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1.
Clin J Am Soc Nephrol ; 16(11): 1755-1765, 2021 11.
Article in English | MEDLINE | ID: covidwho-1526737

ABSTRACT

Despite evidence of multiorgan tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with coronavirus disease 2019 (COVID-19), direct viral kidney invasion has been difficult to demonstrate. The question of whether SARS-CoV2 can directly infect the kidney is relevant to the understanding of pathogenesis of AKI and collapsing glomerulopathy in patients with COVID-19. Methodologies to document SARS-CoV-2 infection that have been used include immunohistochemistry, immunofluorescence, RT-PCR, in situ hybridization, and electron microscopy. In our review of studies to date, we found that SARS-CoV-2 in the kidneys of patients with COVID-19 was detected in 18 of 94 (19%) by immunohistochemistry, 71 of 144 (49%) by RT-PCR, and 11 of 84 (13%) by in situ hybridization. In a smaller number of patients with COVID-19 examined by immunofluorescence, SARS-CoV-2 was detected in 10 of 13 (77%). In total, in kidneys from 102 of 235 patients (43%), the presence of SARS-CoV-2 was suggested by at least one of the methods used. Despite these positive findings, caution is needed because many other studies have been negative for SARS-CoV-2 and it should be noted that when detected, it was only in kidneys obtained at autopsy. There is a clear need for studies from kidney biopsies, including those performed at early stages of the COVID-19-associated kidney disease. Development of tests to detect kidney viral infection in urine samples would be more practical as a noninvasive way to evaluate SARS-CoV-2 infection during the evolution of COVID-19-associated kidney disease.


Subject(s)
COVID-19/virology , Kidney Diseases/virology , Kidney/virology , SARS-CoV-2/pathogenicity , Animals , Biopsy , COVID-19/complications , COVID-19/diagnosis , COVID-19/mortality , COVID-19 Testing , Host-Pathogen Interactions , Humans , Kidney Diseases/diagnosis , Kidney Diseases/mortality , Predictive Value of Tests , Prognosis , Risk Assessment , Risk Factors
2.
Acta Physiol (Oxf) ; 231(1): e13513, 2021 01.
Article in English | MEDLINE | ID: covidwho-1388186

ABSTRACT

The renin angiotensin system (RAS) plays an important role in the pathogenesis of variety of diseases. Targeting the formation and action of angiotensin II (Ang II), the main RAS peptide, has been the key therapeutic target for last three decades. ACE-related carboxypeptidase (ACE2), a monocarboxypeptidase that had been discovered 20 years ago, is one of the catalytically most potent enzymes known to degrade Ang II to Ang-(1-7), a peptide that is increasingly accepted to have organ-protective properties that oppose and counterbalance those of Ang II. In addition to its role as a RAS enzyme ACE2 is the main receptor for SARS-CoV-2. In this review, we discuss various strategies that have been used to achieve amplification of ACE2 activity including the potential therapeutic potential of soluble recombinant ACE2 protein and novel shorter ACE2 variants.


Subject(s)
Angiotensin-Converting Enzyme 2 , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/therapy , Genetic Therapy , Receptors, Virus , SARS-CoV-2/pathogenicity , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme 2/therapeutic use , Animals , COVID-19/enzymology , COVID-19/genetics , COVID-19/virology , Enzyme Activation , Enzyme Activators/therapeutic use , Gene Amplification , Host-Pathogen Interactions , Humans , Receptors, Virus/genetics , Receptors, Virus/metabolism , Receptors, Virus/therapeutic use , Recombinant Proteins/therapeutic use
3.
Clin J Am Soc Nephrol ; 16(11): 1755-1765, 2021 11.
Article in English | MEDLINE | ID: covidwho-1269953

