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Chhabra KH, Shoemaker R, Herath CB, Thomas MC, Filipeanu CM, Lazartigues E. Molecular dissection of the role of ACE2 in glucose homeostasis. Physiol Rev 2025; 105:935-973. [PMID: 39918873 PMCID: PMC12124467 DOI: 10.1152/physrev.00027.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 09/17/2024] [Accepted: 01/07/2025] [Indexed: 02/09/2025] Open
Abstract
Angiotensin-converting enzyme 2 (ACE2) was discovered 25 years ago as a negative regulator of the renin-angiotensin system, opposing the effects of angiotensin II. Beyond its well-demonstrated roles in cardiovascular regulation and COVID-19 pathology, ACE2 is involved in a plethora of physiopathological processes. In this review, we summarize the latest discoveries on the role of ACE2 in glucose homeostasis and regulation of metabolism. In the endocrine pancreas, ACE2 is expressed at low levels in β-cells, but loss of its expression inhibits glucose-stimulated insulin secretion and impairs glucose tolerance. Conversely, overexpression of ACE2 improved glycemia, suggesting that recombinant ACE2 might be a future therapy for diabetes. In the skeletal muscle of ACE2-deficient mice a progressive triglyceride accumulation was observed, whereas in diabetic kidney the initial increase in ACE2 is followed by a chronic reduction of expression in kidney tubules and impairment of glucose metabolism. At the intestinal level dysregulation of the enzyme alters the amino acid absorption and intestinal microbiome, whereas at the hepatic level ACE2 protects against diabetic fatty liver disease. Not least, ACE2 is upregulated in adipocytes in response to nutritional stimuli, and administration of recombinant ACE2 decreased body weight and increased thermogenesis. In addition to tissue-specific regulation of ACE2 function, the enzyme undergoes complex cellular posttranslational modifications that are changed during diabetes evolution, with at least proteolytic cleavage and ubiquitination leading to modifications in ACE2 activity. Detailed characterization of ACE2 in a cellular and tissue-specific manner holds promise for improving therapeutic outcomes in diabetes and metabolic disorders.
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Affiliation(s)
- Kavaljit H Chhabra
- Department of Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, Kentucky, United States
| | - Robin Shoemaker
- Department of Pediatrics, University of Kentucky, Lexington, Kentucky, United States
| | - Chandana B Herath
- Department of Medicine, Melbourne Medical School, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
| | - Merlin C Thomas
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Catalin M Filipeanu
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States
| | - Eric Lazartigues
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States
- Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States
- Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States
- Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States
- Southeast Louisiana Veterans Health Care System, New Orleans, Louisiana, United States
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2
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Yang J, Yang Y, Tan X, Du H, Zhou Z, Chen L, Tian X, Zheng G, Hu J, Zhang C, Qiu Z. Unlocking the potential of the ACE2/Ang-(1-7)/Mas Axis in liver diseases: From molecular mechanisms to translational applications. Diabetes Obes Metab 2025. [PMID: 40344459 DOI: 10.1111/dom.16435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2025] [Revised: 04/11/2025] [Accepted: 04/21/2025] [Indexed: 05/11/2025]
Abstract
Over the past two decades, the identification of new functions within the renin-angiotensin system (RAS) has extended beyond its traditional roles, with the emergence of the angiotensin-converting enzyme 2 (ACE2)/Ang-(1-7)/Mas axis being particularly significant. This axis is hypothesized to balance or modulate the effects of the traditional ACE/Ang II/AT1 axis in various physiological and pathological contexts. ACE2, a membrane-bound carboxypeptidase and an ancient homologue of ACE converts Angiotensin II (Ang II) into Angiotensin 1-7 (Ang-(1-7)). The Mas receptor is a G-protein-coupled receptor that specifically binds Ang-(1-7). Recent research has increasingly focused on the local expression of RAS in different tissues. Ang-(1-7) produces a variety of biological effects by binding to the Mas receptor, including anti-inflammatory, antioxidant, anti-apoptotic and anti-fibrotic actions, thereby influencing a range of mechanisms in the heart, kidneys, brain and other tissues. Preclinical animal model studies indicate that manipulating the protective RAS can significantly alter the progression of multiple liver diseases. Hepatic overexpression of ACE2 or administration of Ang-(1-7) and its analogues has been shown to be therapeutically effective against drug-induced liver injury, metabolic-associated fatty liver disease, liver fibrosis and hepatocellular carcinoma progression. These effects are achieved through various pathways, including the regulation of lipid metabolism, inhibition of epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) production, as well as suppression of aerobic glycolysis. In current clinical trials, while recombinant human ACE2 (Rh-ACE2) has demonstrated safety and good tolerance in most studies, research on the relevance of activating the ACE2/Ang-(1-7) axis in the mechanisms and evolution of human diseases remains in its early stages. Therefore, further elucidation of the complex interactions between the classical and counter-regulatory RAS axes in clinical settings is crucial. This review will summarize the roles of selective activation of the ACE2/Ang-(1-7)/Mas axis, with a focus on its mechanisms in the treatment of liver diseases. Additionally, we will discuss the safety concerns regarding selective activation of the ACE2/Ang-(1-7)/Mas axis in clinical applications and the challenges of tissue-specific activation of this axis, providing effective therapeutic strategies for targeted activation of the hepatic ACE2/Ang-(1-7)/Mas axis in clinical practice.
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Affiliation(s)
- Jun Yang
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Yuan Yang
- Institute of Maternal and Child Health, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Xiangyun Tan
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Hongzhi Du
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Zhongshi Zhou
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Liang Chen
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Xianxiang Tian
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Guohua Zheng
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Junjie Hu
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Cong Zhang
- College of Basic Medical Sciences, China Three Gorges University, Yichang, China
| | - Zhenpeng Qiu
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
- Hubei Key Laboratory of Resources and Chemistry of Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
- Center of Traditional Chinese Medicine Modernization for Liver Diseases, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
- Hubei Shizhen Laboratory, Wuhan, People's Republic of China
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3
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Ivashkin VT, Drapkina OM, Maevskaya MV, Raikhelson KL, Okovityi SV, Zharkova MS, Grechishnikova VR, Abdulganieva DI, Alekseenko SA, Ardatskaya MD, Bakulin IG, Bakulina NV, Bogomolov PO, Breder VV, Vinnitskaya EV, Geyvandova NI, Golovanova EV, Grinevich VB, Doshchitsin VL, Dudinskaya EN, Ershova EV, Kodzoeva KB, Kozlova IV, Komshilova KA, Konev YV, Korochanskaya NV, Kotovskaya YV, Kravchuk YA, Loranskaya ID, Maev IV, Martynov AI, Mekhtiev SN, Mishina EE, Nadinskaia MY, Nikitin IG, Osipenko MF, Ostroumova OD, Pavlov CS, Pogosova NV, Radchenko VG, Roytberg GE, Saifutdinov RG, Samsonov AA, Seliverstov PV, Sitkin SI, Tarasova LV, Tarzimanova AI, Tkacheva ON, Tkachenko EI, Troshina EA, Turkina SV, Uspenskiy YP, Fominykh YA, Khlynova OV, Tsyganova YV, Shamkhalova MS, Sharkhun OO, Shestakova MV. Clinical Guidelines of the Russian Society for the Study of the Liver, Russian Gastroenterological Association, Russian Society for the Prevention of Non-Communicable Diseases, Russian Association of Endocrinologists, Russian Scientific Medical Society of Therapists, National Society of Preventive Cardiology, Russian Association of Gerontologists and Geriatricians on Non-Alcoholic Fatty Liver Disease. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2025; 35:94-152. [DOI: 10.22416/1382-4376-2025-35-1-94-152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/28/2025]
Abstract
Aim. The clinical guidelines are intended to provide information support for making decisions by gastroenterologists, general practitioners and internists that will improve the quality of medical care for patients with non-alcoholic fatty liver disease, taking into account the latest clinical data and principles of evidence-based medicine. Key points. Clinical guidelines contain information about current views on etiology, risk factors and pathogenesis of nonalcoholic fatty liver disease, peculiarities of its clinical course. Also given recommendations provide information on current methods of laboratory and instrumental diagnostics, invasive and non-invasive tools for nonalcoholic fatty liver disease and its clinical phenotypes assessment, approaches to its treatment, considering the presence of comorbidities, features of dispensary monitoring and prophylaxis. The information is illustrated with algorithms of differential diagnosis and physician's actions. In addition, there is information for the patient and criteria for assessing the quality of medical care. Conclusion. Awareness of specialists in the issues of diagnosis, treatment and follow-up of patients with nonalcoholic fatty liver disease contributes to the timely diagnosis and initiation of treatment, which in the long term will significantly affect their prognosis and quality of life.
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Affiliation(s)
- V. T. Ivashkin
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - O. M. Drapkina
- National Medical Research Center for Therapy and Preventive Medicine
| | - M. V. Maevskaya
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - K. L. Raikhelson
- Saint Petersburg State University;
Academician I.P. Pavlov First Saint Petersburg State Medical University
| | - S. V. Okovityi
- Saint Petersburg State Chemical Pharmaceutical University
| | - M. S. Zharkova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | | | | | | | - M. D. Ardatskaya
- Central State Medical Academy of the Department of Presidential Affairs
| | - I. G. Bakulin
- North-Western State Medical University named after I.I. Mechnikov
| | - N. V. Bakulina
- North-Western State Medical University named after I.I. Mechnikov
| | - P. O. Bogomolov
- Russian University of Medicine;
Moscow Regional Research Clinical Institute
| | - V. V. Breder
- National Medical Research Center of Oncology named after N.N. Blokhin
| | | | | | | | | | | | | | | | - K. B. Kodzoeva
- National Medical Research Center for Transplantology and Artificial Organs named after Academician V.I. Shumakov
| | - I. V. Kozlova
- Saratov State Medical University named after V.I. Razumovsky
| | | | | | | | | | | | | | | | | | - S. N. Mekhtiev
- Academician I.P. Pavlov First Saint Petersburg State Medical University
| | | | - M. Yu. Nadinskaia
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - I. G. Nikitin
- N.I. Pirogov Russian National Research Medical University;
National Medical Research Center “Treatment and Rehabilitation Center”
| | | | | | - Ch. S. Pavlov
- I.M. Sechenov First Moscow State Medical University (Sechenov University);
Moscow Multidisciplinary Scientific and Clinical Center named after S.P. Botkin
| | - N. V. Pogosova
- National Medical Research Center of Cardiology named after Academician E.I. Chazov
| | | | - G. E. Roytberg
- N.I. Pirogov Russian National Research Medical University
| | - R. G. Saifutdinov
- Kazan State Medical Academy — Branch Campus of the Russian Medical Academy of Continuous Professional Education
| | | | | | - S. I. Sitkin
- North-Western State Medical University named after I.I. Mechnikov;
V.A. Almazov National Medical Research Center
| | | | - A. I. Tarzimanova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - O. N. Tkacheva
- N.I. Pirogov Russian National Research Medical University
| | | | | | | | - Yu. P. Uspenskiy
- Academician I.P. Pavlov First Saint Petersburg State Medical University;
Saint Petersburg State Pediatric Medical University
| | - Yu. A. Fominykh
- V.A. Almazov National Medical Research Center; Saint Petersburg State Pediatric Medical University
| | - O. V. Khlynova
- Perm State Medical University named after Academician E.A. Wagner
| | | | | | - O. O. Sharkhun
- N.I. Pirogov Russian National Research Medical University
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Luo YW, Huang AL, Tang KF. Angiotensin-converting enzyme 2 and hepatic SARS-CoV-2 infection: Regulation, association, and therapeutic implications. World J Gastroenterol 2025; 31:100864. [PMID: 39958440 PMCID: PMC11752700 DOI: 10.3748/wjg.v31.i6.100864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 12/07/2024] [Accepted: 12/20/2024] [Indexed: 01/10/2025] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells via the angiotensin-converting enzyme 2 (ACE2) receptor. Mounting evidence has indicated the presence of hepatic SARS-CoV-2 infection and liver injury in patients with coronavirus disease 2019 (COVID-19). Understanding the mechanisms of hepatic SARS-CoV-2 infection is crucial for addressing COVID-19-related liver pathology and developing targeted therapies. This editorial discusses the significance of ACE2 in hepatic SARS-CoV-2 infection, drawing on the research by Jacobs et al. Their findings indicate that hepatic ACE2 expression, frequency of hepatic SARS-CoV-2 infection, and severity of liver injury are elevated in patients with pre-existing chronic liver diseases. These data suggest that hepatic ACE2 could be a promising therapeutic target for COVID-19.
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Affiliation(s)
- Yu-Wei Luo
- Key Laboratory of Molecular Biology on Infectious Disease, Ministry of Education, Chongqing Medical University, Chongqing 400016, China
| | - Ai-Long Huang
- Key Laboratory of Molecular Biology on Infectious Disease, Ministry of Education, Chongqing Medical University, Chongqing 400016, China
| | - Kai-Fu Tang
- Key Laboratory of Molecular Biology on Infectious Disease, Ministry of Education, Chongqing Medical University, Chongqing 400016, China
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Komatsu K, Sano K, Fukai K, Nakagawa R, Nakagawa T, Tatemichi M, Nakano T. Standardized evaluation of diabetic retinopathy using artificial intelligence and its association with metabolic dysfunction-associated steatotic liver disease in Japan: A cross-sectional study. PLoS One 2024; 19:e0315752. [PMID: 39689076 DOI: 10.1371/journal.pone.0315752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Accepted: 11/29/2024] [Indexed: 12/19/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is common in patients with obesity and diabetes and can lead to serious complications. This study aimed to evaluate fundus photographs using artificial intelligence to explore the relationships between diabetic retinopathy (DR), MASLD, and related factors. In this cross-sectional study, we included 1,736 patients with a history of diabetes treatment or glycated hemoglobin (HbA1c) levels of ≥6.5%. All participants were negative for hepatitis B surface antigen and hepatitis C virus antibody and were selected from 33,022 examinees at a health facility in Japan. Fundus photographs were analyzed using RetCAD software, and DR scores were quantified. The presence of DR was determined using two cutoffs: sensitivity (CO20) and specificity (CO50). Steatotic liver (SL) stages were assessed via ultrasound and fibrosis indices and classified into three groups: no SL (SL0), SL with low fibrosis (SL1), and SL with high fibrosis (SL2). Odds ratios (ORs) for the risk of DR associated with each SL stage were calculated using logistic regression, adjusted for age, sex, body mass index, HbA1c, C-reactive protein level, and alcohol consumption. The risk of DR was lower in the SL1 (OR: 0.63, 0.54) and SL2 (OR: 0.64, 0.77) groups compared to the SL0 group at CO20 for both the Fibrosis-4 Index (FIB-4) and the non-alcoholic fatty liver disease fibrosis score (NFS), respectively. Additionally, higher levels of cholinesterase were consistently associated with a reduced risk of DR (FIB-4: OR 0.52, NFS: OR 0.54) at CO50. This study demonstrates that MASLD was associated with a reduced risk of DR, with cholinesterase levels providing further protective effects, highlighting the need for further research into the protective mechanisms and refinement of DR evaluation techniques. The standardized AI evaluation method for DR offers a reliable approach for analyzing retinal changes.
