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1
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Bacharaki D, Karagiannis M, Sardeli A, Giannakopoulos P, Tziolos NR, Zoi V, Piliouras N, Arkoudis NA, Oikonomopoulos N, Tzannis K, Kavatha D, Antoniadou A, Vlahakos D, Lionaki S. Clinical presentation and outcomes of chronic dialysis patients with COVID-19: A single center experience from Greece. World J Nephrol 2022; 11:58-72. [PMID: 35433341 PMCID: PMC8968474 DOI: 10.5527/wjn.v11.i2.58] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 01/09/2022] [Accepted: 03/23/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) is still a menacing pandemic, especially in vulnerable patients. Morbidity and mortality from COVID-19 in maintenance hemodialysis (MHD) patients are considered worse than those in the general population, but vary across continents and countries in Europe. AIM To describe the clinical course and outcomes of hospitalized MHD patients with COVID-19 in a retrospective observational single center study in Greece. METHODS We correlated clinical, laboratory, and radiological data with the clinical outcomes of MHD patients hospitalized with COVID-19 during the pandemic. The diagnosis was confirmed by real-time polymerase chain reaction. Outcome was determined as survivors vs non-survivors and "progressors" (those requiring oxygen supplementation because of COVID-19 pneumonia worsening) vs "non-progressors". RESULTS We studied 32 patients (17 males), with a median age of 75.5 (IQR: 58.5-82) years old. Of those, 12 were diagnosed upon screening and 20 with related symptoms. According to the World Health Organization (WHO) score, the severity on admission was mild disease in 16, moderate in 13, and severe in 3 cases. Chest computed tomography (CT) showed 1-10% infiltrates in 24 patients. Thirteen "progressors" were recorded among included patients. The case fatality rate was 5/32 (15.6%). Three deaths occurred among "progressors" and two in "non-progressors", irrespective of co-morbidities and gender. Predictors of mortality on admission included frailty index, chest CT findings, WHO severity score, and thereafter the increasing values of serum LDH and D-dimers and decreasing serum albumin. Predictors of becoming a "progressor" included increasing number of neutrophils and neutrophils/lymphocytes ratio. CONCLUSION Patients on MHD seem to be at higher risk of COVID-19 mortality, distinct from the general population. Certain laboratory parameters on admission and during follow-up may be helpful in risk stratification and management of patients.
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Affiliation(s)
- Dimitra Bacharaki
- Nephrology Unit, Department of Internal Medicine, "Attikon" University Hospital, Chaidari 12462, Greece
- Medical School, National and Kapodistrian University of Athens, Athens 15772, Greece
| | - Minas Karagiannis
- Nephrology Unit, Department of Internal Medicine, "Attikon" University Hospital, Chaidari 12462, Greece
- Medical School, National and Kapodistrian University of Athens, Athens 15772, Greece
| | - Aggeliki Sardeli
- Nephrology Unit, Department of Internal Medicine, "Attikon" University Hospital, Chaidari 12462, Greece
- Medical School, National and Kapodistrian University of Athens, Athens 15772, Greece
| | - Panagiotis Giannakopoulos
- Nephrology Unit, Department of Internal Medicine, "Attikon" University Hospital, Chaidari 12462, Greece
- Medical School, National and Kapodistrian University of Athens, Athens 15772, Greece
| | | | - Vasiliki Zoi
- Nephrology Unit, Department of Internal Medicine, "Attikon" University Hospital, Chaidari 12462, Greece
| | - Nikitas Piliouras
- Nephrology Unit, Department of Internal Medicine, "Attikon" University Hospital, Chaidari 12462, Greece
- Medical School, National and Kapodistrian University of Athens, Athens 15772, Greece
| | | | | | - Kimon Tzannis
- Nephrology Unit, Department of Internal Medicine, "Attikon" University Hospital, Chaidari 12462, Greece
- Medical School, National and Kapodistrian University of Athens, Athens 15772, Greece
| | - Dimitra Kavatha
- Medical School, National and Kapodistrian University of Athens, Athens 15772, Greece
- Department of Internal Medicine, "Attikon" University Hospital, Chaidari 12462, Greece
| | - Anastasia Antoniadou
- Medical School, National and Kapodistrian University of Athens, Athens 15772, Greece