ABSTRACT

Despite evidence of multiorgan tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with coronavirus disease 2019 (COVID-19), direct viral kidney invasion has been difficult to demonstrate. The question of whether SARS-CoV2 can directly infect the kidney is relevant to the understanding of pathogenesis of AKI and collapsing glomerulopathy in patients with COVID-19. Methodologies to document SARS-CoV-2 infection that have been used include immunohistochemistry, immunofluorescence, RT-PCR, in situ hybridization, and electron microscopy. In our review of studies to date, we found that SARS-CoV-2 in the kidneys of patients with COVID-19 was detected in 18 of 94 (19%) by immunohistochemistry, 71 of 144 (49%) by RT-PCR, and 11 of 84 (13%) by in situ hybridization. In a smaller number of patients with COVID-19 examined by immunofluorescence, SARS-CoV-2 was detected in 10 of 13 (77%). In total, in kidneys from 102 of 235 patients (43%), the presence of SARS-CoV-2 was suggested by at least one of the methods used. Despite these positive findings, caution is needed because many other studies have been negative for SARS-CoV-2 and it should be noted that when detected, it was only in kidneys obtained at autopsy. There is a clear need for studies from kidney biopsies, including those performed at early stages of the COVID-19-associated kidney disease. Development of tests to detect kidney viral infection in urine samples would be more practical as a noninvasive way to evaluate SARS-CoV-2 infection during the evolution of COVID-19-associated kidney disease.


Subject(s)
COVID-19/virology , Kidney Diseases/virology , Kidney/virology , SARS-CoV-2/pathogenicity , Animals , Biopsy , COVID-19/complications , COVID-19/diagnosis , COVID-19/mortality , COVID-19 Testing , Host-Pathogen Interactions , Humans , Kidney Diseases/diagnosis , Kidney Diseases/mortality , Predictive Value of Tests , Prognosis , Risk Assessment , Risk Factors
4.
J Am Soc Nephrol ; 2021 Feb 01.
Article in English | MEDLINE | ID: covidwho-1197446

ABSTRACT

BACKGROUND: There is an urgent need for approaches to prevent and treat SARS-CoV-2 infection. Administration of soluble ACE2 protein acting as a decoy to bind to SARS-CoV-2 should limit viral uptake mediated by binding to membrane-bound full-length ACE2, and further therapeutic benefit should result from ensuring enzymatic ACE2 activity to affected organs in patients with COVID-19. METHODS: A short variant of human soluble ACE2 protein consisting of 618 amino acids (hACE2 1-618) was generated and fused with an albumin binding domain (ABD) using an artificial gene encoding ABDCon, with improved albumin binding affinity. Human kidney organoids were used for infectivity studies of SARS-CoV-2 in a BSL-3 facility to examine the neutralizing effect of these novel ACE2 variants. RESULTS: Whereas plasma ACE2 activity of the naked ACE2 1-618 and ACE2 1-740 lasted about 8 hours, the ACE2 1-618-ABD resulted in substantial activity at 96 hours, and it was still biologically active 3 days after injection. Human kidney organoids express ACE2 and TMPRSS2, and when infected with SARS-CoV-2, our modified long-acting ACE2 variant neutralized infection. CONCLUSIONS: This novel ACE2 1-618-ABD can neutralize SARS-CoV-2 infectivity in human kidney organoids, and its prolonged duration of action should ensure improved efficacy to prevent viral escape and dosing convenience.

5.
Clin Kidney J ; 14(Suppl 1): i1-i5, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1160774
6.
Mol Cell Endocrinol ; 529: 111260, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1157602

ABSTRACT

Angiotensin converting enzyme 2 (ACE2), a component of the renin-angiotensin system (RAS), has been identified as the receptor for the SARS-CoV-2. Several RAS components including ACE2 and its substrate Ang II are present in both eye and skin, two stratified squamous epithelial tissues that isolate organisms from external environment. Our recent findings in cornea and others in both skin and eye suggest contribution of this system, and specifically of ACE2 in variety of physiological and pathological responses of these organ systems. This review will focus on the role RAS system plays in both skin and cornea, and will specifically discuss our recent findings on ACE2 in corneal epithelial inflammation, as well as potential implications of ACE2 in patients with COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Epithelium, Corneal/enzymology , Receptors, Coronavirus/metabolism , Skin/enzymology , Autophagy , COVID-19/enzymology , COVID-19/virology , Humans , Inflammation/enzymology , Renin-Angiotensin System/physiology , Wound Healing
7.
Hypertension ; 76(5): 1339-1349, 2020 11.
Article in English | MEDLINE | ID: covidwho-992136

