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1
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Ma X, Liang Y, Chen W, Zheng L, Lin H, Zhou T. The role of endothelin receptor antagonists in kidney disease. Ren Fail 2025; 47:2465810. [PMID: 40015728 PMCID: PMC11869344 DOI: 10.1080/0886022x.2025.2465810] [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: 11/16/2024] [Revised: 01/21/2025] [Accepted: 02/06/2025] [Indexed: 03/01/2025] Open
Abstract
Kidney diseases are among the most prevalent conditions worldwide, impacting over 850 million individuals. They are categorized into acute kidney injury and chronic kidney disease. Current preclinical and clinical trials have demonstrated that endothelin (ET) is linked to the onset and progression of kidney disease. In kidney diseases, pathological conditions such as hyperglycemia, acidosis, insulin resistance, and elevated angiotensin II levels lead to an increase in ET. This elevation activates endothelin receptor type A, resulting in harmful effects like proteinuria and a reduced glomerular filtration rate (GFR). Therefore, to slow the progression of kidney disease, endothelin receptor antagonists (ERAs) have been proposed as promising new therapies. Numerous studies have demonstrated the efficacy of ERAs in significantly reducing proteinuria and improving GFR, thereby slowing the progression of kidney diseases. This review discusses the mechanisms of action of ERAs in treating kidney disease, their efficacy and safety in preclinical and clinical studies, and explores future prospects for ERAs.
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Affiliation(s)
- Xiaoting Ma
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Yuyang Liang
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Wenmin Chen
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Lingqian Zheng
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Haishan Lin
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Tianbiao Zhou
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
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2
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Liu Z, Liu J, Wang W, An X, Luo L, Yu D, Sun W. Epigenetic modification in diabetic kidney disease. Front Endocrinol (Lausanne) 2023; 14:1133970. [PMID: 37455912 PMCID: PMC10348754 DOI: 10.3389/fendo.2023.1133970] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 05/30/2023] [Indexed: 07/18/2023] Open
Abstract
Diabetic kidney disease (DKD) is a common microangiopathy in diabetic patients and the main cause of death in diabetic patients. The main manifestations of DKD are proteinuria and decreased renal filtration capacity. The glomerular filtration rate and urinary albumin level are two of the most important hallmarks of the progression of DKD. The classical treatment of DKD is controlling blood glucose and blood pressure. However, the commonly used clinical therapeutic strategies and the existing biomarkers only partially slow the progression of DKD and roughly predict disease progression. Therefore, novel therapeutic methods, targets and biomarkers are urgently needed to meet clinical requirements. In recent years, increasing attention has been given to the role of epigenetic modification in the pathogenesis of DKD. Epigenetic variation mainly includes DNA methylation, histone modification and changes in the noncoding RNA expression profile, which are deeply involved in DKD-related inflammation, oxidative stress, hemodynamics, and the activation of abnormal signaling pathways. Since DKD is reversible at certain disease stages, it is valuable to identify abnormal epigenetic modifications as early diagnosis and treatment targets to prevent the progression of end-stage renal disease (ESRD). Because the current understanding of the epigenetic mechanism of DKD is not comprehensive, the purpose of this review is to summarize the role of epigenetic modification in the occurrence and development of DKD and evaluate the value of epigenetic therapies in DKD.
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Affiliation(s)
- Zhe Liu
- Public Research Platform, First Hospital of Jilin University, Changchun, Jilin, China
- College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Jiahui Liu
- Public Research Platform, First Hospital of Jilin University, Changchun, Jilin, China
| | - Wanning Wang
- Department of Nephrology, First Hospital of Jilin University, Changchun, Jilin, China
| | - Xingna An
- Public Research Platform, First Hospital of Jilin University, Changchun, Jilin, China
| | - Ling Luo
- Public Research Platform, First Hospital of Jilin University, Changchun, Jilin, China
| | - Dehai Yu
- Public Research Platform, First Hospital of Jilin University, Changchun, Jilin, China
| | - Weixia Sun
- Department of Nephrology, First Hospital of Jilin University, Changchun, Jilin, China
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3
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Zhang S, Li X, Liu S, Zhang W, Li M, Qiao C. Research progress on the role of ET-1 in diabetic kidney disease. J Cell Physiol 2023; 238:1183-1192. [PMID: 37063089 DOI: 10.1002/jcp.31023] [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: 01/18/2023] [Revised: 03/16/2023] [Accepted: 04/03/2023] [Indexed: 04/18/2023]
Abstract
Diabetic kidney disease (DKD) is one of the common complications of diabetes mellitus, which usually progresses to end-stage renal disease and causes great damage to the health of patients. Endothelin-1 (ET-1), a molecule closely associated with the progression of DKD, has increased expression in response to high glucose stimulation and is involved in hemodynamic changes, inflammation, glomerular and tubular dysfunction in the kidney, causing an increase in proteinuria and a decrease in glomerular filtration function, ultimately leading to glomerulosclerosis and renal failure. This paper aims to review the molecular level changes, regulatory mechanisms, and mechanisms of action of ET-1 under DKD, clinical trials of ET-1 receptor antagonists in recent years and current problems, to provide basic information and new research directions and ideas for the treatment of DKD and ET-1-related research.