- Department of Internal Medicine, "Attikon" University Hospital, Chaidari 12462, Greece
| | - Demetrios Vlahakos
- Medical School, National and Kapodistrian University of Athens, Athens 15772, Greece
| | - Sophia Lionaki
- Nephrology Unit, Department of Internal Medicine, "Attikon" University Hospital, Chaidari 12462, Greece
- Medical School, National and Kapodistrian University of Athens, Athens 15772, Greece
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2
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Furuhashi M, Sakai A, Tanaka M, Higashiura Y, Mori K, Koyama M, Ohnishi H, Saitoh S, Shimamoto K. Distinct Regulation of U-ACE2 and P-ACE2 (Urinary and Plasma Angiotensin-Converting Enzyme 2) in a Japanese General Population. Hypertension 2021; 78:1138-1149. [PMID: 34420372 PMCID: PMC8415520 DOI: 10.1161/hypertensionaha.121.17674] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 07/29/2021] [Indexed: 12/20/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Masato Furuhashi
- Department of Cardiovascular, Renal and Metabolic Medicine (M.F., A.S., M.T., Y.H., K.M., M.K., H.O., S.S.), Sapporo Medical University School of Medicine, Japan
| | - Akiko Sakai
- Department of Cardiovascular, Renal and Metabolic Medicine (M.F., A.S., M.T., Y.H., K.M., M.K., H.O., S.S.), Sapporo Medical University School of Medicine, Japan
| | - Marenao Tanaka
- Department of Cardiovascular, Renal and Metabolic Medicine (M.F., A.S., M.T., Y.H., K.M., M.K., H.O., S.S.), Sapporo Medical University School of Medicine, Japan
| | - Yukimura Higashiura
- Department of Cardiovascular, Renal and Metabolic Medicine (M.F., A.S., M.T., Y.H., K.M., M.K., H.O., S.S.), Sapporo Medical University School of Medicine, Japan
| | - Kazuma Mori
- Department of Cardiovascular, Renal and Metabolic Medicine (M.F., A.S., M.T., Y.H., K.M., M.K., H.O., S.S.), Sapporo Medical University School of Medicine, Japan
| | - Masayuki Koyama
- Department of Cardiovascular, Renal and Metabolic Medicine (M.F., A.S., M.T., Y.H., K.M., M.K., H.O., S.S.), Sapporo Medical University School of Medicine, Japan
- Department of Public Health (M.K., H.O.), Sapporo Medical University School of Medicine, Japan
| | - Hirofumi Ohnishi
- Department of Cardiovascular, Renal and Metabolic Medicine (M.F., A.S., M.T., Y.H., K.M., M.K., H.O., S.S.), Sapporo Medical University School of Medicine, Japan
- Department of Public Health (M.K., H.O.), Sapporo Medical University School of Medicine, Japan
| | - Shigeyuki Saitoh
- Department of Cardiovascular, Renal and Metabolic Medicine (M.F., A.S., M.T., Y.H., K.M., M.K., H.O., S.S.), Sapporo Medical University School of Medicine, Japan
- Division of Medical and Behavioral Subjects, Department of Nursing, Sapporo Medical University School of Health Sciences, Japan (S.S.)
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Sharma R, Li J, Krishnan S, Richards E, Raizada M, Mohandas R. Angiotensin-converting enzyme 2 and COVID-19 in cardiorenal diseases. Clin Sci (Lond) 2021; 135:1-17. [PMID: 33399851 PMCID: PMC7796300 DOI: 10.1042/cs20200482] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 12/03/2020] [Accepted: 12/07/2020] [Indexed: 01/08/2023]
Abstract
The rapid spread of the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought into focus the key role of angiotensin-converting enzyme 2 (ACE2), which serves as a cell surface receptor required for the virus to enter cells. SARS-CoV-2 can decrease cell surface ACE2 directly by internalization of ACE2 bound to the virus and indirectly by increased ADAM17 (a disintegrin and metalloproteinase 17)-mediated shedding of ACE2. ACE2 is widely expressed in the heart, lungs, vasculature, kidney and the gastrointestinal (GI) tract, where it counteracts the deleterious effects of angiotensin II (AngII) by catalyzing the conversion of AngII into the vasodilator peptide angiotensin-(1-7) (Ang-(1-7)). The down-regulation of ACE2 by SARS-CoV-2 can be detrimental to the cardiovascular system and kidneys. Further, decreased ACE2 can cause gut dysbiosis, inflammation and potentially worsen the systemic inflammatory response and coagulopathy associated with SARS-CoV-2. This review aims to elucidate the crucial role of ACE2 both as a regulator of the renin-angiotensin system and a receptor for SARS-CoV-2 as well as the implications for Coronavirus disease 19 and its associated cardiovascular and renal complications.