ABSTRACT

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 originated from Wuhan, China, in December 2019 and rapidly spread to other areas worldwide. Since then, coronavirus disease 2019 (COVID-19) has reached pandemic proportions with >570 000 deaths globally by mid-July 2020. The magnitude of the outbreak and the potentially severe clinical course of COVID-19 has led to a burst of scientific research on this novel coronavirus and its host receptor ACE (angiotensin-converting enzyme)-2. ACE2 is a homolog of the ACE that acts on several substrates in the renin-Ang (angiotensin) system. With unprecedented speed, scientific research has solved the structure of SARS-CoV-2 and imaged its binding with the ACE2 receptor. In SARS-CoV-2 infection, the viral S (spike) protein receptor-binding domain binds to ACE2 to enter the host cell. ACE2 expression in the lungs is relatively low, but it is present in type II pneumocytes-a cell type also endowed with TMPRSS2 (transmembrane protease serine 2). This protease is critical for priming the SARS-CoV-2 S protein to complex with ACE2 and enter the cells. Herein, we review the current understanding of the interaction of SARS-CoV-2 with ACE2 as it has rapidly unfolded over the last months. While it should not be assumed that we have a complete picture of SARS-CoV-2 mechanism of infection and its interaction with ACE2, much has been learned with clear therapeutic implications. Potential therapies aimed at intercepting SARS-CoV-2 from reaching the full-length membrane-bound ACE2 receptor using soluble ACE2 protein and other potential approaches are briefly discussed as well.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Betacoronavirus/metabolism , Coronavirus Infections/epidemiology , Pandemics/statistics & numerical data , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/epidemiology , Protein Binding/genetics , Angiotensin-Converting Enzyme 2 , COVID-19 , China , Coronavirus Infections/metabolism , Disease Outbreaks/statistics & numerical data , Female , Humans , Male , Pandemics/prevention & control , Pneumonia, Viral/metabolism , RNA, Viral/genetics , SARS-CoV-2
9.
Clin Sci (Lond) ; 134(21): 2791-2805, 2020 11 13.
Article in English | MEDLINE | ID: covidwho-899997

ABSTRACT

Angiotensin-converting enzyme II (ACE2) is a homologue of angiotensin-converting enzyme discovered in 2000. From the initial discovery, it was recognized that the kidneys were organs very rich on ACE2. Subsequent studies demonstrated the precise localization of ACE2 within the kidney and the importance of this enzyme in the metabolism of Angiotensin II and the formation of Angiotensin 1-7. With the recognition early in 2020 of ACE2 being the main receptor of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), the interest in this protein has dramatically increased. In this review, we will focus on kidney ACE2; its localization, its alterations in hypertension, diabetes, the effect of ACE inhibitors and angiotensin type 1 receptor blockers (ARBs) on ACE2 and the potential use of ACE2 recombinant proteins therapeutically for kidney disease. We also describe the emerging kidney manifestations of COVID-19, namely the frequent development of acute kidney injury. The possibility that binding of SARS-CoV-2 to kidney ACE2 plays a role in the kidney manifestations is also briefly discussed.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/enzymology , Kidney Diseases/enzymology , Kidney/enzymology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/enzymology , Receptors, Virus/metabolism , Acute Kidney Injury/enzymology , Acute Kidney Injury/virology , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Diabetes Mellitus/enzymology , Diabetes Mellitus/physiopathology , History, 21st Century , Host-Pathogen Interactions , Humans , Hypertension/enzymology , Hypertension/physiopathology , Kidney/physiopathology , Kidney Diseases/drug therapy , Kidney Diseases/physiopathology , Pandemics , Peptidyl-Dipeptidase A/history , Peptidyl-Dipeptidase A/therapeutic use , Pneumonia, Viral/virology , Receptors, Virus/history , SARS-CoV-2
10.
Hypertension ; 76(5): 1350-1367, 2020 11.
Article in English | MEDLINE | ID: covidwho-802994

