. Drugs targeting RAAS represent promising therapeutic options for COVID-19 sufferers. Full article
(This article belongs to the Special Issue Upregulation of the Renin-Angiotensin System Pathways and SARS-CoV-2 Infection: Molecular and Cellular Insights and Possible Therapeutic Strategies)
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Other

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14 pages, 955 KiB  
Opinion
Upregulation of the Renin–Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients
by Loris Zamai
Cells 2021, 10(3), 506; https://doi.org/10.3390/cells10030506 - 27 Feb 2021
Cited by 19 | Viewed by 3317
Abstract
The article describes the rationale for the administration of zinc-chelating agents in COVID-19 patients. In a previous work I have highlighted that the binding of the SARS-CoV spike proteins to the zinc-metalloprotease ACE2 has been shown to induce ACE2 shedding by activating the [...] Read more.
The article describes the rationale for the administration of zinc-chelating agents in COVID-19 patients. In a previous work I have highlighted that the binding of the SARS-CoV spike proteins to the zinc-metalloprotease ACE2 has been shown to induce ACE2 shedding by activating the zinc-metalloprotease ADAM17, which ultimately leads to systemic upregulation of ACE2 activity. Moreover, based on experimental models, it was also shown the detrimental effect of the excessive systemic activity of ACE2 through its downstream pathways, which leads to “clinical” manifestations resembling COVID-19. In this regard, strong upregulation of circulating ACE2 activity was recently reported in COVID-19 patients, thus supporting the previous hypothesis that COVID-19 may derive from upregulation of ACE2 activity. Based on this, a reasonable hypothesis of using inhibitors that curb the upregulation of both ACE2 and ADAM17 zinc-metalloprotease activities and consequent positive feedback-loops (initially triggered by SARS-CoV-2 and subsequently sustained independently on viral trigger) is proposed as therapy for COVID-19. In particular, zinc-chelating agents such as citrate and ethylenediaminetetraacetic acid (EDTA) alone or in combination are expected to act in protecting from COVID-19 at different levels thanks to their both anticoagulant properties and inhibitory activity on zinc-metalloproteases. Several arguments are presented in support of this hypothesis and based on the current knowledge of both beneficial/harmful effects and cost/effectiveness, the use of chelating agents in the prevention and therapy of COVID-19 is proposed. In this regard, clinical trials (currently absent) employing citrate/EDTA in COVID-19 are urgently needed in order to shed more light on the efficacy of zinc chelators against SARS-CoV-2 infection in vivo. Full article
(This article belongs to the Special Issue Upregulation of the Renin-Angiotensin System Pathways and SARS-CoV-2 Infection: Molecular and Cellular Insights and Possible Therapeutic Strategies)
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