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Affiliation(s)
- Ravindra K. Sharma
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Medicine, University of Florida College of Medicine, Gainesville, FL 32610, U.S.A
| | - Jing Li
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32610, U.S.A
| | - Suraj Krishnan
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Medicine, University of Florida College of Medicine, Gainesville, FL 32610, U.S.A
| | - Elaine M. Richards
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32610, U.S.A
| | - Mohan K. Raizada
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32610, U.S.A
| | - Rajesh Mohandas
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Medicine, University of Florida College of Medicine, Gainesville, FL 32610, U.S.A
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Rajpal A, Rahimi L, Ismail‐Beigi F. Factors leading to high morbidity and mortality of COVID-19 in patients with type 2 diabetes. J Diabetes 2020; 12:895-908. [PMID: 32671936 PMCID: PMC7405270 DOI: 10.1111/1753-0407.13085] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 07/03/2020] [Accepted: 07/09/2020] [Indexed: 01/08/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is a recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus. Diabetes (mostly type 2 diabetes mellitus, T2DM) and hyperglycemia are among the major comorbidities in patients with COVID-19 leading to poor outcomes. Reports show that patients with diabetes and COVID-19 are at an increased risk for developing severe complications including acute respiratory distress syndrome, multi-organ failure, and death. Here we explore potential mechanistic links that could explain the observed higher morbidity and mortality in this patient population. Patients with T2DM have an underlying increased level of inflammation associated with obesity and insulin resistance in addition to other comorbidities including hypertension, obesity, cardiovascular disease, dyslipidemia, and being older. We review evidence that T2DM with hyperglycemia are among factors that lead to elevated expression of angiotensin-converting enzyme 2 (ACE2) in lungs and other tissues; ACE2 is the cellular "receptor" and port of viral entry. The preexisting chronic inflammation with augmented inflammatory response to the infection and the increasing viral load leads to extreme systemic immune response ("cytokine storm") that is strongly associated with increased severity of COVID-19. Based on the available evidence, it is recommended by a panel of experts that safe but stringent control of blood glucose, blood pressure, and lipids be carried out in patients with T2DM, measures that could potentially serve to decrease the severity of COVID-19 should these patients contract the viral infection. Once the infection occurs, then attention should be directed to proper glycemic control with use of insulin and frequent monitoring of blood glucose levels.
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Affiliation(s)
- Aman Rajpal
- Department of MedicineCase Western Reserve University and Cleveland VA Medical CenterClevelandOhioUSA
| | - Leili Rahimi
- Department of MedicineCase Western Reserve University and University Hospitals Cleveland Medical CenterClevelandOhioUSA
| | - Faramarz Ismail‐Beigi
- Department of MedicineCase Western Reserve University and Cleveland VA Medical CenterClevelandOhioUSA
- Department of MedicineCase Western Reserve University and University Hospitals Cleveland Medical CenterClevelandOhioUSA
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5
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Sparks MA, South AM, Badley AD, Baker-Smith CM, Batlle D, Bozkurt B, Cattaneo R, Crowley SD, Dell’Italia LJ, Ford AL, Griendling K, Gurley SB, Kasner SE, Murray JA, Nath KA, Pfeffer MA, Rangaswami J, Taylor WR, Garovic VD. Severe Acute Respiratory Syndrome Coronavirus 2, COVID-19, and the Renin-Angiotensin System: Pressing Needs and Best Research Practices. Hypertension 2020; 76:1350-1367. [PMID: 32981369 PMCID: PMC7685174 DOI: 10.1161/hypertensionaha.120.15948] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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.