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic is associated with significant morbidity and mortality throughout the world, predominantly due to lung and cardiovascular injury. The virus responsible for COVID-19-severe acute respiratory syndrome coronavirus 2-gains entry into host cells via ACE2 (angiotensin-converting enzyme 2). ACE2 is a primary enzyme within the key counter-regulatory pathway of the renin-angiotensin system (RAS), which acts to oppose the actions of Ang (angiotensin) II by generating Ang-(1-7) to reduce inflammation and fibrosis and mitigate end organ damage. As COVID-19 spans multiple organ systems linked to the cardiovascular system, it is imperative to understand clearly how severe acute respiratory syndrome coronavirus 2 may affect the multifaceted RAS. In addition, recognition of the role of ACE2 and the RAS in COVID-19 has renewed interest in its role in the pathophysiology of cardiovascular disease in general. We provide researchers with a framework of best practices in basic and clinical research to interrogate the RAS using appropriate methodology, especially those who are relatively new to the field. This is crucial, as there are many limitations inherent in investigating the RAS in experimental models and in humans. We discuss sound methodological approaches to quantifying enzyme content and activity (ACE, ACE2), peptides (Ang II, Ang-[1-7]), and receptors (types 1 and 2 Ang II receptors, Mas receptor). Our goal is to ensure appropriate research methodology for investigations of the RAS in patients with severe acute respiratory syndrome coronavirus 2 and COVID-19 to ensure optimal rigor and reproducibility and appropriate interpretation of results from these investigations.


Subject(s)
Coronavirus Infections/epidemiology , Hypertension/epidemiology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/epidemiology , Renin-Angiotensin System/physiology , Severe Acute Respiratory Syndrome/metabolism , Angiotensin-Converting Enzyme 2 , Blood Pressure Determination/methods , COVID-19 , China/epidemiology , Female , Humans , Hypertension/physiopathology , Incidence , Male , Pandemics/statistics & numerical data , Practice Guidelines as Topic , Prognosis , Research Design , Risk Assessment , Severe Acute Respiratory Syndrome/epidemiology
11.
13.
FASEB J ; 34(8): 10505-10515, 2020 08.
Article in English | MEDLINE | ID: covidwho-602184

ABSTRACT

Angiotensin converting enzyme 2 (ACE2) plays an important role in inflammation, which is attributable at least, in part, to the conversion of the pro-inflammatory angiotensin (Ang) II peptide into angiotensin 1-7 (Ang 1-7), a peptide which opposes the actions of AngII. ACE2 and AngII are present in many tissues but information on the cornea is lacking. We observed that mice deficient in the Ace2 gene (Ace2-/- ), developed a cloudy cornea phenotype as they aged. Haze occupied the central cornea, accompanied by corneal edema and neovascularization. In severe cases with marked chronic inflammation, a cell-fate switch from a transparent corneal epithelium to a keratinized, stratified squamous, psoriasiform-like epidermis was observed. The stroma contained a large number of CD11c, CD68, and CD3 positive cells. Corneal epithelial debridement experiments in young ACE2-deficient mice showed normal appearing corneas, devoid of haze. We hypothesized, however, that these mice are "primed" for a corneal inflammatory response, which once initiated, would persist. In vitro studies reveal that interleukins (IL-1a, IL-1b), chemokines (CCL2, CXCL8), and TNF-α, are all significantly elevated, resulting in a cytokine storm-like phenotype. This phenotype could be partially rescued by treatment with the AngII type 1 receptor (AT1R) antagonist, losartan, suggesting that the observed effect was mediated by AngII acting on its main receptor. Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes human ACE2 as the receptor for entry with subsequent downregulation of ACE2, corneal inflammation in Ace2-/- mice may have a similar mechanism with that in COVID-19 patients. Thus the Ace2-/- cornea, because of easy accessibility, may provide an attractive model to explore the molecular mechanisms, immunological changes, and treatment modalities in patients with COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Cornea/pathology , Cytokine Release Syndrome/physiopathology , Disease Models, Animal , Angiotensin II/metabolism , Animals , COVID-19 , Cells, Cultured , Chemokines/metabolism , Epithelial Cells/metabolism , Humans , Interleukins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , SARS-CoV-2 , THP-1 Cells , Tumor Necrosis Factor-alpha/metabolism
14.
Am J Physiol Lung Cell Mol Physiol ; 318(5): L1027-L1028, 2020 05 01.
Article in English | MEDLINE | ID: covidwho-185314
16.
Hypertension ; 75(6): 1382-1385, 2020 06.
Article in English | MEDLINE | ID: covidwho-15781