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Affiliation(s)
- Shenghao Zhang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Xiaodan Li
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Siyu Liu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Wanting Zhang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Meinuo Li
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Chen Qiao
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
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4
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Chan ATP, Tang SCW. Advances in the management of diabetic kidney disease: beyond sodium-glucose co-transporter 2 inhibitors. Kidney Res Clin Pract 2022; 41:682-698. [PMID: 35977903 PMCID: PMC9731775 DOI: 10.23876/j.krcp.21.285] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 04/20/2022] [Accepted: 05/09/2022] [Indexed: 08/09/2023] Open
Abstract
Progress in the treatment of diabetic kidney disease (DKD) has been modest since the early trials on renin-angiotensin-aldosterone system inhibitors (RAASis). Although sodium-glucose co-transporter 2 inhibitors (SGLT2is) have revolutionized the management of DKD by lowering proteinuria and protecting organs, other novel treatment approaches with good evidence and efficacy that can be used in conjunction with a RAASi or SGLT2i in managing DKD have emerged in the past few years. This review discusses the evidence for glucagon-like peptide-1 receptor agonist, selective mineralocorticoid receptor antagonist, and selective endothelin A receptor antagonist, emerging treatment options for DKD beyond SGLT2 inhibition.
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Affiliation(s)
- Anthony T. P. Chan
- Division of Nephrology, Department of Medicine, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Sydney C. W. Tang
- Division of Nephrology, Department of Medicine, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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5
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Yang XH, Zhang BL, Cheng Y, Fu SK, Jin HM. Association of the Coexistence of Somnipathy and Diabetes With the Risks of Cardiovascular Disease Events, Stroke, and All‐Cause Mortality: A Systematic Review and Meta‐analysis. J Am Heart Assoc 2022; 11:e024783. [PMID: 35861844 PMCID: PMC9707815 DOI: 10.1161/jaha.121.024783] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background
Somnipathy and diabetes are independently associated with an increased risk of cardiovascular disease (CVD). However, whether a combination of both conditions is associated with a higher risk of CVD events remains uncertain. Therefore, the aim of this meta‐analysis was to clarify this association.
Methods and Results
We searched MEDLINE, Web of Science, EMBASE,
ClinicalTrials.gov
, and the Cochrane Central Register for Controlled Trials. We included randomized controlled trials, nonrandomized trials, and prospective observational cohort studies that assessed the combined effect of diabetes and comorbid somnipathy on CVD risk and mortality for at least 1 year. Outcomes included CVD, coronary heart disease, stroke, and all‐cause mortality. Twelve studies involving 582 267 participants were included in the meta‐analysis. Patients with somnipathy and comorbid diabetes exhibited increased risks of CVD, coronary heart disease, stroke, and all‐cause mortality (risk ratio [RR], 1.27 [95% CI, 1.12–1.45],
P
<0.0001; RR, 1.40 [95% CI, 1.21–1.62],
P
<0.0001; RR, 1.28 [95% CI, 1.08–1.52],
P
=0.004, and RR, 1.56 [95% CI, 1.26–1.94],
P
<0.0001, respectively).
Conclusions
The coexistence of somnipathy and diabetes is associated with higher risks of CVD, coronary heart disease, stroke, and mortality than somnipathy or diabetes alone. Resolving sleep problems in patients with diabetes may reduce the risks of CVD, stroke, and mortality.
Registration Information
https://www.crd.york.ac.uk/prospero/
. Identifier: PROSPERO CRD42021274566.
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Affiliation(s)
- Xiu Hong Yang
- Division of Nephrology, Shanghai Pudong Hospital Fudan University Pudong Medical Center Shanghai China
| | - Bao Long Zhang
- The Institutes of Biomedical Sciences (IBS) Fudan University Shanghai China
| | - Yun Cheng
- Division of Nephrology, Shanghai Pudong Hospital Fudan University Pudong Medical Center Shanghai China
| | - Shun Kun Fu
- Division of Nephrology, Shanghai Pudong Hospital Fudan University Pudong Medical Center Shanghai China
| | - Hui Min Jin
- Division of Nephrology, Shanghai Pudong Hospital Fudan University Pudong Medical Center Shanghai China
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6
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Haffke M, Freitag H, Rudolf G, Seifert M, Doehner W, Scherbakov N, Hanitsch L, Wittke K, Bauer S, Konietschke F, Paul F, Bellmann-Strobl J, Kedor C, Scheibenbogen C, Sotzny F. Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS). J Transl Med 2022; 20:138. [PMID: 35317812 PMCID: PMC8938726 DOI: 10.1186/s12967-022-03346-2] [Citation(s) in RCA: 147] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 03/08/2022] [Indexed: 12/20/2022] Open
Abstract
Background Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS. Methods We studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers. Results Five of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs. Conclusion A subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03346-2.