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Affiliation(s)
- Koji Komatsu
- Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan
| | - Kei Sano
- Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan
- Department of Preventive Medicine, School of Medicine, Tokai University, Kanagawa, Japan
| | - Kota Fukai
- Department of Preventive Medicine, School of Medicine, Tokai University, Kanagawa, Japan
| | | | | | - Masayuki Tatemichi
- Department of Preventive Medicine, School of Medicine, Tokai University, Kanagawa, Japan
| | - Tadashi Nakano
- Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan
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Nunes-Souza V, Alenina N, Qadri F, Mosienko V, Santos RAS, Bader M, Rabelo LA. ACE2 Knockout Mice Are Resistant to High-Fat Diet-Induced Obesity in an Age-Dependent Manner. Int J Mol Sci 2024; 25:9515. [PMID: 39273464 PMCID: PMC11394789 DOI: 10.3390/ijms25179515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 08/20/2024] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
Angiotensin converting enzyme 2 (ACE2) presents pleiotropic actions. It hydrolyzes angiotensin I (AngI) and angiotensin II (AngII) into angiotensin-(1-9) (Ang-(1-9)) and angiotensin-(1-7) (Ang-(1-7)), respectively, as well as participates in tryptophan uptake in the gut and in COVID-19 infection. Our aim was to investigate the metabolic effect of ACE2 deletion in young adults and elderly mice under conditions of high calorie intake. Male C57Bl/6 (WT) and ACE2-deficient (ACE2-/y) mice were analyzed at the age of 6 and 12 months under standard diet (StD) and high-fat diet (HFD). Under StD, ACE2-/y showed lower body weight and fat depots, improved glucose tolerance, enhanced insulin sensitivity, higher adiponectin, and lower leptin levels compared to WT. This difference was even more pronounced after HFD in 6-month-old mice, but, interestingly, it was blunted at the age of 12 months. ACE2-/y presented a decrease in adipocyte diameter and lipolysis, which reflected in the upregulation of lipid metabolism in white adipose tissue through the increased expression of genes involved in lipid regulation. Under HFD, both food intake and total energy expenditure were decreased in 6-month-old ACE2-/y mice, accompanied by an increase in liquid intake, compared to WT mice, fed either StD or HFD. Thus, ACE2-/y mice are less susceptible to HFD-induced obesity in an age-dependent manner, as well as represent an excellent animal model of human lipodystrophy and a tool to investigate new treatments.
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Affiliation(s)
- Valéria Nunes-Souza
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany; (V.N.-S.); (F.Q.); (V.M.); (M.B.)
- Department of Physiology and Pharmacology, Federal University of Pernambuco, Recife 50670-901, Brazil
- National Institute of Science and Technology in Nanobiopharmaceutics (Nanobiofar), Belo Horizonte 31270-901, Brazil;
| | - Natalia Alenina
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany; (V.N.-S.); (F.Q.); (V.M.); (M.B.)
| | - Fatimunnisa Qadri
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany; (V.N.-S.); (F.Q.); (V.M.); (M.B.)
| | - Valentina Mosienko
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany; (V.N.-S.); (F.Q.); (V.M.); (M.B.)
- School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol BS8 1TD, UK
| | - Robson Augusto Souza Santos
- National Institute of Science and Technology in Nanobiopharmaceutics (Nanobiofar), Belo Horizonte 31270-901, Brazil;
- Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte 31270-901, Brazil
| | - Michael Bader
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany; (V.N.-S.); (F.Q.); (V.M.); (M.B.)
- DZHK (German Center for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, Germany
- Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, 10117 Berlin, Germany
- Institute for Biology, University of Lübeck, 23562 Lübeck, Germany
| | - Luiza Antas Rabelo
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany; (V.N.-S.); (F.Q.); (V.M.); (M.B.)
- National Institute of Science and Technology in Nanobiopharmaceutics (Nanobiofar), Belo Horizonte 31270-901, Brazil;
- Laboratory of Cardiovascular Reactivity, Metabolic Syndrome Center, Institute of Biological Sciences and Health, Federal University of Alagoas, Maceió 57072-900, Brazil
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McGrath MS, Wentworth BJ. The Renin-Angiotensin System in Liver Disease. Int J Mol Sci 2024; 25:5807. [PMID: 38891995 PMCID: PMC11172481 DOI: 10.3390/ijms25115807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 05/23/2024] [Accepted: 05/25/2024] [Indexed: 06/21/2024] Open
Abstract
The renin-angiotensin system (RAS) is a complex homeostatic entity with multiorgan systemic and local effects. Traditionally, RAS works in conjunction with the kidney to control effective arterial circulation, systemic vascular resistance, and electrolyte balance. However, chronic hepatic injury and resulting splanchnic dilation may disrupt this delicate balance. The role of RAS in liver disease, however, is even more extensive, modulating hepatic fibrosis and portal hypertension. Recognition of an alternative RAS pathway in the past few decades has changed our understanding of RAS in liver disease, and the concept of opposing vs. "rebalanced" forces is an ongoing focus of research. Whether RAS inhibition is beneficial in patients with chronic liver disease appears to be context-dependent, but further study is needed to optimize clinical management and reduce organ-specific morbidity and mortality. This review presents the current understanding of RAS in liver disease, acknowledges areas of uncertainty, and describes potential areas of future investigation.
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Affiliation(s)
- Mary S. McGrath
- Department of Medicine, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA;
| | - Brian J. Wentworth
- Division of Gastroenterology & Hepatology, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA
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Zhao BW, Chen YJ, Zhang RP, Chen YM, Huang BW. Angiotensin-converting enzyme 2 alleviates liver fibrosis through the renin-angiotensin system. World J Gastroenterol 2024; 30:607-609. [PMID: 38463024 PMCID: PMC10921144 DOI: 10.3748/wjg.v30.i6.607] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/17/2023] [Accepted: 01/15/2024] [Indexed: 02/05/2024] Open
Abstract
The present letter to the editor is related to the study titled 'Angiotensin-converting enzyme 2 improves liver fibrosis in mice by regulating autophagy of hepatic stellate cells'. Angiotensin-converting enzyme 2 can alleviate liver fibrosis by regulating autophagy of hepatic stellate cells and affecting the renin-angiotensin system.
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Affiliation(s)
- Bai-Wei Zhao
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou 510060, Guangdong Province, China
| | - Ying-Jia Chen
- Health Science Center, Peking University, Beijing 100191, China
| | - Ruo-Peng Zhang
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou 510060, Guangdong Province, China
| | - Yong-Ming Chen
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou 510060, Guangdong Province, China
| | - Bo-Wen Huang
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou 510060, Guangdong Province, China
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Wu Y, Yin AH, Sun JT, Xu WH, Zhang CQ. Angiotensin-converting enzyme 2 improves liver fibrosis in mice by regulating autophagy of hepatic stellate cells. World J Gastroenterol 2023; 29:4975-4990. [PMID: 37732000 PMCID: PMC10507507 DOI: 10.3748/wjg.v29.i33.4975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/27/2023] [Accepted: 08/15/2023] [Indexed: 09/01/2023] Open
Abstract
BACKGROUND Liver fibrosis is the common pathological process associated with the occurrence and development of various chronic liver diseases. At present, there is still a lack of effective prevention and treatment methods in clinical practice. Hepatic stellate cell (HSC) plays a key role in liver fibrogenesis. In recent years, the study of liver fibrosis targeting HSC autophagy has become a hot spot in this research field. Angiotensin-converting enzyme 2 (ACE2) is a key negative regulator of renin-angiotensin system, and its specific molecular mechanism on autophagy and liver fibrosis needs to be further explored. AIM To investigate the effect of ACE2 on hepatic fibrosis in mice by regulating HSC autophagy through the Adenosine monophosphate activates protein kinases (AMPK)/mammalian target of rapamycin (mTOR) pathway. METHODS Overexpression of ACE2 in a mouse liver fibrosis model was induced by injection of liver-specific recombinant adeno-associated virus ACE2 vector (rAAV2/8-ACE2). The degree of liver fibrosis was assessed by histopathological staining and the biomarkers in mouse serum were measured by Luminex multifactor analysis. The number of apoptotic HSCs was assessed by terminal deoxynucleoitidyl transferase-mediated dUTP nick-end labeling (TUNEL) and immunofluorescence staining. Transmission electron microscopy was used to identify the changes in the number of HSC autophagosomes. The effect of ACE2 overexpression on autophagy-related proteins was evaluated by multicolor immunofluorescence staining. The expression of autophagy-related indicators and AMPK pathway-related proteins was measured by western blotting. RESULTS A mouse model of liver fibrosis was successfully established after 8 wk of intraperitoneal injection of carbon tetrachloride (CCl4). rAAV2/8-ACE2 administration reduced collagen deposition and alleviated the degree of liver fibrosis in mice. The serum levels of platelet-derived growth factor, angiopoietin-2, vascular endothelial growth factor and angiotensin II were decreased, while the levels of interleukin (IL)-10 and angiotensin- (1-7) were increased in the rAAV2/8-ACE2 group. In addition, the expression of alpha-smooth muscle actin, fibronectin, and CD31 was down-regulated in the rAAV2/8-ACE2 group. TUNEL and immunofluorescence staining showed that rAAV2/8-ACE2 injection increased HSC apoptosis. Moreover, rAAV2/8-ACE2 injection notably decreased the number of autophagosomes and the expression of autophagy-related proteins (LC3I, LC3II, Beclin-1), and affected the expression of AMPK pathway-related proteins (AMPK, p-AMPK, p-mTOR). CONCLUSION ACE2 overexpression can inhibit HSC activation and promote cell apoptosis by regulating HSC autophagy through the AMPK/mTOR pathway, thereby alleviating liver fibrosis and hepatic sinusoidal remodeling.
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Affiliation(s)
- Ying Wu
- Department of Gastroenterology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong Province, China
| | - Ai-Hong Yin
- Department of Gastroenterology, Shandong Second Provincial General Hospital, Jinan 250000, Shandong Province, China
| | - Jun-Tao Sun
- Department of Gastroenterology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong Province, China
| | - Wei-Hua Xu
- Department of Gastroenterology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong Province, China
| | - Chun-Qing Zhang
- Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong Province, China
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10
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Sansoè G, Aragno M. New Viral Diseases and New Possible Remedies by Means of the Pharmacology of the Renin-Angiotensin System. J Renin Angiotensin Aldosterone Syst 2023; 2023:3362391. [PMID: 37476705 PMCID: PMC10356449 DOI: 10.1155/2023/3362391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 05/01/2023] [Accepted: 06/21/2023] [Indexed: 07/22/2023] Open
Abstract
All strains of SARS-CoV-2, as well as previously described SARS-CoV and MERS-CoV, bind to ACE2, the cell membrane receptor of β-coronaviruses. Monocarboxypeptidase ACE2 activity stops upon viral entry into cells, leading to inadequate tissue production of angiotensin 1-7 (Ang1-7). Acute lung injury due to the human respiratory syncytial virus (hRSV) or avian influenza A H7N9 and H5N1 viruses is also characterized by significant downregulation of lung ACE2 and increased systemic levels of angiotensin II (Ang II). Restoration of Ang1-7 anti-inflammatory, antifibrotic, vasodilating, and natriuretic properties was attempted at least in some COVID-19 patients through i.v. infusion of recombinant human ACE2 or intranasal administration of the modified ACE2 protein, with inconsistent clinical results. Conversely, use of ACE inhibitors (ACEis), which increase ACE2 cell expression, seemed to improve the prognosis of hypertensive patients with COVID-19. To restore Ang1-7 tissue levels in all these viral diseases and avoid the untoward effects frequently seen with ACE2 systemic administration, a different strategy may be hypothesized. Experimentally, when metallopeptidase inhibitors block ACE2, neprilysin (NEP), highly expressed in higher and lower airways, starts cleaving angiotensin I (Ang I) into Ang1-7. We suggest a discerning use of ACEis in normohypertensive patients with β-coronavirus disease as well as in atypical pneumonia caused by avian influenza viruses or hRSV to block the main ACE-dependent effects: Ang II synthesis and Ang1-7 degradation into angiotensin 1-5. At the same time, i.v.-infused Ang I, which is not hypertensive provided ACE is inhibited, may become the primary substrate for local Ang1-7 synthesis via ubiquitous NEP; i.e., NEP could replace inadequate ACE2 function if Ang I was freely available. Moreover, inhibitors of chymase, a serine endopeptidase responsible for 80% of Ang II-forming activity in tissues and vessel walls, could protect patients with atypical pneumonia from Ang II-mediated microvascular damage without reducing arterial blood pressure.