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Affiliation(s)
- Matthew A. Sparks
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC
- Renal Section, Durham VA Health Care System, Durham, NC
- American Heart Association, Council on Kidney in Cardiovascular Disease
| | - Andrew M. South
- American Heart Association, Council on Kidney in Cardiovascular Disease
- American Heart Association, Council on Hypertension
- Section of Nephrology, Department of Pediatrics, Brenner Children’s Hospital, Wake Forest School of Medicine, Winston Salem, NC
- Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston Salem, NC
- Department of Surgery-Hypertension and Vascular Research, Wake Forest School of Medicine, Winston Salem, NC
- Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston Salem, NC
| | - Andrew D. Badley
- Division of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, MN
| | - Carissa M. Baker-Smith
- Director of Preventive Cardiology, Division of Pediatric Cardiology, Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE
- American Heart Association, Council on Lifelong Congenital Heart Disease and Heart Health in the Young
| | - Daniel Batlle
- Division of Nephrology and Hypertension, Northwestern University Feinberg Medical School, Chicago, IL
- American Heart Association, Council on Hypertension
| | - Biykem Bozkurt
- Section of Cardiology, Department of Internal Medicine, Baylor College of Medicine, Houston, TX
- Michael E. DeBakey VA Medical Center, Houston, TX
- American Heart Association, Council on Clinical Cardiology
| | - Roberto Cattaneo
- Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN
| | - Steven D. Crowley
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC
- Renal Section, Durham VA Health Care System, Durham, NC
- American Heart Association, Council on Kidney in Cardiovascular Disease
| | - Louis J. Dell’Italia
- Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL
- Department of Veterans Affairs Medical Center, Birmingham, AL
- American Heart Association, Council on Basic Cardiovascular Sciences
| | - Andria L. Ford
- Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, MO
- American Heart Association, Stroke Council
| | - Kathy Griendling
- American Heart Association, Council on Basic Cardiovascular Sciences
- Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA
| | - Susan B. Gurley
- American Heart Association, Council on Kidney in Cardiovascular Disease
- Department of Medicine, Division of Nephrology and Hypertension, Oregon Health & Science University, Portland, OR
| | - Scott E. Kasner
- Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania
- American Heart Association, Stroke Council
| | - Joseph A. Murray
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
| | - Karl A. Nath
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN
| | - Marc A. Pfeffer
- American Heart Association, Council on Clinical Cardiology
- Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Janani Rangaswami
- American Heart Association, Council on Kidney in Cardiovascular Disease
- Department of Medicine, Einstein Medical Center Philadelphia, Philadelphia, PA
- Sidney Kimmel College of Thomas Jefferson University, Philadelphia, PA
| | - W. Robert Taylor
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA
- Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA
- Division of Cardiology, Atlanta VA Medical Center, Decatur, GA
- American Heart Association, Council on Arteriosclerosis, Thrombosis and Vascular Biology
| | - Vesna D. Garovic
- American Heart Association, Council on Hypertension
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN
- Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, Rochester, MN
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Palau V, Pascual J, Soler MJ, Riera M. Role of ADAM17 in kidney disease. Am J Physiol Renal Physiol 2019; 317:F333-F342. [DOI: 10.1152/ajprenal.00625.2018] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
It is known that the renin-angiotensin system plays a major role in the pathophysiology of cardiovascular disease and renal injury. Within the renin-angiotensin system, angiotensin-converting enzyme 2 (ACE2) cleaves ANG II to generate ANG(1–7) peptide, which counteracts the adverse effects of ANG II accumulation. ACE2 can undergo cleavage or shedding to release the catalytically active ectodomain into the circulation by a disintegrin and metalloprotease (ADAM)17, also known as TNF-α-converting enzyme. ADAM17 is involved in many pathological processes such as cancer, inflammatory diseases, neurological diseases, cardiovascular diseases, atherosclerosis, diabetes, and hypertension. Clinical and experimental studies have shown that ADAM17 is involved in chronic kidney disease (CKD) with a proinflammatory and profibrotic role, suggesting that it could be an important mediator of CKD progression. ADAM17 inhibition attenuates fibrosis and inflammation, suggesting that its inhibition may be a possible new valuable therapeutic tool in fibrotic kidney disease treatment. In addition, in renal disease, some experimental studies have demonstrated that ADAM17 is differently expressed in the kidney. Thus, ADAM17 is highly expressed in distal renal tubules and increased in the whole kidney in diabetic models. In this article, we will review the role of ADAM17 under physiological and pathological conditions. We will mainly focus on the importance of ADAM17 in the context of CKD.
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Affiliation(s)
- Vanesa Palau
- Department of Nephrology, Hospital del Mar Medical Research Institute, Barcelona, Spain
| | - Julio Pascual