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Affiliation(s)
- Milan Haffke
- Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin, Germany.
| | - Helma Freitag
- Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin, Germany
| | - Gordon Rudolf
- Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin, Germany
| | - Martina Seifert
- Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin, Germany.,Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Berlin, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Wolfram Doehner
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Berlin, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.,Department of Cardiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin, Germany.,Center for Stroke Research Berlin (CSB), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin, Germany
| | - Nadja Scherbakov
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Berlin, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.,Department of Cardiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin, Germany.,Center for Stroke Research Berlin (CSB), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin, Germany
| | - Leif Hanitsch
- Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin, Germany
| | - Kirsten Wittke
- Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin, Germany
| | - Sandra Bauer
- Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin, Germany
| | - Frank Konietschke
- Institute of Biometry and Clinical Epidemiology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin, Germany
| | - Friedemann Paul
- Experimental and Clinical Research Center (ECRC), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin, Germany.,NeuroCure Clinical Research Center (NCRC), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin, Germany.,Max Delbrueck Center for Molecular Medicine, Experimental and Clinical Research Center (ECRC), Berlin, Germany
| | - Judith Bellmann-Strobl
- Experimental and Clinical Research Center (ECRC), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin, Germany.,NeuroCure Clinical Research Center (NCRC), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin, Germany.,Max Delbrueck Center for Molecular Medicine, Experimental and Clinical Research Center (ECRC), Berlin, Germany
| | - Claudia Kedor
- Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin, Germany
| | - Carmen Scheibenbogen
- Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin, Germany
| | - Franziska Sotzny
- Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin, Germany
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7
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Mahdi A, Collado A, Tengbom J, Jiao T, Wodaje T, Johansson N, Farnebo F, Färnert A, Yang J, Lundberg JO, Zhou Z, Pernow J. Erythrocytes Induce Vascular Dysfunction in COVID-19. JACC Basic Transl Sci 2022; 7:193-204. [PMID: 35194565 PMCID: PMC8849181 DOI: 10.1016/j.jacbts.2021.12.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 12/03/2021] [Accepted: 12/03/2021] [Indexed: 12/20/2022]
Abstract
Patients hospitalized for COVID-19 display marked impairment in endothelial function, which is persistent following recovery from the acute infection. RBCs from patients with COVID-19 impair vascular function through mechanisms involving increased arginase 1, ROS and IFNγ, and reduced NO bioactivity. These data advance our understanding in COVID-19–associated vascular injury with a clear involvement of RBCs. Targeting these mechanisms might provide a novel therapeutic strategy to alleviate vascular injury in patients with COVID-19. Current knowledge regarding mechanisms underlying cardiovascular complications in patients with COVID-19 is limited and urgently needed. We shed light on a previously unrecognized mechanism and unravel a key role of red blood cells, driving vascular dysfunction in patients with COVID-19 infection. We establish the presence of profound and persistent endothelial dysfunction in vivo in patients with COVID-19. Mechanistically, we show that targeting reactive oxygen species or arginase 1 improves vascular dysfunction mediated by red blood cells. These translational observations hold promise that restoring the redox balance in red blood cells might alleviate the clinical complications of COVID-19–associated vascular dysfunction.
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Key Words
- ACh, acetylcholine
- C19-RBC, red blood cell from patients with COVID-19
- COVID-19
- EDR, endothelium-dependent relaxation
- EIR, endothelium-independent relaxation
- H-RBC, red blood cell from healthy subjects
- HNE, hydroxynonenal
- IFN, interferon
- RBC, red blood cell
- RHI, reactive hyperemia index
- ROS, reactive oxygen species
- SNP, sodium nitroprusside
- TNF, tumor necrosis factor
- arginase
- endothelial dysfunction
- nitric oxide
- reactive oxygen species
- red blood cells
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Affiliation(s)
- Ali Mahdi
- Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Aida Collado
- Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - John Tengbom
- Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Tong Jiao
- Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Tigist Wodaje
- Division of Cardiology, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Niclas Johansson
- Division of Infectious Diseases, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Filip Farnebo
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Stockholm Craniofacial Center, Karolinska University Hospital, Stockholm, Sweden
| | - Anna Färnert
- Division of Infectious Diseases, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Jiangning Yang
- Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Jon O Lundberg
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Zhichao Zhou
- Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - John Pernow
- Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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8
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Ahmad N, Veerapalli H, Lankala CR, Castaneda EE, Aziz A, Rockferry AG, Hamid P. Endothelin Receptor Antagonists as a Potential Treatment of Diabetic Nephropathy: A Systematic Review. Cureus 2021; 13:e19325. [PMID: 34909290 PMCID: PMC8653857 DOI: 10.7759/cureus.19325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 11/07/2021] [Indexed: 11/05/2022] Open
Abstract
Diabetic nephropathy is becoming a more predominant cause of end-stage renal disease, as the prevalence of diabetes mellitus worldwide is on the rise. In this systematic review, we aimed to define the role of endothelin receptor antagonists, in the prevention and treatment of diabetic nephropathy, in addition to determining their safety. For this review, PubMed, Google Scholar, and Cochrane Library databases, in addition to ClinicalTrials.gov, were searched for publications in the last 20 years. We included 14 studies, seven randomized control trials, and seven post hoc analyses in this paper. Atrasentan decreased albuminuria, reduced blood pressure, and improved lipid profiles with more manageable fluid overload-related adverse events than avosentan and bosentan. Overall, endothelin receptor antagonists, in combination with renin-angiotensin-aldosterone system inhibitors, effectively reduce albuminuria and prevent the progression of diabetic kidney disease. However, more extensive clinical trials still need to be conducted to confirm these relationships and to learn more about the specific factors affecting their efficacy in individual patients.