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Affiliation(s)
- Giovanni Sansoè
- Gastroenterology Unit, Humanitas Institute, Gradenigo Hospital, Corso Regina Margherita 10, 10153 Torino, Italy
| | - Manuela Aragno
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
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11
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Brown S, Nores GDG, Sarker A, Ly C, Li C, Park HJ, Hespe GE, Gardenier J, Kuonqui K, Campbell A, Shin J, Kataru RP, Aras O, Mehrara BJ. Topical captopril: a promising treatment for secondary lymphedema. Transl Res 2023; 257:43-53. [PMID: 36736951 PMCID: PMC10192126 DOI: 10.1016/j.trsl.2023.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 01/15/2023] [Accepted: 01/25/2023] [Indexed: 02/04/2023]
Abstract
Transforming growth factor-beta 1 (TGF-β1)-mediated tissue fibrosis is an important regulator of lymphatic dysfunction in secondary lymphedema. However, TGF-β1 targeting can cause toxicity and autoimmune complications, limiting clinical utility. Angiotensin II (Ang II) modulates intracellular TGF-β1 signaling, and inhibition of Ang II production using angiotensin-converting enzyme (ACE) inhibitors, such as captopril, has antifibrotic efficacy in some pathological settings. Therefore, we analyzed the expression of ACE and Ang II in clinical lymphedema biopsy specimens from patients with unilateral breast cancer-related lymphedema (BCRL) and mouse models, and found that cutaneous ACE expression is increased in lymphedematous tissues. Furthermore, topical captopril decreases fibrosis, activation of intracellular TGF-β1 signaling pathways, inflammation, and swelling in mouse models of lymphedema. Captopril treatment also improves lymphatic function and immune cell trafficking by increasing collecting lymphatic pumping. Our results show that the renin-angiotensin system in the skin plays an important role in the regulation of fibrosis in lymphedema, and inhibition of this signaling pathway may hold merit for treating lymphedema.
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Affiliation(s)
- Stav Brown
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Gabriela D G Nores
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ananta Sarker
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Catherine Ly
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Claire Li
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Hyeung Ju Park
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Geoffrey E Hespe
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jason Gardenier
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Kevin Kuonqui
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Adana Campbell
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jinyeon Shin
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Raghu P Kataru
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Omer Aras
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Babak J Mehrara
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York.
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12
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Golab F, Vahabzadeh G, SadeghRoudbari L, Shirazi A, Shabani R, Tanbakooei S, Kooshesh L. The Protective Potential Role of ACE2 against COVID-19. Adv Virol 2023; 2023:8451931. [PMID: 37275947 PMCID: PMC10238138 DOI: 10.1155/2023/8451931] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/22/2022] [Accepted: 05/16/2023] [Indexed: 06/07/2023] Open
Abstract
Due to the coronavirus disease 2019 (COVID-19), researchers all over the world have tried to find an appropriate therapeutic approach for the disease. The angiotensin-converting enzyme 2 (ACE2) has been shown as a necessary receptor to cell fusion, which is involved in infection due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is commonly crucial for all organs and systems. When ACE2 is downregulated via the SARS-CoV-2 spike protein, it results in the angiotensin II (Ang II)/angiotensin type 1 receptor axis overactivation. Ang II has harmful effects, which can be evidenced by dysfunctions in many organs experienced by COVID-19 patients. ACE2 is the SARS-CoV-2 receptor and has an extensive distribution; thus, some COVID-19 cases experience several symptoms and complications. We suggest strategy for the potential protective effect of ACE2 to the viral infection. The current review will provide data to develop new approaches for preventing and controlling the COVID-19 outbreak.
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Affiliation(s)
- Fereshteh Golab
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Gelareh Vahabzadeh
- Razi Drug Research Center, Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Leila SadeghRoudbari
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Arefeh Shirazi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Robabeh Shabani
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Sara Tanbakooei
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Lida Kooshesh
- Department of Cellular and Molecular Biology, Islamic Azad University, Tehran North Branch, Tehran, Iran
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13
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Hartl L, Rumpf B, Domenig O, Simbrunner B, Paternostro R, Jachs M, Poglitsch M, Marculescu R, Trauner M, Reindl-Schwaighofer R, Hecking M, Mandorfer M, Reiberger T. The systemic and hepatic alternative renin-angiotensin system is activated in liver cirrhosis, linked to endothelial dysfunction and inflammation. Sci Rep 2023; 13:953. [PMID: 36653504 PMCID: PMC9849268 DOI: 10.1038/s41598-023-28239-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 01/16/2023] [Indexed: 01/19/2023] Open
Abstract
We aimed to assess the systemic and hepatic renin-angiotensin-system (RAS) fingerprint in advanced chronic liver disease (ACLD). This prospective study included 13 compensated (cACLD) and 12 decompensated ACLD (dACLD) patients undergoing hepatic venous pressure gradient (HVPG) measurement. Plasma components (all patients) and liver-local enzymes (n = 5) of the RAS were analyzed using liquid chromatography-tandem mass spectrometry. Patients with dACLD had significantly higher angiotensin (Ang) I, Ang II and aldosterone plasma levels. Ang 1-7, a major mediator of the alternative RAS, was almost exclusively detectable in dACLD (n = 12/13; vs. n = 1/13 in cACLD). Also, dACLD patients had higher Ang 1-5 (33.5 pmol/L versus cACLD: 6.6 pmol/L, p < 0.001) and numerically higher Ang III and Ang IV levels. Ang 1-7 correlated with HVPG (ρ = 0.655; p < 0.001), von Willebrand Factor (ρ = 0.681; p < 0.001), MELD (ρ = 0.593; p = 0.002) and interleukin-6 (ρ = 0.418; p = 0.047). Considerable activity of ACE, chymase, ACE2, and neprilysin was detectable in all liver biopsies, with highest chymase and ACE2 activity in cACLD patients. While liver-local classical and alternative RAS activity was already observed in cACLD, systemic activation of alternative RAS components occurred only in dACLD. Increased Ang 1-7 was linked to severe liver disease, portal hypertension, endothelial dysfunction and inflammation.
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Affiliation(s)
- Lukas Hartl
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Benedikt Rumpf
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Department of Surgery, Medical University of Vienna, Vienna, Austria
| | | | - Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Rafael Paternostro
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Mathias Jachs
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | | | - Rodrig Marculescu
- Department for Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Roman Reindl-Schwaighofer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Manfred Hecking
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. .,Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria. .,Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria.
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14
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Rosso C, Demelas C, Agostini G, Abate ML, Vernero M, Caviglia GP, D’Amato D, Armandi A, Tapparo M, Guariglia M, Troshina G, Massano A, Olivero A, Nicolosi A, Zannetti A, Pellicano R, Ciancio A, Saracco GM, Ribaldone DG, Bugianesi E, Fagoonee S. Expression of SARS-Cov-2 Entry Factors in Patients with Chronic Hepatitis. Viruses 2022; 14:2397. [PMID: 36366497 PMCID: PMC9699546 DOI: 10.3390/v14112397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 01/31/2023] Open
Abstract
Chronic hepatitis (CH) of dysmetabolic or viral etiology has been associated with poor prognosis in patients who experienced the severe acute respiratory coronavirus virus-2 (SARS-Cov-2) infection. We aimed to explore the impact of SARS-Cov-2 infection on disease severity in a group of patients with CH. Forty-two patients with CH of different etiology were enrolled (median age, 56 years; male gender, 59%). ACE2 and TMPRSS2 were measured in plasma samples of all patients by ELISA and in the liver tissue of a subgroup of 15 patients by Western blot. Overall, 13 patients (31%) experienced SARS-Cov-2 infection: 2/15 (15%) had CHB, 5/12 (39%) had CHC, and 6/15 (46%) had non-alcoholic fatty liver disease (NAFLD). Compared to viral CH patients, NAFLD subjects showed higher circulating ACE2 levels (p = 0.0019). Similarly, hepatic expression of ACE2 was higher in subjects who underwent SARS-Cov-2 infection compared to the counterpart, (3.24 ± 1.49 vs. 1.49 ± 1.32, p = 0.032). Conversely, hepatic TMPRSS2 was significantly lower in patients who experienced symptomatic COVID-19 disease compared to asymptomatic patients (p = 0.0038). Further studies are necessary to understand the impact of COVID-19 in patients with pre-existing liver diseases.
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Affiliation(s)
- Chiara Rosso
- Department of Medical Sciences, University of Turin, 10126 Torino, Italy
| | - Cristina Demelas
- Department of Medical Sciences, University of Turin, 10126 Torino, Italy
| | - Greta Agostini
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, 10126 Turin, Italy
| | - Maria Lorena Abate
- Department of Medical Sciences, University of Turin, 10126 Torino, Italy
| | - Marta Vernero
- Department of Medical Sciences, University of Turin, 10126 Torino, Italy
| | | | - Daphne D’Amato
- Department of Medical Sciences, University of Turin, 10126 Torino, Italy
| | - Angelo Armandi
- Department of Medical Sciences, University of Turin, 10126 Torino, Italy
| | - Marta Tapparo
- Department of Medical Sciences, University of Turin, 10126 Torino, Italy
| | - Marta Guariglia
- Department of Medical Sciences, University of Turin, 10126 Torino, Italy
| | - Giulia Troshina
- Department of Medical Sciences, University of Turin, 10126 Torino, Italy
| | - Alessandro Massano
- Department of Medical Sciences, University of Turin, 10126 Torino, Italy
| | - Antonella Olivero
- Department of Medical Sciences, University of Turin, 10126 Torino, Italy
| | - Aurora Nicolosi
- Department of Medical Sciences, University of Turin, 10126 Torino, Italy
| | | | - Rinaldo Pellicano
- Gastroenterology Unit, Città della salute e della Scienza Hospital, 10121 Turin, Italy
| | - Alessia Ciancio
- Department of Medical Sciences, University of Turin, 10126 Torino, Italy
| | | | | | | | - Sharmila Fagoonee
- Institute of Biostructure and Bioimaging, CNR c/o Molecular Biotechnology Centre, 10126 Turin, Italy
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15
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Angiotensin-converting Enzyme-2 (ACE2) Expression in Pediatric Liver Disease. Appl Immunohistochem Mol Morphol 2022; 30:647-653. [PMID: 36222506 DOI: 10.1097/pai.0000000000001068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 08/20/2022] [Indexed: 11/25/2022]
Abstract
The membrane protein angiotensin-converting enzyme-2 (ACE2) has gained notoriety as the receptor for severe acute respiratory syndrome coronavirus 2. Prior evidence has shown ACE2 is expressed within the liver but its function has not been fully discerned. Here, we utilized novel methodology to assess ACE2 expression in pediatric immune-mediated liver disease to better understand its presence in liver diseases and its role during infections such as COVID-19. We stained liver tissue with ACE2-specific immunofluorescent antibodies, analyzed via confocal microscopy. Computational deep learning-based segmentation models identified nuclei and cells, allowing the quantification of mean cellular and cytosolic immunofluorescent. Spatial transcriptomics provided high-throughput gene expression analysis in tissue to determine cellular composition for ACE2 expression. ACE2 plasma expression was quantified via enzyme-linked immunosorbent assay. High ACE2 expression was seen at the apical surface of cholangiocytes, with lower expression within hepatocyte cytosol and nonparenchymal cells (P<0.001). Children with liver disease had higher ACE2 hepatic expression than pediatric control tissue (P<0.001). Adult control tissue had higher expression than pediatric control (P<0.001). Plasma ACE2 was not found to be statistically different between samples. Spatial transcriptomics identified cell composition of ACE2-expressing spots containing antibody-secreting cells. Our results show ACE2 expression throughout the liver, with strongest localization to cholangiocyte membranes. Machine learning can be used to rapidly identify hepatic cellular components for histologic analysis. ACE2 expression in the liver may be increased in pediatric liver disease. Future work is needed to better understand the role of ACE2 in chronic disease and acute infections.
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16
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Bu FT, Jia PC, Zhu Y, Yang YR, Meng HW, Bi YH, Huang C, Li J. Emerging therapeutic potential of adeno-associated virus-mediated gene therapy in liver fibrosis. Mol Ther Methods Clin Dev 2022; 26:191-206. [PMID: 35859692 PMCID: PMC9271983 DOI: 10.1016/j.omtm.2022.06.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Liver fibrosis is a wound-healing response that results from various chronic damages. If the causes of damage are not removed or effective treatments are not given in a timely manner, it will progress to cirrhosis, even liver cancer. Currently, there are no specific medical therapies for liver fibrosis. Adeno-associated virus (AAV)-mediated gene therapy, one of the frontiers of modern medicine, has gained more attention in many fields due to its high safety profile, low immunogenicity, long-term efficacy in mediating gene expression, and increasingly known tropism. Notably, increasing evidence suggests a promising therapeutic potential for AAV-mediated gene therapy in different liver fibrosis models, which helps to correct abnormally changed target genes in the process of fibrosis and improve liver fibrosis at the molecular level. Moreover, the addition of cell-specific promoters to the genome of recombinant AAV helps to limit gene expression in specific cells, thereby producing better therapeutic efficacy in liver fibrosis. However, animal models are considered to be powerless predictive of tissue tropism, immunogenicity, and genotoxic risks in humans. Thus, AAV-mediated gene therapy will face many challenges. This review systemically summarizes the recent advances of AAV-mediated gene therapy in liver fibrosis, especially focusing on cellular and molecular mechanisms of transferred genes, and presents prospective challenges.
