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Mayo Clin Proc ; 98(2): 213-215, 2023 Feb.
Article in English | MEDLINE | ID: covidwho-2300761
Mayo Clin Proc ; 98(1): 18-20, 2023 01.
Article in English | MEDLINE | ID: covidwho-2273778
Mayo Clin Proc ; 97(3): 427-429, 2022 03.
Article in English | MEDLINE | ID: covidwho-2181427
Hypertension ; 76(5): 1350-1367, 2020 11.
Article in English | MEDLINE | ID: covidwho-2153223


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.

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
Mayo Clin Proc ; 97(9): 1589-1591, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-2061641
Mayo Clin Proc ; 97(1): 1-3, 2022 01.
Article in English | MEDLINE | ID: covidwho-1996419
Kidney360 ; 2(7): 1095-1106, 2021 07 29.
Article in English | MEDLINE | ID: covidwho-1776832


Background: The actions of angiotensin-converting enzyme 2 (ACE2) oppose those of the renin-angiotensin-aldosterone system. ACE2 may be a cytoprotectant in some tissues. This study examined ACE2 expression in models of AKI. Methods: ACE2 mRNA and protein expression and ACE2 activity were assessed in murine ischemic AKI. Renal ACE2 mRNA expression was evaluated in LPS-induced AKI in wild-type (C57BL/6J) mice, in heme oxygenase-1+/+ and heme oxygenase-1-/- mice, and after unilateral ureteral obstruction (UUO) in wild-type mice. The effect of sex and age on renal ACE2 protein expression was also assessed. Results: In ischemic AKI, ACE2 mRNA and protein expression and ACE2 activity were reduced as compared with such indices in the intact kidney. In ischemic AKI, ACE2, which, in health, is prominently expressed in the tubular epithelium, especially proximal tubules, is decreased in expression in these segments. Decreased ACE2 expression in AKI did not reflect reduced GFR, because ACE2 mRNA expression was unaltered after UUO. LPS induced renal ACE2 mRNA expression in wild-type mice, but this effect did not occur in heme oxygenase-1-deficient mice. In ischemic and LPS-induced AKI, renal expression of the Mas receptor was increased. In the intact kidney, renal ACE2 protein expression decreased in female mice as compared with male mice, but was unaltered with age. Conclusion: We conclude that renal ACE2 expression is decreased in ischemic AKI, characterized by decreased GFR and abundant cell death, but is upregulated in LPS-induced AKI, an effect requiring heme oxygenase-1. Determining the significance of ACE2 expression in experimental AKI merits further study. We suggest that understanding the mechanism underlying ACE2 downregulation in AKI may offer insights relevant to COVID-19: ACE2 expression is downregulated after ACE2 mediates SARS-CoV-2 cellular entry; such downregulation is proinflammatory; and AKI commonly occurs and determines outcomes in COVID-19.

Acute Kidney Injury , Angiotensin-Converting Enzyme 2 , Acute Kidney Injury/genetics , Angiotensin-Converting Enzyme 2/genetics , Animals , Female , Kidney , Male , Mice , Mice, Inbred C57BL , Mice, Knockout
Biochim Biophys Acta Mol Basis Dis ; 1868(3): 166322, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1637812


BACKGROUND: Acute kidney injury (AKI) is both a consequence and determinant of outcomes in COVID-19. The kidney is one of the major organs infected by the causative virus, SARS-CoV-2. Viral entry into cells requires the viral spike protein, and both the virus and its spike protein appear in the urine of COVID-19 patients with AKI. We examined the effects of transfecting the viral spike protein of SARS-CoV-2 in kidney cell lines. METHODS: HEK293, HEK293-ACE2+ (stably overexpressing ACE2), and Vero E6 cells having endogenous ACE2 were transfected with SARS-CoV-2 spike or control plasmid. Assessment of gene and protein expression, and syncytia formation was performed, and the effects of quercetin on syncytia formation examined. FINDINGS: Spike transfection in HEK293-ACE2+ cells caused syncytia formation, cellular sloughing, and focal denudation of the cell monolayer; transfection in Vero E6 cells also caused syncytia formation. Spike expression upregulated potentially nephrotoxic genes (TNF-α, MCP-1, and ICAM1). Spike upregulated the cytoprotective gene HO-1 and relevant signaling pathways (p-Akt, p-STAT3, and p-p38). Quercetin, an HO-1 inducer, reduced syncytia formation and spike protein expression. INTERPRETATION: The major conclusions of the study are: 1) Spike protein expression in kidney cells provides a relevant model for the study of maladaptive and adaptive responses germane to AKI in COVID-19; 2) such spike protein expression upregulates HO-1; and 3) quercetin, an HO-1 inducer, may provide a clinically relevant/feasible protective strategy in AKI occurring in the setting of COVID-19. FUNDING: R01-DK119167 (KAN), R01-AI100911 (JPG), P30-DK079337; R01-DK059600 (AA).

COVID-19/metabolism , Heme Oxygenase-1/metabolism , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism , Animals , COVID-19/virology , Cell Line , Chlorocebus aethiops , HEK293 Cells , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/physiology , Humans , Protein Binding/drug effects , Protein Binding/physiology , Quercetin/pharmacology , Signal Transduction/drug effects , Signal Transduction/physiology , Up-Regulation/drug effects , Up-Regulation/physiology , Vero Cells , Virus Internalization/drug effects
Mayo Clin Proc ; 96(5): 1101-1104, 2021 05.
Article in English | MEDLINE | ID: covidwho-1382669
Mayo Clin Proc ; 95(9): 1813-1815, 2020 09.
Article in English | MEDLINE | ID: covidwho-1382662
Mayo Clin Proc ; 96(6): 1383-1386, 2021 06.
Article in English | MEDLINE | ID: covidwho-1251401
Mayo Clin Proc ; 96(1): 1-3, 2021 01.
Article in English | MEDLINE | ID: covidwho-1034133
Mayo Clin Proc ; 96(3): 515-517, 2021 03.
Article in English | MEDLINE | ID: covidwho-1123021
Mayo Clin Proc ; 95(11): 2303-2305, 2020 11.
Article in English | MEDLINE | ID: covidwho-1043401
Mayo Clin Proc ; 95(10): 2051-2053, 2020 10.
Article in English | MEDLINE | ID: covidwho-809405

Smoking , Humans