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Affiliation(s)
- Noorain Ahmad
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Harish Veerapalli
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Chetan Reddy Lankala
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Everardo E Castaneda
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Afia Aziz
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Amy G Rockferry
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Pousette Hamid
- Neurology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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9
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Wang J, Xiang H, Lu Y, Wu T, Ji G. New progress in drugs treatment of diabetic kidney disease. Biomed Pharmacother 2021; 141:111918. [PMID: 34328095 DOI: 10.1016/j.biopha.2021.111918] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 07/08/2021] [Accepted: 07/12/2021] [Indexed: 02/08/2023] Open
Abstract
Diabetic kidney disease (DKD) is not only one of the main complications of diabetes, but also the leading cause of the end-stage renal disease (ESRD). The occurrence and development of DKD have always been a serious clinical problem that leads to the increase of morbidity and mortality and the severe damage to the quality of life of human beings. Controlling blood glucose, blood pressure, blood lipids, and improving lifestyle can help slow the progress of DKD. In recent years, with the extensive research on the pathological mechanism and molecular mechanism of DKD, there are more and more new drugs based on this, such as new hypoglycemic drugs sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors with good efficacy in clinical treatment. Besides, there are some newly developed drugs, including protein kinase C (PKC) inhibitors, advanced glycation end product (AGE) inhibitors, aldosterone receptor inhibitors, endothelin receptor (ETR) inhibitors, transforming growth factor-β (TGF-β) inhibitors, Rho kinase (ROCK) inhibitors and so on, which show positive effects in animal or clinical trials and bring hope for the treatment of DKD. In this review, we sort out the progress in the treatment of DKD in recent years, the research status of some emerging drugs, and the potential drugs for the treatment of DKD in the future, hoping to provide some directions for clinical treatment of DKD.
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Affiliation(s)
- Junmin Wang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hongjiao Xiang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yifei Lu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tao Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Guang Ji
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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10
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Nicholas SB. Novel Anti-inflammatory and Anti-fibrotic Agents for Diabetic Kidney Disease-From Bench to Bedside. Adv Chronic Kidney Dis 2021; 28:378-390. [PMID: 34922694 DOI: 10.1053/j.ackd.2021.09.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 08/30/2021] [Accepted: 09/17/2021] [Indexed: 02/08/2023]
Abstract
Chronic low-grade inflammation, now coined by the new paradigm as "metaflammation" or "metainflammation", has been linked to chronic kidney disease and its progression. In diabetes, altered metabolism denotes factors associated with the metabolic syndrome and hyperglycemia, among others. The interplay among hyperglycemia, oxidative stress, and inflammation in the pathogenesis of diabetic kidney disease (DKD) has been broadly explored. Identification of mediators of inflammatory processes involving macrophage infiltration, production of inflammasomes, release of cytokines, and activation of pertinent signaling pathways including mitogen-activated protein kinase, Jun N-terminal kinase, Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway (JAK/STAT), and apoptosis signal-regulating kinase 1 signaling mechanisms have enabled the development of therapeutic agents for DKD. This review describes the evidence supporting the contribution of the inflammatory response and fibrotic changes and focuses on selected, novel, promising drugs as well as repurposed drugs that have made it to phase 2, 3, or 4 of clinical trials in adults with type 2 diabetes mellitus and their potential to become an important part of our armamentarium to improve the management of DKD. Importantly, drugs that solely target inflammatory processes may be insufficient to fully optimize care of patients with DKD because of the complex nature of the disease.