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Affiliation(s)
- Fang-Tian Bu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 81 Mei Shan Road, Hefei, Anhui Province 230032, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Peng-Cheng Jia
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 81 Mei Shan Road, Hefei, Anhui Province 230032, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Yan Zhu
- The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ya-Ru Yang
- The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hong-Wu Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 81 Mei Shan Road, Hefei, Anhui Province 230032, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Yi-Hui Bi
- The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 81 Mei Shan Road, Hefei, Anhui Province 230032, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 81 Mei Shan Road, Hefei, Anhui Province 230032, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
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17
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Olmesartan Improves Hepatic Sinusoidal Remodeling in Mice with Carbon Tetrachloride-Induced Liver Fibrosis. BIOMED RESEARCH INTERNATIONAL 2022; 2022:4710993. [PMID: 36060127 PMCID: PMC9439923 DOI: 10.1155/2022/4710993] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 07/04/2022] [Accepted: 07/30/2022] [Indexed: 11/24/2022]
Abstract
Aim In mice with liver fibrosis produced by carbon tetrachloride (CCl4), the effects of olmesartan on intrahepatic angiogenesis and sinusoidal remodeling will be evaluated. Methods By injecting CCl4 into the peritoneal cavity, we established a mouse model of liver fibrosis. Using Sirius red and Masson trichrome staining, the extent of liver fibrosis in the animals was determined. Using immunohistochemical labeling and western blotting, the level of α-smooth muscle actin (α-SMA) expression, a characteristic of hepatic stellate cell activation, was assessed. Electron microscopy was used to determine the effect of olmesartan on hepatic sinusoidal capillarization, and immunohistochemical labeling was used to determine the expression levels of endothelial and basement membrane proteins in mouse liver tissues. Platelet-derived growth factor (PDGF), IL-10, vascular endothelial growth factor (VEGF), and angiotensin II levels in mouse serum were measured by Luminex multifactor analysis and ELISA. Olmesartan's effect on the angiotensin II type 1 receptor (AT1R) and the VEGF receptor (VEGFR) was evaluated using western blotting. Results Olmesartan reduced CCl4-induced inflammatory cell infiltration and collagen deposition to alleviate liver fibrosis. α-SMA expression was decreased, and HSC activation was inhibited in mouse liver tissues by olmesartan treatment. In addition, hepatic sinusoidal capillarization was improved under the action of olmesartan. The expression of collagen IV, fibronectin, CD31, and von Willebrand factor (VWF) in the olmesartan group was also markedly downregulated. In fibrotic mice, olmesartan medication decreased the levels of PDGF, VEGF, and angiotensin II, but it increased the level of IL-10. Moreover, olmesartan reduced the expression of VEGFR-1, VEGFR-2, and AT1R relative to CCl4-induced liver fibrosis. Conclusions In mice with CCl4-induced fibrosis, olmesartan lowers angiogenesis and improves hepatic sinusoidal remodeling, according to our findings. By acting on the angiotensin II-AT1R-VEGF axis, this is achieved.
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Sharma N, Sircar A, Anders HJ, Gaikwad AB. Crosstalk between kidney and liver in non-alcoholic fatty liver disease: mechanisms and therapeutic approaches. Arch Physiol Biochem 2022; 128:1024-1038. [PMID: 32223569 DOI: 10.1080/13813455.2020.1745851] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Liver and kidney are vital organs that maintain homeostasis and injury to either of them triggers pathogenic pathways affecting the other. For example, non-alcoholic fatty liver disease (NAFLD) promotes the progression of chronic kidney disease (CKD), vice versa acute kidney injury (AKI) endorses the induction and progression of liver dysfunction. Progress in clinical and basic research suggest a role of excessive fructose intake, insulin resistance, inflammatory cytokines production, activation of the renin-angiotensin system, redox imbalance, and their impact on epigenetic regulation of gene expression in this context. Recent developments in experimental and clinical research have identified several biochemical and molecular pathways for AKI-liver interaction, including altered liver enzymes profile, metabolic acidosis, oxidative stress, activation of inflammatory and regulated cell death pathways. This review focuses on the current preclinical and clinical findings on kidney-liver crosstalk in NAFLD-CKD and AKI-liver dysfunction settings and highlights potential molecular mechanisms and therapeutic targets.
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Affiliation(s)
- Nisha Sharma
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan, India
| | - Anannya Sircar
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan, India
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Internal Medicine IV, University Hospital of the Ludwig Maximilians University Munich, Munich, Germany
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan, India
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Attia H, Albekairi N, Albdeirat L, Soliman A, Rajab R, Alotaibi H, Ali R, Badr A. Chrysin Attenuates Fructose-Induced Nonalcoholic Fatty Liver in Rats via Antioxidant and Anti-Inflammatory Effects: The Role of Angiotensin-Converting Enzyme 2/Angiotensin (1-7)/Mas Receptor Axis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9479456. [PMID: 35720181 PMCID: PMC9200559 DOI: 10.1155/2022/9479456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 05/12/2022] [Indexed: 11/25/2022]
Abstract
AIM Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and if untreated, it may propagate into end-stage liver disease. The classical arm of the renin-angiotensin system (RAS) has a fundamental role in triggering oxidative stress and inflammation, which play potential roles in the pathogenesis of NAFLD. However, the nonclassical alternative axis of RAS, angiotensin- (Ang-) converting enzyme 2 (ACE2)/Ang (1-7)/Mas receptor, opposes the actions of the classical arm, mitigates the metabolic dysfunction, and improves hepatic lipid metabolism rendering it a promising protective target against NAFLD. The current study is aimed at investigating the impact of chrysin, a well-known antioxidant flavonoid, on this defensive RAS axis in NAFLD. METHODS Rats were randomly distributed and treated daily for eight weeks as follows: the normal control, chrysin control (50 mg/kg, p.o), NAFLD group (received 20% fructose in drinking water), and treated groups (25 and 50 mg/kg chrysin given orally and concomitantly with fructose). Diminazene aceturate (DIZE) (15 mg/kg, s.c.) was used as a reference ACE2 activator. Key Findings. High fructose induced significant weight gain, hepatocyte degeneration with fat accumulation, and inflammatory cell infiltration (as examined by H&E staining). This was accompanied by a substantial increase in liver enzymes, glucose, circulating and hepatic triglycerides, lipid peroxides, inflammatory cytokines, and Ang II (the main component of classical RAS). At the same time, protein levels of ACE2, Ang (1-7), and Mas receptors were markedly reduced. Chrysin (25 and 50 mg/kg) significantly ameliorated these abnormalities, with a prominent effect of the dose of 50 mg/kg over DIZE and the lower dose in improving ACE2, Ang (1-7), and Mas. Significance. Chrysin is a promising efficient protective remedy against NAFLD; mechanisms include the activation of ACE2/Ang (1-7)/Mas axis.
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Affiliation(s)
- Hala Attia
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
- Department of Biochemistry, College of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Norah Albekairi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
| | - Layal Albdeirat
- College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
| | - Arwa Soliman
- College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
| | - Reem Rajab
- College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
| | - Hend Alotaibi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
| | - Rehab Ali
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
| | - Amira Badr
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
- Department of Pharmacology and Toxicology, College of Pharmacy, Ain Shams University, Heliopolis, Cairo, Egypt
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Renin–Angiotensin System in Liver Metabolism: Gender Differences and Role of Incretins. Metabolites 2022; 12:metabo12050411. [PMID: 35629915 PMCID: PMC9143858 DOI: 10.3390/metabo12050411] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/12/2022] [Accepted: 04/27/2022] [Indexed: 02/04/2023] Open
Abstract
The impaired hepatic lipids and carbohydrates metabolism result in various metabolic disorders, including obesity, diabetes, insulin resistance, hyperlipidemia and metabolic syndrome. The renin–angiotensin system (RAS) has been identified in the liver and it is now recognized as an important modulator of body metabolic processes. This review is intended to provide an update of the impact of the renin–angiotensin system on lipid and carbohydrate metabolism, regarding gender difference and prenatal undernutrition, specifically focused on the role of the liver. The discovery of angiotensin-converting enzyme 2 (ACE2) has renewed interest in the potential therapeutic role of RAS modulation. RAS is over activated in non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma. Glucagon-like peptide-1 (GLP-1) has been shown to modulate RAS. The GLP-I analogue liraglutide antagonizes hepatocellular steatosis and exhibits liver protection. Liraglutide has a negative effect on the ACE/AngII/AT1R axis and a positive impact on the ACE2/Ang(1-7)/Mas axis. Activation of the ACE2/Ang(1-7)/Mas counter-regulatory axis is able to prevent liver injuries. Angiotensin(1-7) and ACE2 shows more favorable effects on lipid homeostasis in males but there is a need to do more investigation in female models. Prenatal undernutrition exerts long-term effects in the liver of offspring and is associated with a number of metabolic and endocrine alterations. These findings provide a novel therapeutic regimen to prevent and treat many chronic diseases by accelerating the effect of the ACE2/Ang1-7/Mas axis and inhibiting the ACE/AngII/AT1R axis.
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21
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Kariyawasam JC, Jayarajah U, Abeysuriya V, Riza R, Seneviratne SL. Involvement of the Liver in COVID-19: A Systematic Review. Am J Trop Med Hyg 2022; 106:1026-1041. [PMID: 35203056 PMCID: PMC8991364 DOI: 10.4269/ajtmh.21-1240] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 01/16/2022] [Indexed: 01/11/2023] Open
Abstract
COVID-19, a respiratory viral infection, has affected 388 million individuals worldwide as of the February 4, 2022. In this review, we have outlined the important liver manifestations of COVID-19 and discussed the possible underlying pathophysiological mechanisms and their diagnosis and management. Factors that may contribute to hepatic involvement in COVID-19 include direct viral cytopathic effects, exaggerated immune responses/systemic inflammatory response syndrome, hypoxia-induced changes, vascular changes due to coagulopathy, endothelitis, cardiac congestion from right heart failure, and drug-induced liver injury. The majority of COVID-19-associated liver symptoms are mild and self-limiting. Thus management is generally supportive. Liver function tests and abdominal imaging are the primary investigations done in relation to liver involvement in COVID-19 patients. However, imaging findings are nonspecific. Severe acute respiratory syndrome coronavirus 2 RNA has been found in liver biopsies. However, there is limited place for liver biopsy in the clinical context, as it does not influence management. Although, the management is supportive in the majority of patients without previous liver disease, special emphasis is needed in those with nonalcoholic fatty liver disease, cirrhosis, hepatocellular carcinoma, hepatitis B and C infections, and alcoholic liver disease, and in liver transplant recipients.
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Affiliation(s)
| | - Umesh Jayarajah
- Postgraduate Institute of Medicine, University of Colombo, Colombo, Sri Lanka
| | - Visula Abeysuriya
- Nawaloka Hospital Research and Education Foundation, Nawaloka Hospitals, Colombo, Sri Lanka
| | - Rishdha Riza
- Colombo South Teaching Hospital, Colombo, Sri Lanka
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22
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Well-differentiated liver cancers reveal the potential link between ACE2 dysfunction and metabolic breakdown. Sci Rep 2022; 12:1859. [PMID: 35115564 PMCID: PMC8814043 DOI: 10.1038/s41598-021-03710-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 12/08/2021] [Indexed: 01/08/2023] Open
Abstract
Angiotensin-converting enzyme 2 (ACE2) is the receptor of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causing Coronavirus disease 2019 (COVID-19). Transmembrane serine protease 2 (TMPRSS2) is a coreceptor. Abnormal hepatic function in COVID-19 suggests specific or bystander liver disease. Because liver cancer cells express the ACE2 viral receptor, they are widely used as models of SARS-CoV-2 infection in vitro. Therefore, the purpose of this study was to analyze ACE2 and TMPRSS2 expression and localization in human liver cancers and in non-tumor livers. We studied ACE2 and TMPRSS2 in transcriptomic datasets totaling 1503 liver cancers, followed by high-resolution confocal multiplex immunohistochemistry and quantitative image analysis of a 41-HCC tissue microarray. In cancers, we detected ACE2 and TMPRSS2 at the biliary pole of tumor hepatocytes. In whole mount sections of five normal liver samples, we identified ACE2 in hepatocyte’s bile canaliculi, biliary epithelium, sinusoidal and capillary endothelial cells. Tumors carrying mutated β-catenin showed ACE2 DNA hypomethylation and higher mRNA and protein expression, consistently with predicted β-catenin response sites in the ACE2 promoter. Finally, ACE2 and TMPRSS2 co-expression networks highlighted hepatocyte-specific functions, oxidative stress and inflammation, suggesting a link between inflammation, ACE2 dysfunction and metabolic breakdown.
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23
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Sabri S, Bourron O, Phan F, Nguyen LS. Interactions between diabetes and COVID-19: A narrative review. World J Diabetes 2021; 12:1674-1692. [PMID: 34754370 PMCID: PMC8554367 DOI: 10.4239/wjd.v12.i10.1674] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/29/2021] [Accepted: 08/31/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes, whether due to pancreatic beta cells insufficiency or peripheral resistance to insulin, has been suggested as a risk factor of developing severe acute respiratory disease coronavirus-2 (SARS-CoV-2) infections. Indeed, diabetes has been associated with a higher risk of infections and higher risk of developing severe forms of coronavirus disease 2019 (COVID-19) related pneumonia. Diabetic patients often present associated comorbidities such as obesity, hypertension and cardiovascular diseases, and complications of diabetes, including chronic kidney disease, vasculopathy and relative immune dysfunction, all of which make them more susceptible to infectious complications. Moreover, they often present low-grade inflammation with increased circulating interleukin levels, endothelial susceptibility to inflammation and dysfunction, and finally, hyperglycemia, which increases this risk. Additionally, corticosteroids, which count among the few medications which showed benefit on survival and mechanical ventilation requirement in COVID-19 pneumonia in large randomized controlled trials, are associated to new onsets of diabetes, and metabolic disorders in patients with previous history of diabetes. Finally, SARS-CoV-2 via the alternate effects of the renin-angiotensin system, mediated by the angiotensin-converting-enzyme 2, was also associated with insulin resistance in key tissues involved in glucose homeostasis, such as liver, skeletal muscles, and adipose tissue; and also, with impaired insulin secretion by pancreatic β-cells. In this work, we reviewed all elements which may help understand how diabetes affects patients with COVID-19, how treatments affect outcomes in patients with COVID-19, how they may cause new onsets of diabetes, and finally review how SARS-CoV-2 may inherently be a risk factor of developing diabetes, through immune-mediated diabetogenic mechanisms.