- Department of Nephrology, Hospital del Mar Medical Research Institute, Barcelona, Spain
| | - Maria José Soler
- Department of Nephrology, Hospital del Mar Medical Research Institute, Barcelona, Spain
| | - Marta Riera
- Department of Nephrology, Hospital del Mar Medical Research Institute, Barcelona, Spain
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Zhou X, Zhang P, Liang T, Chen Y, Liu D, Yu H. Relationship between circulating levels of angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis and coronary heart disease. Heart Vessels 2019; 35:153-161. [PMID: 31359146 PMCID: PMC7100072 DOI: 10.1007/s00380-019-01478-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023]
Abstract
As a counter-regulatory arm of the renin angiotensin system (RAS), the angiotensin-converting enzyme 2-angiotensin-(1–7)-MAS axis (ACE2-Ang-(1–7)-MAS axis) plays a protective role in cardiovascular diseases. However, the link between circulating levels of ACE2-Ang-(1–7)-Mas axis and coronary atherosclerosis in humans is not determined. The object of present study was to investigate the association of circulating levels of ACE2, Ang-(1–7) and Ang-(1–9) with coronary heart disease (CHD) defined by coronary angiography (CAG). 275 patients who were referred to CAG for the evaluation of suspected CHD were enrolled and divided into two groups: CHD group (diameter narrowing ≥ 50%, n = 218) and non-CHD group (diameter narrowing < 50%, n = 57). Circulating ACE2, Ang-(1–7) and Ang-(1–9) levels were detected by enzyme-linked immunosorbent assay (ELISA). In females, circulating ACE2 levels were higher in the CHD group than in the non-CHD group (5617.16 ± 5206.67 vs. 3124.06 ± 3005.36 pg/ml, P = 0.009), and subgroup analysis showed the significant differences in ACE2 levels between the two groups only exist in patients with multi-vessel lesions (P = 0.009). In multivariate logistic regression, compared with the people in the lowest ACE2 quartile, those in the highest quartile had an OR of 4.33 (95% CI 1.20–15.61) for the CHD (P for trend = 0.025), the OR was 5.94 (95% CI 1.08–32.51) for the third ACE2 quartile and 9.58 (95% CI 1.61–56.95) for the highest ACE2 quartile after adjusting for potential confounders (P for trend = 0.022). However, circulating Ang-(1–7) and Ang-(1–9) levels had no significant differences between the two groups. In males, there were no significant differences in the levels of ACE2-Ang-(1–7)-MAS axis between two groups. Together, circulating ACE2 levels, but not Ang-(1–7) and Ang-(1–9) levels, significantly increased in female CHD group when compared with non-CHD group, increased ACE2 was independently associated with CHD in female and in patients with multi-vessel lesions even after adjusting for the confounding factors, indicating that ACE2 may participate as a compensatory mechanism in CHD.
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Affiliation(s)
- Xiaomin Zhou
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Ping Zhang
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Tao Liang
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yongyue Chen
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Department of Cardiology, Shantou Central Hospital and Affiliated Shantou Hospital of SunYat-Sen University, Shantou, China
| | - Dan Liu
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Department of Cardiology, Hospital of Panyu District, Guangzhou, China
| | - Huimin Yu
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China. .,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China. .,Department of Cardiology, Guangdong General Hospital's Nanhai Hospital, Foshan, China.
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Yang CW, Lu LC, Chang CC, Cho CC, Hsieh WY, Tsai CH, Lin YC, Lin CS. Imbalanced plasma ACE and ACE2 level in the uremic patients with cardiovascular diseases and its change during a single hemodialysis session. Ren Fail 2018; 39:719-728. [PMID: 29157100 PMCID: PMC6446170 DOI: 10.1080/0886022x.2017.1398665] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Background: The renin-angiotensin system (RAS) has significant influences on heart and renal disease progression. Angiotensin converting enzyme (ACE) and angiotensin converting enzyme II (ACE2) are major peptidases of RAS components and play counteracting functions through angiotensin II (Ang II)/ATIR and angiotensin-(1–7) (Ang-(1–7))/Mas axis, respectively. Methods: There were 360 uremic patients on regular hemodialysis (HD) treatment (inclusive of 119 HD patients with cardiovascular diseases (CVD) and 241 HD patients without CVD and 50 healthy subjects were enrolled in this study. Plasma ACE, ACE2, Ang II and Ang-(1–7) levels of the HD patients were determined. Results: We compared pre-HD levels of plasma ACE, ACE2, Ang II and Ang-(1–7) in the HD patients with and without CVD to those of the controls. The HD patients, particularly those with CVD, showed a significant increase in the levels of ACE and Ang II, whereas ACE2 and Ang-(1–7) levels were lower than those in the healthy controls. Therefore, imbalanced ACE/ACE2 was observed in the HD patients with CVD. In the course of a single HD session, the plasma ACE, ACE/ACE2 and Ang II levels in the HD patients with CVD were increased from pre-HD to post-HD. On the contrary, ACE2 levels were decreased after the HD session. These changes were not detected in the HD patients without CVD. Conclusions: Pathogenically imbalanced circulating ACE/ACE2 was detected in the HD patients, particularly those with CVD. HD session could increase ACE/Ang II/AT1R axis and decrease ACE2/Ang-(1–7)/Mas axis activity in the circulation of HD patients with CVD.