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11
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Zhou Y, Chi J, Huang Y, Dong B, Lv W, Wang YG. Efficacy and safety of endothelin receptor antagonists in type 2 diabetic kidney disease: A systematic review and meta-analysis of randomized controlled trials. Diabet Med 2021; 38:e14411. [PMID: 33000477 DOI: 10.1111/dme.14411] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 09/10/2020] [Accepted: 09/22/2020] [Indexed: 01/01/2023]
Abstract
AIM To analyse the efficacy and safety of endothelin receptor antagonists for people with diabetic kidney disease. METHODS Randomized controlled trials comparing endothelin receptor antagonists with placebo in people with diabetic kidney disease were identified through PubMed, Embase and the Cochrane Library. We used a random-effect model to calculate the mean difference or risk ratio with the 95% CI. RESULTS Seven studies with a total of 4730 participants were included. Overall, endothelin receptor antagonists significantly reduced albuminuria compared with placebo (standardized mean difference -0.48, 95% CI -0.64 to -0.33). Atrasentan, in particular, effectively reduced albuminuria (standardized mean difference -0.58, 95% CI -1.00 to -0.17) and the risk of composite renal endpoints (risk ratio 0.65; 95% CI 0.49 to 0.88), with insignificant change in the rate of congestive heart failure (risk ratio 1.40, 95% CI 0.76 to 2.56) and mortality (risk ratio 1.11, 95% CI 0.77 to 1.61). In contrast, although avosentan reduced albuminuria (standardized mean difference -0.47, 95% CI -0.57 to -0.36) and the risk of composite renal endpoints (risk ratio 0.63, 95% CI 0.42 to 0.94), it was associated with a significant increase in congestive heart failure risk (risk ratio 2.61, 95% CI 1.36 to 5.00) and an insignificant increase in mortality risk (risk ratio 1.50, 95% CI 0.81, 2.78). No significant change in efficacy or safety outcomes with bosentan was detected. Dose-response analysis indicated that 0.75 mg/day atrasentan is expected to be optimal for renoprotection, with maximal albuminuria reduction and minimal fluid retention events. CONCLUSIONS Among the endothelin receptor antagonists, atrasentan and avosentan, but not bosentan, are effective for renoprotection in people with diabetic kidney disease. Compared with other types and doses, atrasentan 0.75 mg/day is the most promising, with maximal albuminuria reduction and minimal fluid retention. Vigilant monitoring of congestive heart failure risk is needed in future clinical practice. (PROSPERO registration no. CRD42020169840).
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Affiliation(s)
- Y Zhou
- Department of Endocrinology, Affiliated Hospital of Medical College Qingdao University, Qingdao, China
| | - J Chi
- Department of Endocrinology, Affiliated Hospital of Medical College Qingdao University, Qingdao, China
| | - Y Huang
- Department of Endocrinology, Affiliated Hospital of Medical College Qingdao University, Qingdao, China
| | - B Dong
- Department of Endocrinology, Affiliated Hospital of Medical College Qingdao University, Qingdao, China
| | - W Lv
- Department of Endocrinology, Affiliated Hospital of Medical College Qingdao University, Qingdao, China
| | - Y G Wang
- Department of Endocrinology, Affiliated Hospital of Medical College Qingdao University, Qingdao, China
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12
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Jenkins HN, Rivera-Gonzalez O, Gibert Y, Speed JS. Endothelin-1 in the pathophysiology of obesity and insulin resistance. Obes Rev 2020; 21:e13086. [PMID: 32627269 PMCID: PMC7669671 DOI: 10.1111/obr.13086] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 05/07/2020] [Accepted: 05/23/2020] [Indexed: 12/29/2022]
Abstract
The association between plasma endothelin-1 (ET-1) and obesity has been documented for decades, yet the contribution of ET-1 to risk factors associated with obesity is not fully understood. In 1994, one of first papers to document this association also noted a positive correlation between plasma insulin and ET-1, suggesting a potential contribution of ET-1 to the development of insulin resistance. Both endogenous receptors for ET-1, ETA and ETB are present in all insulin-sensitive tissues including adipose, liver and muscle, and ET-1 actions within these tissues suggest that ET-1 may be playing a role in the pathogenesis of insulin resistance. Further, antagonists for ET-1 receptors are clinically approved making these sites attractive therapeutic targets. This review focuses on known mechanisms through which ET-1 affects plasma lipid profiles and insulin signalling in these metabolically important tissues and also identifies gaps in our understanding of ET-1 in obesity-related pathophysiology.
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Affiliation(s)
- Haley N. Jenkins
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39047
| | - Osvaldo Rivera-Gonzalez
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39047
| | - Yann Gibert
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, MS 39047
| | - Joshua S. Speed
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39047
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13
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Zhang L, Xue S, Hou J, Chen G, Xu ZG. Endothelin receptor antagonists for the treatment of diabetic nephropathy: A meta-analysis and systematic review. World J Diabetes 2020; 11:553-566. [PMID: 33269066 PMCID: PMC7672789 DOI: 10.4239/wjd.v11.i11.553] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 08/22/2020] [Accepted: 10/15/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is the main cause of chronic kidney disease and end-stage renal disease worldwide. Although available clinical trials have shown that endothelin receptor (ER) antagonists may be a novel and beneficial drug for DN, no consistent conclusions regarding their sufficient effectiveness and safety for patients with DN have been presented. AIM To assess the effectiveness and safety of ER antagonists among patients with DN. METHODS The EMBASE, PubMed, MEDLINE, Cochrane, and ClinicalTrials.gov databases were searched without any language restrictions. Relative risks with 95% confidence intervals (CIs) for dichotomous data and mean differences or standardized mean difference with 95%CIs for continuous data were calculated using Review Manager 5.3 software. Publication bias was assessed using Egger's test with Stata/SE software. RESULTS We enrolled seven studies with six data sets and 5271 participants. The ER antagonists group showed a significantly greater reduction in albuminuria and more patients with 40% reduction in urinary albumin-to-creatinine ratio than the control group (P < 0.0001 and P = 0.02, respectively). Subgroup analysis for reductions in estimated glomerular filtration rate (eGFR) showed that for the middle-dosage subgroup, the ER antagonists group exhibited lower eGFR reduction than the control group (P < 0.00001; mean difference, 0.70 95%CI: 0.66, 0.74). Moreover, significant reductions in systolic and diastolic blood pressure were observed in the invention group. CONCLUSION ER blockades combined with angiotensin converting enzyme inhibitor /angiotensin II type 1 receptor blockers may be an effective treatment to lower blood pressure and reduce proteinuria in DN with declined eGFR. However, attention should be given to adverse events, including cardiac failure, anemia, and hypoglycemia, as well as serious adverse events.