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Affiliation(s)
- Sophia Sabri
- Intensive Care Medicine, CMC Ambroise Paré, Neuilly-Sur-Seine 92200, France
| | - Olivier Bourron
- Sorbonne Université Médecine; Assistance publique Hôpitaux de Paris (APHP), Service de Diabétologie, Hôpital Pitié-Salpêtrière; INSERM UMRS_1138, Centre de recherche des Cordeliers; Institute of CArdiometabolisme and Nutrition (ICAN), Paris 75013, France
| | - Franck Phan
- Sorbonne Université Médecine; Assistance publique Hôpitaux de Paris (APHP), Service de Diabétologie, Hôpital Pitié-Salpêtrière; INSERM UMRS_1138, Centre de recherche des Cordeliers; Institute of CArdiometabolisme and Nutrition (ICAN), Paris 75013, France
| | - Lee S Nguyen
- Research and Innovation, RICAP, CMC Ambroise Paré, Neuilly-Sur-Seine 92200, France
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24
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Sansoè G, Aragno M, Wong F. COVID-19 and Liver Cirrhosis: Focus on the Nonclassical Renin-Angiotensin System and Implications for Therapy. Hepatology 2021; 74:1074-1080. [PMID: 33524188 PMCID: PMC8013494 DOI: 10.1002/hep.31728] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/28/2020] [Accepted: 01/27/2021] [Indexed: 02/06/2023]
Affiliation(s)
- Giovanni Sansoè
- Division of GastroenterologyHumanitas InstituteGradenigo HospitalTorinoItaly
| | - Manuela Aragno
- Department of Clinical and Biological SciencesUniversity of TorinoTorinoItaly
| | - Florence Wong
- Department of MedicineUniversity of TorontoToronto General HospitalTorontoOntarioCanada
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25
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Nath KA, Singh RD, Grande JP, Garovic VD, Croatt AJ, Ackerman AW, Barry MA, Agarwal A. Expression of ACE2 in the Intact and Acutely Injured Kidney. KIDNEY360 2021; 2:1095-1106. [PMID: 35368365 PMCID: PMC8786087 DOI: 10.34067/kid.0001562021] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 05/14/2021] [Indexed: 02/04/2023]
Abstract
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.
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Affiliation(s)
- Karl A. Nath
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Raman Deep Singh
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Joseph P. Grande
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Vesna D. Garovic
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Anthony J. Croatt
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Allan W. Ackerman
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Michael A. Barry
- Division of Infectious Diseases, Mayo Clinic Rochester, Minnesota
| | - Anupam Agarwal
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
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26
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Laghlam D, Jozwiak M, Nguyen LS. Renin-Angiotensin-Aldosterone System and Immunomodulation: A State-of-the-Art Review. Cells 2021; 10:cells10071767. [PMID: 34359936 PMCID: PMC8303450 DOI: 10.3390/cells10071767] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 06/30/2021] [Accepted: 07/09/2021] [Indexed: 12/11/2022] Open
Abstract
The renin–angiotensin system (RAS) has long been described in the field of cardiovascular physiology as the main player in blood pressure homeostasis. However, other effects have since been described, and include proliferation, fibrosis, and inflammation. To illustrate the immunomodulatory properties of the RAS, we chose three distinct fields in which RAS may play a critical role and be the subject of specific treatments. In oncology, RAS hyperactivation has been associated with tumor migration, survival, cell proliferation, and angiogenesis; preliminary data showed promise of the benefit of RAS blockers in patients treated for certain types of cancer. In intensive care medicine, vasoplegic shock has been associated with severe macro- and microcirculatory imbalance. A relative insufficiency in angiotensin II (AngII) was associated to lethal outcomes and synthetic AngII has been suggested as a specific treatment in these cases. Finally, in solid organ transplantation, both AngI and AngII have been associated with increased rejection events, with a regional specificity in the RAS activity. These elements emphasize the complexity of the direct and indirect interactions of RAS with immunomodulatory pathways and warrant further research in the field.
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27
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An X, Lin W, Liu H, Zhong W, Zhang X, Zhu Y, Wang X, Li J, Sheng Q. SARS-CoV-2 Host Receptor ACE2 Protein Expression Atlas in Human Gastrointestinal Tract. Front Cell Dev Biol 2021; 9:659809. [PMID: 34178985 PMCID: PMC8226145 DOI: 10.3389/fcell.2021.659809] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 04/26/2021] [Indexed: 01/08/2023] Open
Abstract
Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells through interactions with its receptor, Angiotensin-converting enzyme 2 (ACE2), causing severe acute respiratory syndrome and death in a considerable proportion of people. Patients infected with SARS-CoV-2 experience digestive symptoms. However, the precise protein expression atlas of ACE2 in the gastrointestinal tract remains unclear. In this study, we aimed to explore the ACE2 protein expression pattern and the underlying function of ACE2 in the gastrointestinal tract, including the colon, stomach, liver, and pancreas. Methods We measured the protein expression of ACE2 in the gastrointestinal tract using immunohistochemical (IHC) staining with an ACE2-specific antibody of paraffin-embedded colon, stomach, liver, and pancreatic tissues. The correlation between the protein expression of ACE2 and the prognosis of patients with gastrointestinal cancers was analyzed by the log-rank (Mantel–Cox) test. The influence of ACE2 on colon, stomach, liver, and pancreatic tumor cell line proliferation was tested using a Cell Counting Kit 8 (CCK-8) assay. Results ACE2 presented heterogeneous expression patterns in the gastrointestinal tract, and it showed a punctate distribution in hepatic cells. Compared to that in parallel adjacent non-tumor tissues, the protein expression of ACE2 was significantly increased in colon cancer, stomach cancer, and pancreatic cancer tissues but dramatically decreased in liver cancer tissues. However, the expression level of the ACE2 protein was not correlated with the survival of patients with gastrointestinal cancers. Consistently, ACE2 did not affect the proliferation of gastrointestinal cancer cells in vitro. Conclusion The ACE2 protein is widely expressed in the gastrointestinal tract, and its expression is significantly altered in gastrointestinal tumor tissues. ACE2 is not an independent prognostic marker of gastrointestinal cancers.
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Affiliation(s)
- Xiang An
- Institute of Immunology and Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Wenlong Lin
- Institute of Immunology and Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Huan Liu
- Institute of Immunology and Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Weixiang Zhong
- Department of Pathology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiuming Zhang
- Department of Pathology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yimin Zhu
- Department of Epidemiology and Biostatistics, School of Public Health, Zhejiang University, Hangzhou, China
| | - Xiaojian Wang
- Institute of Immunology and Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jun Li
- Department of Pathology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Qinsong Sheng
- Department of Colorectal Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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28
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Ma C, Yan K, Wang Z, Zhang Q, Gao L, Xu T, Sai J, Cheng F, Du Y. The association between hypertension and nonalcoholic fatty liver disease (NAFLD): literature evidence and systems biology analysis. Bioengineered 2021; 12:2187-2202. [PMID: 34096467 PMCID: PMC8806441 DOI: 10.1080/21655979.2021.1933302] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become a major public health issue as its progression increases risks of multisystem morbidity and mortality. Recent evidence indicates a more complex relationship between hypertension and NAFLD than previously thought. In this study, a comprehensive literature search was used to gather information supporting the comorbidity phenomenon of hypertension and NAFLD. Then, systems biology approach was applied to identify the potential genes and mechanisms simultaneously associated with hypertension and NAFLD. With the help of protein-protein interaction network-based algorithm, we found that the distance between hypertension and NAFLD was much less than random ones. Sixty-four shared genes of hypertension and NAFLD modules were identified as core genes. Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis indicated that some inflammatory, metabolic and endocrine signals were related to the potential biological functions of core genes. More importantly, drugs used to treat cardiovascular diseases, hypertension, hyperlipidemia, inflammatory diseases and depression could be potential therapeutics against hypertension-NAFLD co-occurrence. After analyzing public OMICs data, ALDH1A1 was identified as a potential therapeutic target, without being affected by reverse causality. These findings give a clue for the potential mechanisms of comorbidity of hypertension and NAFLD and highlight the multiple target-therapeutic strategy of NAFLD for future clinical research.
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Affiliation(s)
- Chongyang Ma
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Kai Yan
- Department of Traditional Chinese Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Zisong Wang
- Department of Traditional Chinese Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Qiuyun Zhang
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Lianyin Gao
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Tian Xu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Jiayang Sai
- Department of Oncology, The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Fafeng Cheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yuqiong Du
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
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29
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Raghav PK, Kalyanaraman K, Kumar D. Human cell receptors: potential drug targets to combat COVID-19. Amino Acids 2021; 53:813-842. [PMID: 33950300 PMCID: PMC8097256 DOI: 10.1007/s00726-021-02991-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 04/21/2021] [Indexed: 01/08/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19). The World Health Organization (WHO) has announced that COVID-19 is a pandemic having a higher spread rate rather than the mortality. Identification of a potential approach or therapy against COVID-19 is still under consideration. Therefore, it is essential to have an insight into SARS-CoV-2, its interacting partner, and domains for an effective treatment. The present study is divided into three main categories, including SARS-CoV-2 prominent receptor and its expression levels, other interacting partners, and their binding domains. The first section focuses primarily on coronaviruses' general aspects (SARS-CoV-2, SARS-CoV, and the Middle East Respiratory Syndrome Coronaviruses (MERS-CoV)) their structures, similarities, and mode of infections. The second section discusses the host receptors which includes the human targets of coronaviruses like dipeptidyl peptidase 4 (DPP4), CD147, CD209L, Angiotensin-Converting Enzyme 2 (ACE2), and other miscellaneous targets (type-II transmembrane serine proteases (TTSPs), furin, trypsin, cathepsins, thermolysin, elastase, phosphatidylinositol 3-phosphate 5-kinase, two-pore segment channel, and epithelium sodium channel C-α subunit). The human cell receptor, ACE2 plays an essential role in the Renin-Angiotensin system (RAS) pathway and COVID-19. Thus, this section also discusses the ACE2 expression and risk of COVID-19 infectivity in various organs and tissues such as the liver, lungs, intestine, heart, and reproductive system in the human body. Absence of ACE2 protein expression in immune cells could be used for limiting the SARS-CoV-2 infection. The third section covers the current available approaches for COVID-19 treatment. Overall, this review focuses on the critical role of human cell receptors involved in coronavirus pathogenesis, which would likely be used in designing target-specific drugs to combat COVID-19.
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Affiliation(s)
| | - Keerthana Kalyanaraman
- Amity Institute of Biotechnology, Amity University, Sector-125, Noida, Uttar Pradesh, India
| | - Dinesh Kumar
- ICMR-National Institute of Cancer Prevention & Research, Noida, 201301, India.
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30
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Wiese O, Zemlin AE, Pillay TS. Molecules in pathogenesis: angiotensin converting enzyme 2 (ACE2). J Clin Pathol 2021; 74:285-290. [PMID: 32759311 PMCID: PMC7409947 DOI: 10.1136/jclinpath-2020-206954] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 07/22/2020] [Indexed: 12/14/2022]
Abstract
The renin-angiotensin system is mainly associated with the regulation of blood pressure, but recently many other functions of this system have been described. ACE2, an 805-amino acid monocarboxypeptidase type I transmembrane glycoprotein, was discovered in 2000 and has sequence similarity to two other proteins, namely ACE and collectrin. The ACE2 gene is located on Xp22 and is highly polymorphic. ACE2 is expressed in numerous tissues especially the lung alveolar epithelial cells, heart, kidney and gastrointestinal tract. Animal studies have found that ACE2 is central in diseases affecting almost all organ systems, among other cardiac, respiratory, renal and endocrine functions. ACE2 was identified as the cellular contact point for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the global pandemic (COVID-19), and is a potential drug target. SARS-CoV-2 infection has several effects on the renin-angiotensin system and conversely, regulation of this receptor may affect the progress of infection. We describe the genetics and functions of ACE2, explore its various physiological functions in the renin-angiotensin system and discuss its role in the pathophysiology of disease. ACE2 opposes the vasopressor ACE pathway of the renin-angiotensin system by converting angiotensin (Ang) I to Ang (1-9) and Ang II to Ang (1-7) which initiates the vasodilatory pathway. ACE2 may have a protective effect in the lung and kidney as knockout mice display susceptibility to acute respiratory distress and hypertensive nephropathy. Binding of SARS-CoV-2 and the subsequent fusion and downregulation of this pathway during SARS-CoV-2 infection may explain some of the unusual sequelae seen in COVID-19.
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Affiliation(s)
- Owen Wiese
- Division of Chemical Pathology, Faculty of Health Sciences, Stellenbosch University & National Health Laboratory Service (NHLS), Cape Town, South Africa
| | - Annalise E Zemlin
- Division of Chemical Pathology, Faculty of Health Sciences, Stellenbosch University & National Health Laboratory Service (NHLS), Cape Town, South Africa
| | - Tahir S Pillay
- Department of Chemical Pathology, University of Pretoria & National Health Laboratory Service (NHLS), Pretoria, South Africa
- Division of Chemical Pathology, University of Cape Town, Cape Town, South Africa
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Sidhom S, Schneider A, Fang Y, McFadden S, Darcy J, Sathiaseelan R, Palmer AK, Steyn FJ, Grillari J, Kopchick JJ, Bartke A, Siddiqi S, Masternak MM, Stout MB. 17α-Estradiol Modulates IGF1 and Hepatic Gene Expression in a Sex-Specific Manner. J Gerontol A Biol Sci Med Sci 2021; 76:778-785. [PMID: 32857104 PMCID: PMC8087270 DOI: 10.1093/gerona/glaa215] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Indexed: 12/13/2022] Open
Abstract
Aging is the greatest risk factor for most chronic diseases. The somatotropic axis is one of the most conserved biological pathways that regulates aging across species. 17α-Estradiol (17α-E2), a diastereomer of 17β-estradiol (17β-E2), was recently found to elicit health benefits, including improved insulin sensitivity and extend longevity exclusively in male mice. Given that 17β-E2 is known to modulate somatotropic signaling in females through actions in the pituitary and liver, we hypothesized that 17α-E2 may be modulating the somatotropic axis in males, thereby contributing to health benefits. Herein, we demonstrate that 17α-E2 increases hepatic insulin-like growth factor 1 (IGF1) production in male mice without inducing any changes in pulsatile growth hormone (GH) secretion. Using growth hormone receptor knockout (GHRKO) mice, we subsequently determined that the induction of hepatic IGF1 by 17α-E2 is dependent upon GH signaling in male mice, and that 17α-E2 elicits no effects on IGF1 production in female mice. We also determined that 17α-E2 failed to feminize the hepatic transcriptional profile in normal (N) male mice, as evidenced by a clear divergence between the sexes, regardless of treatment. Conversely, significant overlap in transcriptional profiles was observed between sexes in GHRKO mice, and this was unaffected by 17α-E2 treatment. Based on these findings, we propose that 17α-E2 acts as a pleiotropic pathway modulator in male mice by uncoupling IGF1 production from insulin sensitivity. In summary, 17α-E2 treatment upregulates IGF1 production in wild-type (and N) male mice in what appears to be a GH-dependent fashion, while no effects in female IGF1 production are observed following 17α-E2 treatment.