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Affiliation(s)
- Chung-Wei Yang
- a Department of Biological Science and Technology , National Chiao Tung University , Hsinchu , Taiwan.,b Division of Nephrology, Department of Internal Medicine , National Taiwan University Hospital Hsinchu Branch , Hsinchu , Taiwan
| | - Li-Che Lu
- c Division of Nephrology, Department of Internal Medicine , Shin Kong Wu Ho-Su Memorial Hospital , Taipei , Taiwan
| | - Chia-Chu Chang
- d Division of Nephrology, Department of Internal Medicine , Changhua Christian Hospital , Changhua , Taiwan.,e School of Medicine , Chung-Shan Medical University , Taichung , Taiwan
| | - Ching-Chang Cho
- a Department of Biological Science and Technology , National Chiao Tung University , Hsinchu , Taiwan
| | - Wen-Yeh Hsieh
- f Division of Chest Medicine, Department of Internal Medicine , Hsinchu Mackay Memorial Hospital , Hsinchu , Taiwan.,g Department of Senior Citizen Service Management , Minghsin University of Science and Technology , Hsinchu , Taiwan
| | - Chin-Hung Tsai
- a Department of Biological Science and Technology , National Chiao Tung University , Hsinchu , Taiwan
| | - Yi-Chang Lin
- a Department of Biological Science and Technology , National Chiao Tung University , Hsinchu , Taiwan
| | - Chih-Sheng Lin
- a Department of Biological Science and Technology , National Chiao Tung University , Hsinchu , Taiwan
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Malik U, Raizada V. Some Aspects of the Renin-Angiotensin-System in Hemodialysis Patients. Kidney Blood Press Res 2015; 40:614-22. [PMID: 26618349 PMCID: PMC6133239 DOI: 10.1159/000368537] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/10/2015] [Indexed: 12/25/2022] Open
Abstract
Understanding of the renin-angiotensin system (RAS) has changed remarkably over the past decade. Renin, angiotensin converting enzyme (ACE), angiotensin II (Ang II), and Ang II receptors are the main components of the RAS. Recent studies identified the ACE2/Ang 1–7/ Mas receptor axis, which counter-regulates the classical RAS. Many studies have examined the effects of the RAS on the progression of cardiovascular disease and chronic kidney disease (CKD). In addition, many studies have documented increased levels of ACE in hemodialysis (HD) patients, raising concerns about the negative effects of RAS activation on the progression of renal disease. Elevated ACE increases the level of Ang II, leading to vasoconstriction and cell proliferation. Ang II stimulation of the sympathetic system leads to renal and cardiovascular complications that are secondary to uncontrolled hypertension. This review provides an overview of the RAS, evaluates new research on the role of ACE2 in dialysis, and reviews the evidence for potentially better treatments for patients undergoing HD. Further understanding of the role of ACE and ACE2 in HD patients may aid the development of targeted therapies that slow the progression of CKD and cardiovascular disease.
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Affiliation(s)
- Umar Malik
- University of New Mexico School of Medicine, Albuquerque, New Mexico, USA
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Anguiano L, Riera M, Pascual J, Valdivielso JM, Barrios C, Betriu A, Mojal S, Fernández E, Soler MJ. Circulating angiotensin-converting enzyme 2 activity in patients with chronic kidney disease without previous history of cardiovascular disease. Nephrol Dial Transplant 2015; 30:1176-85. [PMID: 25813276 PMCID: PMC7107869 DOI: 10.1093/ndt/gfv025] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2014] [Accepted: 01/10/2015] [Indexed: 01/01/2023] Open
Abstract
Background Patients with cardiovascular (CV) disease have an increased circulating angiotensin-converting enzyme 2 (ACE2) activity, but there is little information about changes in ACE2 in chronic kidney disease (CKD) patients without history of CV disease. We examined circulating ACE2 activity in CKD patients at stages 3–5 (CKD3-5) and in dialysis (CKD5D) without any history of CV disease. Methods Circulating ACE2 activity was measured in human ethylenediamine-tetraacetic acid (EDTA)-plasma samples from the NEFRONA study (n = 2572): control group (CONT) (n = 568), CKD3-5 (n = 1458) and CKD5D (n = 546). Different clinical and analytical variables such as gender; age; history of diabetes mellitus (DM), dyslipidemia and hypertension; glycaemic, renal, lipid and anaemia profiles; vitamin D analogues treatment and antihypertensive treatments (angiotensin-converting enzyme inhibitor and angiotensin receptor blockade) were analysed. Circulating ACE2 and ACE activities were measured using modified fluorimetric assay for EDTA-plasma samples, where zinc chloride was added to recover enzymatic activity. Results In CKD3-5 and CKD5D, significant decrease in circulating ACE2 activity was observed when compared with CONT, but no differences were found between CKD3-5 and CKD5 when performing paired case-control studies. By multivariate linear regression analysis, male gender and advanced age were identified as independent predictors of ACE2 activity in all groups. Diabetes was identified as independent predictor of ACE2 activity in CKD3-5. Significant increase in the activity of circulating ACE was found in CKD3-5 and CKD5D when compared with CONT and in CKD5D when compared with CKD3-5. By multiple regression analysis, female gender and younger age were identified as independent predictors of ACE activity in CONT and CKD3-5. Diabetes was also identified as an independent predictor of ACE activity in CKD3-5 patients. Conclusions Circulating ACE2 and ACE activities can be measured in human EDTA-plasma samples with zinc added to recover enzymatic activity. In a CKD population without previous history of CV disease, ACE2 activity from human EDTA-plasma samples directly correlated with the classical CV risk factors namely older age, diabetes and male gender. Our data suggest that circulating ACE2 is altered in CKD patients at risk for CV event.