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Affiliation(s)
- Li Zhang
- Department of Nephrology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Shuai Xue
- Department of Thyroid Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Jie Hou
- Department of Nephrology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Guang Chen
- Department of Thyroid Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Zhong-Gao Xu
- Department of Nephrology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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14
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Abstract
Discovered in 1987 as a potent endothelial cell-derived vasoconstrictor peptide, endothelin-1 (ET-1), the predominant member of the endothelin peptide family, is now recognized as a multifunctional peptide with cytokine-like activity contributing to almost all aspects of physiology and cell function. More than 30 000 scientific articles on endothelin were published over the past 3 decades, leading to the development and subsequent regulatory approval of a new class of therapeutics-the endothelin receptor antagonists (ERAs). This article reviews the history of the discovery of endothelin and its role in genetics, physiology, and disease. Here, we summarize the main clinical trials using ERAs and discuss the role of endothelin in cardiovascular diseases such as arterial hypertension, preecclampsia, coronary atherosclerosis, myocardial infarction in the absence of obstructive coronary artery disease (MINOCA) caused by spontaneous coronary artery dissection (SCAD), Takotsubo syndrome, and heart failure. We also discuss how endothelins contributes to diabetic kidney disease and focal segmental glomerulosclerosis, pulmonary arterial hypertension, as well as cancer, immune disorders, and allograft rejection (which all involve ETA autoantibodies), and neurological diseases. The application of ERAs, dual endothelin receptor/angiotensin receptor antagonists (DARAs), selective ETB agonists, novel biologics such as receptor-targeting antibodies, or immunization against ETA receptors holds the potential to slow the progression or even reverse chronic noncommunicable diseases. Future clinical studies will show whether targeting endothelin receptors can prevent or reduce disability from disease and improve clinical outcome, quality of life, and survival in patients.
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Affiliation(s)
- Matthias Barton
- From Molecular Internal Medicine, University of Zürich, Switzerland (M.B.)
- Andreas Grüntzig Foundation, Zürich, Switzerland (M.B.)
| | - Masashi Yanagisawa
- International Institute for Integrative Sleep Medicine (WPI-IIIS) and Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, Japan (M.Y.)
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX (M.Y.)
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15
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Trapping endothelin-1 to hunt down cardiovascular disease? Drug Discov Today 2019; 24:2108-2110. [PMID: 31654816 DOI: 10.1016/j.drudis.2019.10.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 10/14/2019] [Accepted: 10/15/2019] [Indexed: 12/25/2022]
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16
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Farrah TE, Anand A, Gallacher PJ, Kimmitt R, Carter E, Dear JW, Mills NL, Webb DJ, Dhaun N. Endothelin Receptor Antagonism Improves Lipid Profiles and Lowers PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) in Patients With Chronic Kidney Disease. Hypertension 2019; 74:323-330. [PMID: 31177906 PMCID: PMC6635059 DOI: 10.1161/hypertensionaha.119.12919] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Dyslipidemia is common in chronic kidney disease (CKD). Despite statins, many patients fail to adequately lower lipids and remain at increased risk of cardiovascular disease. Selective ETA (endothelin-A) receptor antagonists reduce cardiovascular disease risk factors. Preclinical data suggest that ETA antagonism has beneficial effects on circulating lipids. We assessed the effects of selective ETA antagonism on circulating lipids and PCSK9 (proprotein convertase subtilisin/kexin type 9) in CKD. This was a secondary analysis of a fully randomized, double-blind, 3-phase crossover study. Twenty-seven subjects with predialysis CKD on optimal cardio- and renoprotective treatment were randomly assigned to receive 6 weeks dosing with placebo, the selective ETA receptor antagonist, sitaxentan, or long-acting nifedipine. We measured circulating lipids and PCSK9 at baseline and then after 3 and 6 weeks. Baseline lipids and PCSK9 did not differ before each study phase. Whereas placebo and nifedipine had no effect on lipids, 6 weeks of ETA antagonism significantly reduced total (-11±1%) and low-density lipoprotein-associated (-20±3%) cholesterol, lipoprotein (a) (-16±2%) and triglycerides (-20±4%); high-density lipoprotein-associated cholesterol increased (+14±2%), P<0.05 versus baseline for all. Additionally, ETA receptor antagonism, but neither placebo nor nifedipine, reduced circulating PCSK9 (-19±2%; P<0.001 versus baseline; P<0.05 versus nifedipine and placebo). These effects were independent of statin use and changes in blood pressure or proteinuria. Selective ETA antagonism improves lipid profiles in optimally-managed patients with CKD, effects that may occur through a reduction in circulating PCSK9. ETA receptor antagonism offers a potentially novel strategy to reduce cardiovascular disease risk in CKD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00810732.