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Affiliation(s)
- Silvana Sidhom
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando
| | - Augusto Schneider
- Faculdade de Nutrição, Universidade Federal de Pelotas, Rio Grande do Sul, Brazil
| | - Yimin Fang
- Department of Physiology, Southern Illinois University School of Medicine, Springfield
| | - Samuel McFadden
- Department of Physiology, Southern Illinois University School of Medicine, Springfield
| | - Justin Darcy
- Department of Physiology, Southern Illinois University School of Medicine, Springfield
| | - Roshini Sathiaseelan
- Department of Nutritional Sciences, University of Oklahoma Health Sciences Center
| | - Allyson K Palmer
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota
| | - Frederik J Steyn
- University of Queensland Centre for Clinical Research, Faculty of Medicine, Brisbane, Australia
| | - Johannes Grillari
- Department of Biotechnology, BOKU – University of Natural Resources and Life Sciences, Vienna, Austria
| | - John J Kopchick
- Edison Biotechnology Institute & Heritage College of Osteopathic Medicine, Ohio University, Athens
| | - Andrzej Bartke
- Department of Physiology, Southern Illinois University School of Medicine, Springfield
| | - Shadab Siddiqi
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando
| | - Michal M Masternak
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando
| | - Michael B Stout
- Department of Nutritional Sciences, University of Oklahoma Health Sciences Center
- Oklahoma Center for Geroscience, University of Oklahoma Health Sciences Center
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Das UN. Bioactive lipid-based therapeutic approach to COVID-19 and other similar infections. Arch Med Sci 2021; 19:1327-1359. [PMID: 37732033 PMCID: PMC10507771 DOI: 10.5114/aoms/135703] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 04/11/2021] [Indexed: 09/22/2023] Open
Abstract
COVID-19 is caused by SARS-CoV-2 infection. Epithelial and T, NK, and other immunocytes release bioactive lipids especially arachidonic acid (AA) in response to microbial infections to inactivate them and upregulate the immune system. COVID-19 (coronavirus) and other enveloped viruses including severe acute respiratory syndrome (SARS-CoV-1 of 2002-2003) and Middle East respiratory syndrome (MERS; 2012-ongoing) and hepatitis B and C (HBV and HCV) can be inactivated by AA, γ-linolenic acid (GLA, dihomo-GLA (DGLA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), which are precursors to several eicosanoids. Prostaglandin E1, lipoxin A4, resolvins, protectins and maresins enhance phagocytosis of macrophages and leukocytes to clear debris from the site(s) of infection and injury, enhance microbial clearance and wound healing to restore homeostasis. Bioactive lipids modulate the generation of M1 and M2 macrophages and the activity of other immunocytes. Mesenchymal and adipose tissue-derived stem cells secrete LXA4 and other bioactive lipids to bring about their beneficial actions in COVID-19. Bioactive lipids regulate vasomotor tone, inflammation, thrombosis, immune response, inactivate enveloped viruses, regulate T cell proliferation and secretion of cytokines, stem cell survival, proliferation and differentiation, and leukocyte and macrophage functions, JAK kinase activity and neutrophil extracellular traps and thus, have a critical role in COVID-19.
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Affiliation(s)
- Undurti N. Das
- UND Life Sciences, Battle Ground, WA, USA
- Department of Medicine, Omega Hospitals, Gachibowli, Hyderabad, India
- International Research Centre, Biotechnologies of the third Millennium, ITMO University, Saint-Petersburg, Russia
- Department of Biotechnology, Indian Institute of Technology-Hyderabad, Telangana, India
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ACE2 as therapeutic agent. Clin Sci (Lond) 2021; 134:2581-2595. [PMID: 33063820 DOI: 10.1042/cs20200570] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 09/28/2020] [Accepted: 10/01/2020] [Indexed: 12/11/2022]
Abstract
The angiotensin-converting enzyme 2 (ACE2) has emerged as a critical regulator of the renin-angiotensin system (RAS), which plays important roles in cardiovascular homeostasis by regulating vascular tone, fluid and electrolyte balance. ACE2 functions as a carboxymonopeptidase hydrolyzing the cleavage of a single C-terminal residue from Angiotensin-II (Ang-II), the key peptide hormone of RAS, to form Angiotensin-(1-7) (Ang-(1-7)), which binds to the G-protein-coupled Mas receptor and activates signaling pathways that counteract the pathways activated by Ang-II. ACE2 is expressed in a variety of tissues and overwhelming evidence substantiates the beneficial effects of enhancing ACE2/Ang-(1-7)/Mas axis under many pathological conditions in these tissues in experimental models. This review will provide a succinct overview on current strategies to enhance ACE2 as therapeutic agent, and discuss limitations and future challenges. ACE2 also has other functions, such as acting as a co-factor for amino acid transport and being exploited by the severe acute respiratory syndrome coronaviruses (SARS-CoVs) as cellular entry receptor, the implications of these functions in development of ACE2-based therapeutics will also be discussed.
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Malinowska B, Baranowska-Kuczko M, Kicman A, Schlicker E. Opportunities, Challenges and Pitfalls of Using Cannabidiol as an Adjuvant Drug in COVID-19. Int J Mol Sci 2021; 22:1986. [PMID: 33671463 PMCID: PMC7922403 DOI: 10.3390/ijms22041986] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/11/2021] [Accepted: 02/12/2021] [Indexed: 02/06/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to coronavirus disease 2019 (COVID-19) which, in turn, may be associated with multiple organ dysfunction. In this review, we present advantages and disadvantages of cannabidiol (CBD), a non-intoxicating phytocannabinoid from the cannabis plant, as a potential agent for the treatment of COVID-19. CBD has been shown to downregulate proteins responsible for viral entry and to inhibit SARS-CoV-2 replication. Preclinical studies have demonstrated its effectiveness against diseases of the respiratory system as well as its cardioprotective, nephroprotective, hepatoprotective, neuroprotective and anti-convulsant properties, that is, effects that may be beneficial for COVID-19. Only the latter two properties have been demonstrated in clinical studies, which also revealed anxiolytic and antinociceptive effects of CBD (given alone or together with Δ9-tetrahydrocannabinol), which may be important for an adjuvant treatment to improve the quality of life in patients with COVID-19 and to limit post-traumatic stress symptoms. However, one should be aware of side effects of CBD (which are rarely serious), drug interactions (also extending to drugs acting against COVID-19) and the proper route of its administration (vaping may be dangerous). Clearly, further clinical studies are necessary to prove the suitability of CBD for the treatment of COVID-19.
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Affiliation(s)
- Barbara Malinowska
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, 15-222 Białystok, Poland; (M.B.-K.); (A.K.)
| | - Marta Baranowska-Kuczko
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, 15-222 Białystok, Poland; (M.B.-K.); (A.K.)
- Department of Clinical Pharmacy, Medical University of Białystok, 15-222 Białystok, Poland
| | - Aleksandra Kicman
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, 15-222 Białystok, Poland; (M.B.-K.); (A.K.)
| | - Eberhard Schlicker
- Department of Pharmacology and Toxicology, University of Bonn, 53127 Bonn, Germany
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35
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ACE2 and energy metabolism: the connection between COVID-19 and chronic metabolic disorders. Clin Sci (Lond) 2021; 135:535-554. [PMID: 33533405 DOI: 10.1042/cs20200752] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 12/13/2022]
Abstract
The renin-angiotensin system (RAS) has currently attracted increasing attention due to its potential function in regulating energy homeostasis, other than the actions on cellular growth, blood pressure, fluid, and electrolyte balance. The existence of RAS is well established in metabolic organs, including pancreas, liver, skeletal muscle, and adipose tissue, where activation of angiotensin-converting enzyme (ACE) - angiotensin II pathway contributes to the impairment of insulin secretion, glucose transport, fat distribution, and adipokines production. However, the activation of angiotensin-converting enzyme 2 (ACE2) - angiotensin (1-7) pathway, a novel branch of the RAS, plays an opposite role in the ACE pathway, which could reverse these consequences by improving local microcirculation, inflammation, stress state, structure remolding, and insulin signaling pathway. In addition, new studies indicate the protective RAS arm possesses extraordinary ability to enhance brown adipose tissue (BAT) activity and induces browning of white adipose tissue, and consequently, it leads to increased energy expenditure in the form of heat instead of ATP synthesis. Interestingly, ACE2 is the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is threating public health worldwide. The main complications of SARS-CoV-2 infected death patients include many energy metabolism-related chronic diseases, such as diabetes. The specific mechanism leading to this phenomenon is largely unknown. Here, we summarize the latest pharmacological and genetic tools on regulating ACE/ACE2 balance and highlight the beneficial effects of the ACE2 pathway axis hyperactivity on glycolipid metabolism, as well as the thermogenic modulation.
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Update on New Aspects of the Renin-Angiotensin System in Hepatic Fibrosis and Portal Hypertension: Implications for Novel Therapeutic Options. J Clin Med 2021; 10:jcm10040702. [PMID: 33670126 PMCID: PMC7916881 DOI: 10.3390/jcm10040702] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/29/2021] [Accepted: 02/06/2021] [Indexed: 02/07/2023] Open
Abstract
There is considerable experimental evidence that the renin angiotensin system (RAS) plays a central role in both hepatic fibrogenesis and portal hypertension. Angiotensin converting enzyme (ACE), a key enzyme of the classical RAS, converts angiotensin I (Ang I) to angiotensin II (Ang II), which acts via the Ang II type 1 receptor (AT1R) to stimulate hepatic fibrosis and increase intrahepatic vascular tone and portal pressure. Inhibitors of the classical RAS, drugs which are widely used in clinical practice in patients with hypertension, have been shown to inhibit liver fibrosis in animal models but their efficacy in human liver disease is yet to be tested in adequately powered clinical trials. Small trials in cirrhotic patients have demonstrated that these drugs may lower portal pressure but produce off-target complications such as systemic hypotension and renal failure. More recently, the alternate RAS, comprising its key enzyme, ACE2, the effector peptide angiotensin-(1–7) (Ang-(1–7)) which mediates its effects via the putative receptor Mas (MasR), has also been implicated in the pathogenesis of liver fibrosis and portal hypertension. This system is activated in both preclinical animal models and human chronic liver disease and it is now well established that the alternate RAS counter-regulates many of the deleterious effects of the ACE-dependent classical RAS. Work from our laboratory has demonstrated that liver-specific ACE2 overexpression reduces hepatic fibrosis and liver perfusion pressure without producing off-target effects. In addition, recent studies suggest that the blockers of the receptors of alternate RAS, such as the MasR and Mas related G protein-coupled receptor type-D (MrgD), increase splanchnic vascular resistance in cirrhotic animals, and thus drugs targeting the alternate RAS may be useful in the treatment of portal hypertension. This review outlines the role of the RAS in liver fibrosis and portal hypertension with a special emphasis on the possible new therapeutic approaches targeting the ACE2-driven alternate RAS.
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Pola A, Murthy KS, Santhekadur PK. COVID-19 and gastrointestinal system: A brief review. Biomed J 2021; 44:245-251. [PMID: 34130944 PMCID: PMC7832457 DOI: 10.1016/j.bj.2021.01.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 12/25/2020] [Accepted: 01/11/2021] [Indexed: 01/08/2023] Open
Abstract
COVID-19 is a recent pandemic that is still a major health problem of modern times and already more than 17.5 lakhs people succumbed to this deadly disease. This disease is caused by novel coronavirus which is named SARS-COV-2 by the International Committee on Taxonomy of Viruses. This virus originated from Wuhan city in Hubei province of China in December 2019 and within a short period spread across the many countries in the globe. There are a lot of basic as well as clinical research is going on to study the mode of transmission and the mechanism of action of SARS-COV-2 infection and its therapeutics. SARS-COV-2 is not only known to infect lungs, but it also infects other organs in the human body including the gastrointestinal (GI) tract, the liver, and the pancreas via the angiotensin-converting enzyme (ACE) 2, an important component of the renin-angiotensin system. In this short review, we are mainly discussing the mode of SARS-COV-2 transmission, physiological counterbalancing roles of ACE2 and ACE and the tissue patterns of ACE2 expression, and the overall effect of COVID19 on human gastrointestinal System. Therefore, this review sheds light on the possible mechanism of SARS-COV-2 infection in the GI system and its pathological symptoms raising a potential possibility of GI tract acting as a secondary site for SARS-CoV-2 tropism and infection. Finally, future studies to understand the fecal-oral transmission of the virus and the correlation of viral load and severity of GI symptoms are proposed to gain knowledge of the GI symptoms in COVID-19 to aid in early diagnosis and prognosis.
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Affiliation(s)
- Akhil Pola
- Department of Biochemistry, Center of Excellence in Molecular Biology & Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, Karnataka, India
| | - Karnam S Murthy
- Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, USA
| | - Prasanna K Santhekadur
- Department of Biochemistry, Center of Excellence in Molecular Biology & Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, Karnataka, India.