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Affiliation(s)
- Lidia Anguiano
- Department of Nephrology, Hospital del Mar-IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Marta Riera
- Department of Nephrology, Hospital del Mar-IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Julio Pascual
- Department of Nephrology, Hospital del Mar-IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | | | - Clara Barrios
- Department of Nephrology, Hospital del Mar-IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Angels Betriu
- Nephrology Research Laboratory, Institute for Biomedical Research, IRB Lleida, Spain Department of Nephrology and UDETMA, University Hospital Arnau de Vilanova, Lleida, Spain
| | | | - Elvira Fernández
- Nephrology Research Laboratory, Institute for Biomedical Research, IRB Lleida, Spain Department of Nephrology and UDETMA, University Hospital Arnau de Vilanova, Lleida, Spain
| | - María José Soler
- Department of Nephrology, Hospital del Mar-IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
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Mizuiri S, Ohashi Y. ACE and ACE2 in kidney disease. World J Nephrol 2015; 4:74-82. [PMID: 25664248 PMCID: PMC4317630 DOI: 10.5527/wjn.v4.i1.74] [Citation(s) in RCA: 134] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Revised: 07/16/2014] [Accepted: 10/27/2014] [Indexed: 02/06/2023] Open
Abstract
Renin angiotensin system (RAS) activation has a significant influence on renal disease progression. The classical angiotensin-converting enzyme (ACE)-angiotensin II (Ang II)-Ang II type 1 (AT1) axis is considered to control the effects of RAS activation on renal disease. However, since its discovery in 2000 ACE2 has also been demonstrated to have a significant impact on the RAS. The synthesis and catabolism of Ang II are regulated via a complex series of interactions, which involve ACE and ACE2. In the kidneys, ACE2 is expressed in the proximal tubules and less strongly in the glomeruli. The synthesis of inactive Ang 1-9 from Ang I and the catabolism of Ang II to produce Ang 1-7 are the main functions of ACE2. Ang 1-7 reduces vasoconstriction, water retention, salt intake, cell proliferation, and reactive oxygen stress, and also has a renoprotective effect. Thus, in the non-classical RAS the ACE2-Ang 1-7-Mas axis counteracts the ACE-Ang II-AT1 axis. This review examines recent human and animal studies about renal ACE and ACE2.
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Furuhashi M, Moniwa N, Mita T, Fuseya T, Ishimura S, Ohno K, Shibata S, Tanaka M, Watanabe Y, Akasaka H, Ohnishi H, Yoshida H, Takizawa H, Saitoh S, Ura N, Shimamoto K, Miura T. Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by olmesartan, an angiotensin II receptor blocker. Am J Hypertens 2015; 28:15-21. [PMID: 24842388 DOI: 10.1093/ajh/hpu086] [Citation(s) in RCA: 196] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Angiotensin-converting enzyme 2 (ACE2) is highly expressed in the kidney and converts angiotensin (Ang) II to Ang-(1-7), a renoprotective peptide. Urinary ACE2 has been shown to be elevated in patients with chronic kidney disease. However, the effects of antihypertensive agents on urinary ACE2 remain unclear. METHODS Of participants in the Tanno-Sobetsu cohort study in 2011 (n = 617), subjects on no medication (n = 101) and hypertensive patients treated with antihypertensive agents, including the calcium channel blockers amlodipine and long-acting nifedipine; the ACE inhibitor enalapril; and the Ang II receptor blockers losartan, candesartan, valsartan, telmisartan, and olmesartan, for more than 1 year (n = 100) were enrolled, and urinary ACE2 level was measured. RESULTS Glucose and hemoglobin A1c were significantly higher in patients treated with enalapril, telmisartan or olmesartan than in the control subjects. Urinary albumin-to-creatinine ratio (UACR) was significantly higher in patients treated with enalapril than in the control subjects. Urinary ACE2 level was higher in the olmesartan-treated group, but not the other treatment groups, than in the control group. Urinary ACE2 level was positively correlated with systolic blood pressure (r = 0.211; P = 0.003), UACR (r = 0.367; P < 0.001), and estimated salt intake (r = 0.260; P < 0.001). Multivariable regression analysis after adjustment of age, sex, and the correlated indices showed that the use of olmesartan was an independent predictor of urinary ACE2 level. CONCLUSIONS In contrast with other antihypertensive drugs, olmesartan may uniquely increase urinary ACE2 level, which could potentially offer additional renoprotective effects.