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Affiliation(s)
- Tariq E. Farrah
- From the University/British Heart Foundation Centre of Research Excellence, Centre of Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute (T.E.F., A.A., P.J.G., R.K., E.C., J.W.D., N.L.M., D.J.W., N.D.),Department of Renal Medicine, Royal Infirmary of Edinburgh (T.E.F., P.J.G., N.D.)
| | - Atul Anand
- From the University/British Heart Foundation Centre of Research Excellence, Centre of Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute (T.E.F., A.A., P.J.G., R.K., E.C., J.W.D., N.L.M., D.J.W., N.D.)
| | - Peter J. Gallacher
- From the University/British Heart Foundation Centre of Research Excellence, Centre of Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute (T.E.F., A.A., P.J.G., R.K., E.C., J.W.D., N.L.M., D.J.W., N.D.),Department of Renal Medicine, Royal Infirmary of Edinburgh (T.E.F., P.J.G., N.D.)
| | - Robert Kimmitt
- From the University/British Heart Foundation Centre of Research Excellence, Centre of Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute (T.E.F., A.A., P.J.G., R.K., E.C., J.W.D., N.L.M., D.J.W., N.D.)
| | - Edwin Carter
- From the University/British Heart Foundation Centre of Research Excellence, Centre of Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute (T.E.F., A.A., P.J.G., R.K., E.C., J.W.D., N.L.M., D.J.W., N.D.)
| | - James W. Dear
- From the University/British Heart Foundation Centre of Research Excellence, Centre of Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute (T.E.F., A.A., P.J.G., R.K., E.C., J.W.D., N.L.M., D.J.W., N.D.)
| | - Nicholas L. Mills
- From the University/British Heart Foundation Centre of Research Excellence, Centre of Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute (T.E.F., A.A., P.J.G., R.K., E.C., J.W.D., N.L.M., D.J.W., N.D.)
| | - David J. Webb
- From the University/British Heart Foundation Centre of Research Excellence, Centre of Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute (T.E.F., A.A., P.J.G., R.K., E.C., J.W.D., N.L.M., D.J.W., N.D.)
| | - Neeraj Dhaun
- From the University/British Heart Foundation Centre of Research Excellence, Centre of Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute (T.E.F., A.A., P.J.G., R.K., E.C., J.W.D., N.L.M., D.J.W., N.D.),Department of Renal Medicine, Royal Infirmary of Edinburgh (T.E.F., P.J.G., N.D.)
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17
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Marques B, Antunes M, Guerreiro Castro S, de Figueiredo IR, Vieira Alves R, Gruner H. Digital ulcers in systemic sclerosis and insulin-dependent diabetes mellitus type 2. Rheumatol Adv Pract 2019; 3:rkz019. [PMID: 31460491 PMCID: PMC6704314 DOI: 10.1093/rap/rkz019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 07/22/2019] [Accepted: 07/22/2019] [Indexed: 11/18/2022] Open
Affiliation(s)
- Bernardo Marques
- Endocrinology Department, Instituto Português de Oncologia de Coimbra FG, EPE, Coimbra
| | - Margarida Antunes
- Internal Medicine Department 7.2, Hospital Curry Cabral – Centro Hospitalar Universitário Lisboa Central, EPE, Lisbon
- Clinical Medicine Department, NOVA Medical School, Lisbon, Portugal
| | - Sara Guerreiro Castro
- Internal Medicine Department 7.2, Hospital Curry Cabral – Centro Hospitalar Universitário Lisboa Central, EPE, Lisbon
| | - Inês Rego de Figueiredo
- Internal Medicine Department 7.2, Hospital Curry Cabral – Centro Hospitalar Universitário Lisboa Central, EPE, Lisbon
| | - Rita Vieira Alves
- Internal Medicine Department 7.2, Hospital Curry Cabral – Centro Hospitalar Universitário Lisboa Central, EPE, Lisbon
| | - Heidi Gruner
- Internal Medicine Department 7.2, Hospital Curry Cabral – Centro Hospitalar Universitário Lisboa Central, EPE, Lisbon
- Clinical Medicine Department, NOVA Medical School, Lisbon, Portugal
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18
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Schinzari F, Tesauro M, Cardillo C. Increased endothelin-1-mediated vasoconstrictor tone in human obesity: effects of gut hormones. Physiol Res 2018; 67:S69-S81. [PMID: 29947529 DOI: 10.33549/physiolres.933821] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The heavy impact of obesity on the development and progression of cardiovascular disease has sparked sustained efforts to uncover the mechanisms linking excess adiposity to vascular dysfunction. Impaired vasodilator reactivity has been recognized as an early hemodynamic abnormality in obese patients, but also increased vasoconstrictor tone importantly contributes to their vascular damage. In particular, upregulation of the endothelin (ET)-1 system, consistently reported in these patients, might accelerate atherosclerosis and its complication, given the pro-inflammatory and mitogenic properties of ET-1. In recent years, a number of gut hormones, in addition to their role as modulators of food intake, energy balance, glucose and lipid metabolism, and insulin secretion and action, have demonstrated favorable vascular actions. They increase the bioavailability of vasodilator mediators like nitric oxide, but they have also been shown to inhibit the ET-1 system. These features make gut hormones promising tools for targeting both the metabolic and cardiovascular complications of obesity, a view supported by recent large-scale clinical trials indicating that novel drugs for type 2 diabetes with cardiovascular potential may translate into clinically significant advantages. Therefore, there is real hope that better understanding of the properties of gut-derived substances might provide more effective therapies for the obesity-related cardiometabolic syndrome.