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Hammoud SH, Wehbe Z, Abdelhady S, Kobeissy F, Eid AH, El-Yazbi AF. Dysregulation of Angiotensin Converting Enzyme 2 Expression and Function in Comorbid Disease Conditions Possibly Contributes to Coronavirus Infectious Disease 2019 Complication Severity. Mol Pharmacol 2021; 99:17-28. [PMID: 33082267 DOI: 10.1124/molpharm.120.000119] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 10/09/2020] [Indexed: 01/08/2023] Open
Abstract
ACE2 has emerged as a double agent in the COVID-19 ordeal, as it is both physiologically protective and virally conducive. The identification of ACE2 in as many as 72 tissues suggests that extrapulmonary invasion and damage is likely, which indeed has already been demonstrated by cardiovascular and gastrointestinal symptoms. On the other hand, identifying ACE2 dysregulation in patients with comorbidities may offer insight as to why COVID-19 symptoms are often more severe in these individuals. This may be attributed to a pre-existing proinflammatory state that is further propelled with the cytokine storm induced by SARS-CoV-2 infection or the loss of functional ACE2 expression as a result of viral internalization. Here, we aim to characterize the distribution and role of ACE2 in various organs to highlight the scope of damage that may arise upon SARS-CoV-2 invasion. Furthermore, by examining the disruption of ACE2 in several comorbid diseases, we offer insight into potential causes of increased severity of COVID-19 symptoms in certain individuals. SIGNIFICANCE STATEMENT: Cell surface expression of ACE2 determines the tissue susceptibility for coronavirus infectious disease 2019 infection. Comorbid disease conditions altering ACE2 expression could increase the patient's vulnerability for the disease and its complications, either directly, through modulation of viral infection, or indirectly, through alteration of inflammatory status.
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Affiliation(s)
- Safaa H Hammoud
- Department of Pharmacology and Therapeutics, Beirut Arab University, Beirut, Lebanon (S.H.); Departments of Biology (Z.W.), Biochemistry and Molecular Genetics (F.K.), and Pharmacology and Toxicology (A.H.E., A.F.E.-Y.), American University of Beirut, Beirut, Lebanon; Department of Pharmacology and Toxicology, Faculty of Pharmacy (A.F.E.-Y.) and Faculty of Medicine (S.A.), Alexandria University, Alexandria, Egypt; and Department of Basic Medical Sciences, College of Medicine, and Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar (A.H.E.)
| | - Zena Wehbe
- Department of Pharmacology and Therapeutics, Beirut Arab University, Beirut, Lebanon (S.H.); Departments of Biology (Z.W.), Biochemistry and Molecular Genetics (F.K.), and Pharmacology and Toxicology (A.H.E., A.F.E.-Y.), American University of Beirut, Beirut, Lebanon; Department of Pharmacology and Toxicology, Faculty of Pharmacy (A.F.E.-Y.) and Faculty of Medicine (S.A.), Alexandria University, Alexandria, Egypt; and Department of Basic Medical Sciences, College of Medicine, and Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar (A.H.E.)
| | - Samar Abdelhady
- Department of Pharmacology and Therapeutics, Beirut Arab University, Beirut, Lebanon (S.H.); Departments of Biology (Z.W.), Biochemistry and Molecular Genetics (F.K.), and Pharmacology and Toxicology (A.H.E., A.F.E.-Y.), American University of Beirut, Beirut, Lebanon; Department of Pharmacology and Toxicology, Faculty of Pharmacy (A.F.E.-Y.) and Faculty of Medicine (S.A.), Alexandria University, Alexandria, Egypt; and Department of Basic Medical Sciences, College of Medicine, and Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar (A.H.E.)
| | - Firas Kobeissy
- Department of Pharmacology and Therapeutics, Beirut Arab University, Beirut, Lebanon (S.H.); Departments of Biology (Z.W.), Biochemistry and Molecular Genetics (F.K.), and Pharmacology and Toxicology (A.H.E., A.F.E.-Y.), American University of Beirut, Beirut, Lebanon; Department of Pharmacology and Toxicology, Faculty of Pharmacy (A.F.E.-Y.) and Faculty of Medicine (S.A.), Alexandria University, Alexandria, Egypt; and Department of Basic Medical Sciences, College of Medicine, and Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar (A.H.E.)
| | - Ali H Eid
- Department of Pharmacology and Therapeutics, Beirut Arab University, Beirut, Lebanon (S.H.); Departments of Biology (Z.W.), Biochemistry and Molecular Genetics (F.K.), and Pharmacology and Toxicology (A.H.E., A.F.E.-Y.), American University of Beirut, Beirut, Lebanon; Department of Pharmacology and Toxicology, Faculty of Pharmacy (A.F.E.-Y.) and Faculty of Medicine (S.A.), Alexandria University, Alexandria, Egypt; and Department of Basic Medical Sciences, College of Medicine, and Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar (A.H.E.)
| | - Ahmed F El-Yazbi
- Department of Pharmacology and Therapeutics, Beirut Arab University, Beirut, Lebanon (S.H.); Departments of Biology (Z.W.), Biochemistry and Molecular Genetics (F.K.), and Pharmacology and Toxicology (A.H.E., A.F.E.-Y.), American University of Beirut, Beirut, Lebanon; Department of Pharmacology and Toxicology, Faculty of Pharmacy (A.F.E.-Y.) and Faculty of Medicine (S.A.), Alexandria University, Alexandria, Egypt; and Department of Basic Medical Sciences, College of Medicine, and Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar (A.H.E.)
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Abdul-Hafez A, Mohamed T, Uhal BD. Angiotensin Converting Enzyme-2 (ACE-2) role in disease and future in research. JOURNAL OF LUNG, PULMONARY & RESPIRATORY RESEARCH 2021; 8:54-60. [PMID: 34414260 PMCID: PMC8373052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Coronavirus Disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Like the 2002-2003 epidemic severe acute respiratory syndrome coronavirus (SARS-CoV), angiotensin converting enzyme-2 (ACE-2) has been identified as the SARS-CoV-2 receptor.1-3 The virus docks into host cell via its spike protein binding to ACE-2 and undergoes proteolytic cleavage by TMPRSS2 protease to facilitate membrane fusion. The spike protein binding to ACE-2 has been shown to be stronger in the novel SARS-CoV-2 virus.1 This review will present an overview of ACE-2 biology.
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Affiliation(s)
- Amal Abdul-Hafez
- Department of Pediatrics and Human Development, Michigan State University, USA
| | - Tarek Mohamed
- Department of Pediatrics and Human Development, Michigan State University, USA
| | - Bruce D. Uhal
- Department of Physiology, Michigan State University, USA
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40
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ACE2: from protection of liver disease to propagation of COVID-19. Clin Sci (Lond) 2020; 134:3137-3158. [PMID: 33284956 DOI: 10.1042/cs20201268] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 11/19/2020] [Accepted: 11/23/2020] [Indexed: 01/08/2023]
Abstract
Twenty years ago, the discovery of angiotensin-converting enzyme 2 (ACE2) was an important breakthrough dramatically enhancing our understanding of the renin-angiotensin system (RAS). The classical RAS is driven by its key enzyme ACE and is pivotal in the regulation of blood pressure and fluid homeostasis. More recently, it has been recognised that the protective RAS regulated by ACE2 counterbalances many of the deleterious effects of the classical RAS. Studies in murine models demonstrated that manipulating the protective RAS can dramatically alter many diseases including liver disease. Liver-specific overexpression of ACE2 in mice with liver fibrosis has proved to be highly effective in antagonising liver injury and fibrosis progression. Importantly, despite its highly protective role in disease pathogenesis, ACE2 is hijacked by SARS-CoV-2 as a cellular receptor to gain entry to alveolar epithelial cells, causing COVID-19, a severe respiratory disease in humans. COVID-19 is frequently life-threatening especially in elderly or people with other medical conditions. As an unprecedented number of COVID-19 patients have been affected globally, there is an urgent need to discover novel therapeutics targeting the interaction between the SARS-CoV-2 spike protein and ACE2. Understanding the role of ACE2 in physiology, pathobiology and as a cellular receptor for SARS-CoV-2 infection provides insight into potential new therapeutic strategies aiming to prevent SARS-CoV-2 infection related tissue injury. This review outlines the role of the RAS with a strong focus on ACE2-driven protective RAS in liver disease and provides therapeutic approaches to develop strategies to prevent SARS-CoV-2 infection in humans.
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Jia H, Yue X, Lazartigues E. ACE2 mouse models: a toolbox for cardiovascular and pulmonary research. Nat Commun 2020; 11:5165. [PMID: 33057007 PMCID: PMC7560817 DOI: 10.1038/s41467-020-18880-0] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 09/18/2020] [Indexed: 12/13/2022] Open
Abstract
Angiotensin-converting enzyme 2 (ACE2) has been identified as the host entry receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the COVID-19 pandemic. ACE2 is a regulatory enzyme of the renin-angiotensin system and has protective functions in many cardiovascular, pulmonary and metabolic diseases. This review summarizes available murine models with systemic or organ-specific deletion of ACE2, or with overexpression of murine or human ACE2. The purpose of this review is to provide researchers with the genetic tools available for further understanding of ACE2 biology and for the investigation of ACE2 in the pathogenesis and treatment of COVID-19.
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Affiliation(s)
- Hongpeng Jia
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Xinping Yue
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA
| | - Eric Lazartigues
- Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA. .,Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA. .,Southeast Louisiana Veterans Health Care Systems, New Orleans, LA, 70119, USA.
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Tebani A, Gummesson A, Zhong W, Koistinen IS, Lakshmikanth T, Olsson LM, Boulund F, Neiman M, Stenlund H, Hellström C, Karlsson MJ, Arif M, Dodig-Crnković T, Mardinoglu A, Lee S, Zhang C, Chen Y, Olin A, Mikes J, Danielsson H, von Feilitzen K, Jansson PA, Angerås O, Huss M, Kjellqvist S, Odeberg J, Edfors F, Tremaroli V, Forsström B, Schwenk JM, Nilsson P, Moritz T, Bäckhed F, Engstrand L, Brodin P, Bergström G, Uhlen M, Fagerberg L. Integration of molecular profiles in a longitudinal wellness profiling cohort. Nat Commun 2020; 11:4487. [PMID: 32900998 PMCID: PMC7479148 DOI: 10.1038/s41467-020-18148-7] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 08/03/2020] [Indexed: 12/19/2022] Open
Abstract
An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, we sample a longitudinal wellness cohort with 100 healthy individuals and analyze blood molecular profiles including proteomics, transcriptomics, lipidomics, metabolomics, autoantibodies and immune cell profiling, complemented with gut microbiota composition and routine clinical chemistry. Overall, our results show high variation between individuals across different molecular readouts, while the intra-individual baseline variation is low. The analyses show that each individual has a unique and stable plasma protein profile throughout the study period and that many individuals also show distinct profiles with regards to the other omics datasets, with strong underlying connections between the blood proteome and the clinical chemistry parameters. In conclusion, the results support an individual-based definition of health and show that comprehensive omics profiling in a longitudinal manner is a path forward for precision medicine. An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, the authors sample a longitudinal wellness cohort and analyse blood molecular profiles as well as gut microbiota composition.
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Affiliation(s)
- Abdellah Tebani
- Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Anders Gummesson
- Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Genetics and Genomics, Gothenburg, Sweden
| | - Wen Zhong
- Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Ina Schuppe Koistinen
- Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden.,Center for Translational Microbiome Research, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Tadepally Lakshmikanth
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Lisa M Olsson
- Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Fredrik Boulund
- Center for Translational Microbiome Research, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Maja Neiman
- Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Hans Stenlund
- Swedish Metabolomics Centre, Department of Molecular Biology, Umeå University, 901 87, Umeå, Sweden
| | - Cecilia Hellström
- Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Max J Karlsson
- Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Muhammad Arif
- Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Tea Dodig-Crnković
- Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Adil Mardinoglu
- Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden.,Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK
| | - Sunjae Lee
- Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Cheng Zhang
- Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Yang Chen
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Axel Olin
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Jaromir Mikes
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Hanna Danielsson
- Center for Translational Microbiome Research, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Kalle von Feilitzen
- Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Per-Anders Jansson
- Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Sahlgrenska University Hospital, Department of Internal Medicine, Gothenburg, Sweden
| | - Oskar Angerås
- Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Sahlgrenska University Hospital, Department of Cardiology, Gothenburg, Sweden
| | - Mikael Huss
- Codon Consulting, 118 26, Stockholm, Sweden.,Department of Learning, Informatics, Management and Ethics, Karolinska Institutet, Stockholm, Sweden
| | - Sanela Kjellqvist
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Jacob Odeberg
- Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Fredrik Edfors
- Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Valentina Tremaroli
- Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Björn Forsström
- Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Jochen M Schwenk
- Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Peter Nilsson
- Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Thomas Moritz
- Swedish Metabolomics Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, 907 36, Umeå, Sweden
| | - Fredrik Bäckhed
- Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Physiology, Gothenburg, Sweden.,Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lars Engstrand
- Center for Translational Microbiome Research, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Petter Brodin
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Göran Bergström
- Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Physiology, Gothenburg, Sweden
| | - Mathias Uhlen
- Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden.,Center for Biosustainability, Danish Technical University, Copenhagen, Denmark
| | - Linn Fagerberg
- Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden.
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Hashimoto Y, Hamaguchi M, Kaji A, Sakai R, Kitagawa N, Fukui M. Serum levels of mac-2 binding protein are associated with diabetic microangiopathy and macroangiopathy in people with type 2 diabetes. BMJ Open Diabetes Res Care 2020; 8:8/1/e001189. [PMID: 32847841 PMCID: PMC7451284 DOI: 10.1136/bmjdrc-2020-001189] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 07/04/2020] [Accepted: 07/18/2020] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Non-alcoholic fatty liver disease is reportedly associated with type 2 diabetes and progressive liver fibrosis, as evaluated by transient elastography, and has been linked with micro- and macroangiopathy in people with type 2 diabetes. The purpose of this cross-sectional study was to investigate the association between serum mac-2 binding protein glycosylation isomer (M2BPGi) levels and diabetic complications in people with type 2 diabetes. RESEARCH DESIGN AND METHODS Serum M2BPGi levels were measured in terms of cut-off index (C.O.I.) units. Urinary albumin excretion (UAE) was calculated and nephropathy was graded as normoalbuminuria, microalbuminuria, or macroalbuminuria. Retinopathy was divided into three groups: no-diabetic retinopathy (NoDR), non-proliferative-diabetic retinopathy (NPDR), or proliferative-diabetic retinopathy (PDR) . RESULTS The mean age for the 363 studied subjects (212 males) was 66.4±10.6 years, the median serum M2BPGi level was 0.77 (0.57-1.04) C.O.I., and the median UAE was 22 (9-82.1) mg/g creatinine. M2BPGi levels in microalbuminuria (0.83 (0.61 to 1.18) C.O.I.) and macroalbuminuria (0.88 (0.67 to 1.22) C.O.I.) cases were higher than those in normoalbuminuria cases (0.71 (0.54 to 0.92) C.O.I.). M2BPGi levels in NPDR (0.93 (0.68 to 1.28) C.O.I.) and PDR (0.95 (0.71 to 1.31) C.O.I.) cases were higher than in cases with NoDR (0.73 (0.56 to 0.99) C.O.I.). Furthermore, M2BPGi levels in subjects with a history of cardiovascular diseases were higher than in those with no such history (0.82 (0.65 to 1.22) vs 0.76 (0.55 to 1.03) C.O.I., p=0.019). The logarithm of (M2BPGi+1) was associated with the logarithm of UAE values after adjusting for covariates (standardized β=0.107, p=0.031). CONCLUSIONS This study reveals a close association between serum M2BPGi levels and diabetic microangiopathy and macroangiopathy in people with type 2 diabetes. The results also show that liver fibrosis, evaluated by M2BPGi, is independently associated with an increased risk of albuminuria.