ABSTRACT

During the spread of the severe acute respiratory syndrome coronavirus-2, some reports of data still emerging and in need of full analysis indicate that certain groups of patients are at risk of COVID-19. This includes patients with hypertension, heart disease, diabetes mellitus, and clearly the elderly. Many of those patients are treated with renin-angiotensin system blockers. Because the ACE2 (angiotensin-converting enzyme 2) protein is the receptor that facilitates coronavirus entry into cells, the notion has been popularized that treatment with renin-angiotensin system blockers might increase the risk of developing a severe and fatal severe acute respiratory syndrome coronavirus-2 infection. The present article discusses this concept. ACE2 in its full-length form is a membrane-bound enzyme, whereas its shorter (soluble) form circulates in blood at very low levels. As a mono-carboxypeptidase, ACE2 contributes to the degradation of several substrates including angiotensins I and II. ACE (angiotensin-converting enzyme) inhibitors do not inhibit ACE2 because ACE and ACE2 are different enzymes. Although angiotensin II type 1 receptor blockers have been shown to upregulate ACE2 in experimental animals, the evidence is not always consistent and differs among the diverse angiotensin II type 1 receptor blockers and differing organs. Moreover, there are no data to support the notion that ACE inhibitor or angiotensin II type 1 receptor blocker administration facilitates coronavirus entry by increasing ACE2 expression in either animals or humans. Indeed, animal data support elevated ACE2 expression as conferring potential protective pulmonary and cardiovascular effects. In summary, based on the currently available evidence, treatment with renin-angiotensin system blockers should not be discontinued because of concerns with coronavirus infection.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Betacoronavirus , Coronavirus Infections/drug therapy , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/drug therapy , Receptors, Virus/physiology , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , COVID-19 , Coronavirus Infections/metabolism , Coronavirus Infections/physiopathology , Humans , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/physiopathology , Receptors, Virus/antagonists & inhibitors , SARS-CoV-2
17.
Clin Sci (Lond) ; 134(5): 543-545, 2020 03 13.
Article in English | MEDLINE | ID: covidwho-8347

ABSTRACT

A new coronavirus, referred to as SARS-CoV-2, is responsible for the recent outbreak of severe respiratory disease. This outbreak first detected in Wuhan, China in December 2019, has spread to other regions of China and to 25 other countries as of January, 2020. It has been known since the 2003 SARS epidemic that the receptor critical for SARS-CoV entry into host cells is the angiotensin-converting enzyme 2 (ACE2). The S1 domain of the spike protein of SARS-CoV attaches the virus to its cellular receptor ACE2 on the host cells. We thought that it is timely to explain the connection between the SARS-CoV, SARS-CoV-2, ACE2 and the rationale for soluble ACE2 as a potential therapy.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/drug therapy , Peptidyl-Dipeptidase A , Pneumonia, Viral/drug therapy , SARS Virus/pathogenicity , Virus Attachment , Angiotensin-Converting Enzyme 2 , Animals , COVID-19 , Cell Line , Haplorhini , Humans , Peptidyl-Dipeptidase A/physiology , Recombinant Proteins/therapeutic use , SARS-CoV-2 , Solubility , Virus Replication
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