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Affiliation(s)
- Masato Furuhashi
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan;
| | - Norihito Moniwa
- Department of Nephrology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Tomohiro Mita
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takahiro Fuseya
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Shutaro Ishimura
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kohei Ohno
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Satoru Shibata
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Marenao Tanaka
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yuki Watanabe
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroshi Akasaka
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Educational Development, Sapporo Medical University Center for Medical Education, Sapporo, Japan
| | - Hirofumi Ohnishi
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Public Health, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hideaki Yoshida
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hideki Takizawa
- Department of Nephrology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Shigeyuki Saitoh
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Nursing, Division of Medical and Behavioral Subjects, Sapporo Medical University School of Health Sciences, Sapporo, Japan
| | | | | | - Tetsuji Miura
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
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Kovarik JJ, Antlanger M, Domenig O, Kaltenecker CC, Hecking M, Haidinger M, Werzowa J, Kopecky C, Säemann MD. Molecular regulation of the renin-angiotensin system in haemodialysis patients. Nephrol Dial Transplant 2014; 30:115-23. [PMID: 25107336 DOI: 10.1093/ndt/gfu265] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Blockade of the renin-angiotensin system (RAS) exerts beneficial effects in patients with mild-to-moderate chronic kidney disease, yet evidence suggesting a similar benefit in haemodialysis (HD) patients is not available. Furthermore, knowledge of the effects of RAS blockade on systemic RAS components in HD patients is limited. Analysis of the quantity and dynamics of all known peripheral constituents of the RAS may yield important pathomechanistic information of a widespread therapeutic measure in HD patients. METHODS Fifty-two HD patients from the following groups were analysed cross-sectionally: patients without RAS blockade (n = 16), angiotensin-converting enzyme inhibitor (ACEi) users (n = 8), angiotensin receptor blocker (ARB) users (n = 11), patients on ACEi plus ARB (dual blockade, n = 8) and anephric patients (n = 9). Ten healthy volunteers served as controls. Angiotensin metabolites were quantified by mass spectrometry. RESULTS In general, HD patients showed a broad variability of RAS activity. Patients without RAS blockade displayed angiotensin metabolite patterns similar to healthy controls. ACEi therapy increased plasma Ang 1-10 and Ang 1-7 concentrations, whereas ARB treatment increased both Ang 1-8 and Ang 1-5, while suppressing Ang 1-7 to minimal levels. Dual RAS blockade resulted in high levels of Ang 1-10 and suppressed levels of other angiotensins. Anephric patients were completely devoid of detectable levels of circulating angiotensins. CONCLUSION In HD patients, the activity status of the systemic RAS is highly distorted with the emergence of crucial angiotensin metabolites upon distinct RAS blockade. The characterization of molecular RAS patterns associated with specific RAS interfering therapies may help to individualize future clinical studies and therapies.
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Affiliation(s)
- Johannes J Kovarik
- Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Marlies Antlanger
- Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Oliver Domenig
- Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Christopher C Kaltenecker
- Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Manfred Hecking
- Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Michael Haidinger
- Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Johannes Werzowa
- Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Chantal Kopecky
- Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Marcus D Säemann
- Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
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Soler MJ, Wysocki J, Batlle D. ACE2 alterations in kidney disease. Nephrol Dial Transplant 2013; 28:2687-97. [PMID: 23956234 PMCID: PMC3811059 DOI: 10.1093/ndt/gft320] [Citation(s) in RCA: 99] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Accepted: 06/20/2013] [Indexed: 12/16/2022] Open
Abstract
Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that degrades angiotensin (Ang) II to Ang-(1-7). ACE2 is highly expressed within the kidneys, it is largely localized in tubular epithelial cells and less prominently in glomerular epithelial cells and in the renal vasculature. ACE2 activity has been shown to be altered in diabetic kidney disease, hypertensive renal disease and in different models of kidney injury. There is often a dissociation between tubular and glomerular ACE2 expression, particularly in diabetic kidney disease where ACE2 expression is increased at the tubular level but decreased at the glomerular level. In this review, we will discuss alterations in circulating and renal ACE2 recently described in different renal pathologies and disease models as well as their possible significance.
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Affiliation(s)
- María José Soler
- Department of Nephrology, Hospital del Mar-Fundació IMIM, Barcelona, Spain
| | - Jan Wysocki
- Division of Nephrology & Hypertension, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Daniel Batlle
- Division of Nephrology & Hypertension, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
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