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Affiliation(s)
- Yoshitaka Hashimoto
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Masahide Hamaguchi
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Ayumi Kaji
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Ryosuke Sakai
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Noriyuki Kitagawa
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
- Department of Diabetology, Kameoka Municipal Hospital, Kameoka, Japan
| | - Michiaki Fukui
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
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Kitagawa N, Hashimoto Y, Hamaguchi M, Osaka T, Fukuda T, Yamazaki M, Fukui M. Liver Stiffness Is Associated With Progression of Albuminuria in Adults With Type 2 Diabetes: Nonalcoholic Fatty Disease Cohort Study. Can J Diabetes 2020; 44:428-433. [PMID: 32616276 DOI: 10.1016/j.jcjd.2020.03.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 02/12/2020] [Accepted: 03/10/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Previous studies have shown the association between liver fibrosis and albuminuria. However, the effect of liver fibrosis on change in albuminuria is unclear. Thus, we investigated the effect of liver fibrosis on change in albuminuria in patients with type 2 diabetes. METHODS In this retrospective cohort study, we assessed 105 patients with type 2 diabetes concomitant with nonalcoholic fatty disease. A change in urinary albumin excretion (UAE) was defined as follows: change in UAE=(logarithm [UAE+1] at follow-up examination minus logarithm [UAE+1] at baseline examination) / follow-up duration (1 year in this study). Elastography was performed to assess controlled attenuation parameter (dB/m) and liver stiffness measurement (LSM; kPa) values. RESULTS Mean (standard deviation) data were as follows: age, 63.3 (12.1) years; body mass index, 25.4 (4.3) kg/m2; controlled attenuation parameter, 273.1 (53.0) dB/m; and LSM, 6.2 (3.4) kPa. Median UAE value (interquartile range) was 16 (6 to 43) mg/g creatinine. LSM was associated with changes in UAE (r=0.27, p=0.005). Multiple regression analysis demonstrated that LSM was associated with change in UAE (β=0.28, p=0.015) after adjusting for sex, age, duration of diabetes, smoking status, exercise habits, glycated hemoglobin, body mass index, estimated glomerular filtration rate, systolic blood pressure, logarithm (UAE+1) at baseline examination, use of renin‒angiotensin system inhibitors, new use of sodium glucose cotransporter-2 inhibitors and glucagon-like peptide-1 and controlled attenuation parameter. CONCLUSIONS Liver stiffness is an independent risk factor for the progression of albuminuria in patients with type 2 diabetes.
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Affiliation(s)
- Nobuko Kitagawa
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshitaka Hashimoto
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Masahide Hamaguchi
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takafumi Osaka
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Endocrinology and Diabetology, Ayabe city Hospital, Ayabe, Japan
| | - Takuya Fukuda
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Masahiro Yamazaki
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Michiaki Fukui
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
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Banu N, Panikar SS, Leal LR, Leal AR. Protective role of ACE2 and its downregulation in SARS-CoV-2 infection leading to Macrophage Activation Syndrome: Therapeutic implications. Life Sci 2020; 256:117905. [PMID: 32504757 PMCID: PMC7832382 DOI: 10.1016/j.lfs.2020.117905] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 05/25/2020] [Accepted: 05/30/2020] [Indexed: 02/06/2023]
Abstract
In light of the outbreak of the 2019 novel coronavirus disease (COVID-19), the international scientific community has joined forces to develop effective treatment strategies. The Angiotensin-Converting Enzyme (ACE) 2, is an essential receptor for cell fusion and engulfs the SARS coronavirus infections. ACE2 plays an important physiological role, practically in all the organs and systems. Also, ACE2 exerts protective functions in various models of pathologies with acute and chronic inflammation. While ACE2 downregulation by SARS-CoV-2 spike protein leads to an overactivation of Angiotensin (Ang) II/AT1R axis and the deleterious effects of Ang II may explain the multiorgan dysfunction seen in patients. Specifically, the role of Ang II leading to the appearance of Macrophage Activation Syndrome (MAS) and the cytokine storm in COVID-19 is discussed below. In this review, we summarized the latest research progress in the strategies of treatments that mainly focus on reducing the Ang II-induced deleterious effects rather than attenuating the virus replication.
Protective role of ACE2 in the organs and system Downregulation of ACE2 expression by SARS-CoV-2 leads to Ang II-induced organ damage. The appearance of MAS in COVID-19 patient Suggested treatment to diminish the deleterious effect of Ang II or appearance of MAS
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Affiliation(s)
- Nehla Banu
- Instituto de Enfermedades Crónico-Degenerativas, Departamento de Biología Molecular y Genómica, CUCS, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
| | - Sandeep Surendra Panikar
- Centro de Física Aplicada y Tecnología Avanzada, Universidad Nacional Autonoma de México (UNAM), Apartado Postal 1-1010, Queretaro, Queretaro 76000, Mexico
| | - Lizbeth Riera Leal
- Hospital General Regional número 45, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico
| | - Annie Riera Leal
- UC DAVIS Institute for Regenerative Cure, Department of Dermatology, University of California, 2921 Stockton Blvd, Rm 1630, 95817 Sacramento, CA, USA.
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Sansoè G, Aragno M, Wong F. Pathways of hepatic and renal damage through non-classical activation of the renin-angiotensin system in chronic liver disease. Liver Int 2020; 40:18-31. [PMID: 31580514 DOI: 10.1111/liv.14272] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 09/24/2019] [Accepted: 09/30/2019] [Indexed: 12/17/2022]
Abstract
In liver cirrhosis, renin-angiotensin system (RAS) activation sustains renal sodium retention and hepatic fibrogenesis. New information has recently enlivened the traditional concept of RAS. For instance, renin and prorenin bind their ubiquitous receptors, resulting in the local production of angiotensin (Ang) II; increased serum calcium and calcimimetic agents, through stimulation of extracellular calcium-sensing receptors (CaSR), blunt renin production and lead to natriuretic effects in human and experimental cirrhosis. Alongside systemic production, there is Ang II tissue production within various organs through RAS enzymes different from angiotensin-converting enzyme (ACE), that is chymase, tissue plasminogen activator and several cathepsins. In experimental cirrhosis, inhibition of chymase leads to natriuretic and hepatic antifibrotic effects, without changes in systemic haemodynamics. In the kidney, local RAS coordinates proximal and distal tubular sodium reabsorption. However, renalase, whose plasma and tissue levels are severely altered in experimental cirrhosis, degrades systemic and renal tubule catecholamines, antagonizing the effects of renal RAS. Angiotensinogen-derived natriuretic and vasodilating peptides (Ang1-9, Ang1-7, Ang3-8) and their receptors have been described. Receptor agonists or antagonists are available to affect portal hypertension and sodium retention in cirrhosis. ACE2-dependent generation of Ang1-7 may inhibit experimental liver fibrosis. inhibition of Ang1-7 clearance by means of neprilysin blockade has portal hypotensive and natriuretic effects. Ang1-12, whose production renin does not regulate, is converted to several different angiotensin peptides via chymase. Finally, Ang II behaves as either an antinatriuretic or a natriuretic agent, based on the tissue content of AT1 R and AT2 R receptors, their ratio being prone to pharmacological modulation.
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Affiliation(s)
- Giovanni Sansoè
- Division of Gastroenterology, Humanitas Gradenigo Hospital, Torino, Italy
| | - Manuela Aragno
- Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
| | - Florence Wong
- Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, ON, Canada
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47
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Raj D, Tomar B, Lahiri A, Mulay SR. The gut-liver-kidney axis: Novel regulator of fatty liver associated chronic kidney disease. Pharmacol Res 2019; 152:104617. [PMID: 31881272 DOI: 10.1016/j.phrs.2019.104617] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 12/09/2019] [Accepted: 12/21/2019] [Indexed: 12/12/2022]
Abstract
Increased interest in understanding the liver-kidney axis in health and disease during the last decade unveiled multiple recent evidence that suggested a strong association of fatty liver diseases with chronic kidney disease (CKD). Low-grade systemic inflammation is thought to be the major contributing factor to the pathogenesis of CKD associated with fatty liver. However, other contributing factors largely remained unclear, for example, gut microbiota and intestinal barrier integrity. Homeostasis of the gut microbiome is very crucial for the health of an individual. Imbalance in the gut microbiota leads to various diseases like fatty liver disease and CKD. On the contrary, disease conditions can also distinctly change gut microbiota. In this review, we propose the pathogenic role of the gut-liver-kidney axis in the development and progression of CKD associated with chronic fatty liver diseases, either non-alcoholic fatty liver disease or non-alcoholic steatohepatitis in experimental models and humans. Further, we discuss the therapeutic potential and highlight the future research directions for therapeutic targeting of the gut-liver-kidney axis.
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Affiliation(s)
- Desh Raj
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India
| | - Bhawna Tomar
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Amit Lahiri
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India
| | - Shrikant R Mulay
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India.
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NAFLD and Extra-Hepatic Comorbidities: Current Evidence on a Multi-Organ Metabolic Syndrome. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16183415. [PMID: 31540048 PMCID: PMC6765902 DOI: 10.3390/ijerph16183415] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 09/06/2019] [Accepted: 09/08/2019] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and its incidence is definitely increasing. NAFLD is a metabolic disease with extensive multi-organ involvement, whose extra-hepatic manifestations include type 2 diabetes mellitus, cardiovascular disease, obstructive sleep apnea, chronic kidney disease, osteoporosis, and polycystic ovarian syndrome. Recently, further evidence has given attention to pathological correlations not strictly related to metabolic disease, also incorporating in this broad spectrum of systemic involvement hypothyroidism, psoriasis, male sexual dysfunction, periodontitis, and urolithiasis. The most common cause of mortality in NAFLD is represented by cardiovascular disease, followed by liver-related complications. Therefore, clinicians should learn to screen and initiate treatment for these extra-hepatic manifestations, in order to provide appropriate multidisciplinary assessments and rigorous surveillance. This review evaluates the current evidence regarding extra-hepatic associations of NAFLD, focusing on the pathogenic hypothesis and the clinical implications.
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49
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Lelis DDF, Freitas DFD, Machado AS, Crespo TS, Santos SHS. Angiotensin-(1-7), Adipokines and Inflammation. Metabolism 2019; 95:36-45. [PMID: 30905634 DOI: 10.1016/j.metabol.2019.03.006] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Revised: 03/11/2019] [Accepted: 03/20/2019] [Indexed: 12/12/2022]
Abstract
Nowadays the adipose tissue is recognized as one of the most critical endocrine organs releasing many adipokines that regulate metabolism, inflammation and body homeostasis. There are several described adipokines, including the renin-angiotensin system (RAS) components that are especially activated in some diseases with increased production of angiotensin II and several pro-inflammatory hormones. On the other hand, RAS also expresses angiotensin-(1-7), which is now recognized as the main peptide on counteracting Ang II effects. New studies have shown that increased activation of ACE2/Ang-(1-7)/MasR arm can revert and prevent local and systemic dysfunctions improving lipid profile and insulin resistance by modulating insulin actions, and reducing inflammation. In this context, the present review shows the interaction and relevance of Ang-(1-7) effects on regulating adipokines, and as one adipokine itself, modulating body homeostasis, with emphasis on its anti-inflammatory properties, especially in the context of metabolic disorders with focus on obesity and type 2 diabetes mellitus pandemic.
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Affiliation(s)
- Deborah de Farias Lelis
- Laboratory of Health Sciences, Post Graduate Program in Health Sciences, Universidade Estadual de Montes Claros (UNIMONTES), Montes Claros, Minas Gerais, Brazil
| | - Daniela Fernanda de Freitas
- Laboratory of Health Sciences, Post Graduate Program in Health Sciences, Universidade Estadual de Montes Claros (UNIMONTES), Montes Claros, Minas Gerais, Brazil
| | - Amanda Souto Machado
- Laboratory of Health Sciences, Post Graduate Program in Health Sciences, Universidade Estadual de Montes Claros (UNIMONTES), Montes Claros, Minas Gerais, Brazil
| | - Thaísa Soares Crespo
- Laboratory of Health Sciences, Post Graduate Program in Health Sciences, Universidade Estadual de Montes Claros (UNIMONTES), Montes Claros, Minas Gerais, Brazil
| | - Sérgio Henrique Sousa Santos
- Institute of Agricultural Sciences, Food Engineering College, Universidade Federal de Minas Gerais (UFMG), Montes Claros, Minas Gerais, Brazil; Laboratory of Health Sciences, Post Graduate Program in Health Sciences, Universidade Estadual de Montes Claros (UNIMONTES), Montes Claros, Minas Gerais, Brazil.
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50
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Manka P, Zeller A, Syn WK. Fibrosis in Chronic Liver Disease: An Update on Diagnostic and Treatment Modalities. Drugs 2019; 79:903-927. [DOI: 10.1007/s40265-019-01126-9] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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