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Affiliation(s)
- F Schinzari
- Policlinico A. Gemelli, Rome, Italy, Istituto di Patologia Speciale Medica e Semeiotica Medica, Universita Cattolica del Sacro Cuore, Rome, Italy.
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19
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Gradin K, Persson B. Endothelin A receptor blockade improves endothelium-dependent relaxation in obese woman. Physiol Res 2018; 67:S167-S174. [PMID: 29947537 DOI: 10.33549/physiolres.933813] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Hypertension in obesity is associated with increased insulin resistance, vascular mass and body mass index (BMI). The purpose of the study was to visualize endothelin-1 (ET-1) mediated constriction in arteries isolated from subcutaneous adipose tissue from obese hypertensive women previously operated by gastric bypass. Functional studies were conducted in a microvascular myograph. Expressed as percentage of contraction elicited by 124 mM KCl concentration-response curves for ET-1 were shifted leftward in arteries from obese hypertensive patients compared to healthy normotensive subjects. The vasodilator response to the ET-1 antagonist BQ123 (1 microM) was significantly higher in arteries from obese hypertensive patients (p<0.001). BQ123 induced relaxation was inhibited by NO synthase inhibitor L-NAME (0.1 nM). Preincubation with BQ123 enhanced the relaxation induced by acetylcholine (ACh; 0.1 nM - 0.1 mM) (p<0.001), but not that induced by NO donor sodium nitroprusside (SNP; 0.1 nM - 0.1 mM), in arteries from obese hypertensive patients. The present study show that hypertension yet prevail after gastric bypass surgery and the ET(A) receptor antagonist BQ123 may be a useful tool in reducing blood pressure in obese hypertensive patients.
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Affiliation(s)
- K Gradin
- Department of Pharmacology, University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden, Division of Internal Medicine, Sahlgrenska University Hospital, Sahlgrenska, Gothenburg, Sweden.
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20
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Huang YC, Liao WL, Lin JM, Chen CC, Liu SP, Chen SY, Lin YN, Lei YJ, Liu HT, Chen YJ, Tsai FJ. High levels of circulating endothelial progenitor cells in patients with diabetic retinopathy are positively associated with ARHGAP22 expression. Oncotarget 2018; 9:17858-17866. [PMID: 29707151 PMCID: PMC5915159 DOI: 10.18632/oncotarget.24909] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 09/21/2017] [Indexed: 01/08/2023] Open
Abstract
Diabetic retinopathy (DR) is a common microvascular complication of diabetes. Circulating endothelial progenitor cells (EPCs) are derived from bone marrow and are characterized by pathological retinal neovascularization. Rho GTPase Activating Protein 22 (ARHGAP22) is a DR susceptibility gene that interacts with its downstream regulatory protein ras-related C3 botulinum toxin substrate 1 (Rac1), to assist in endothelial cell angiogenesis and increasing capillary permeability. The aim of this study was to elucidate the relationship between ARHGAP22 expression and EPC levels in type 2 diabetes (T2D) patients with DR. Fifty T2D patients with DR were recruited. Circulating EPCs were characterized as CD31+/vascular endothelial growth factor-2+/CD45dim/CD133+ and were quantified using triple staining flow cytometry. Real-time polymerase chain reaction tests were used to quantify ARHGAP22 expression. We found that T2D patients with proliferative DR had significantly lower EPC levels than those with non-proliferative DR (P = 0.028). T2D patients with EPC levels above the median value (> 4 cells/105 events) had higher levels of ARHGAP22 expression (P = 0.002). EPC levels were positively correlated with ARHGAP22 expression (r = 0.364, P = 0.009). Among T2D patients with DR, a higher expression of ARHGAP22 was associated with higher levels of EPCs. ARHGAP22 may be involved in the mobilization or active circulation of EPCs, thus contributing to neovascularization during DR development.
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Affiliation(s)
- Yu-Chuen Huang
- Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan.,School of Chinese Medicine, China Medical University, Taichung 404, Taiwan
| | - Wen-Ling Liao
- Center for Personalized Medicine, China Medical University Hospital, Taichung 404, Taiwan.,Graduate Institute of Integrated Medicine, China Medical University, Taichung 404, Taiwan
| | - Jane-Ming Lin
- Department of Ophthalmology, China Medical University Hospital, Taichung 404, Taiwan.,School of Chinese Medicine, China Medical University, Taichung 404, Taiwan
| | - Ching-Chu Chen
- Division of Endocrinology and Metabolism, China Medical University Hospital, Taichung 404, Taiwan.,School of Chinese Medicine, China Medical University, Taichung 404, Taiwan
| | - Shih-Ping Liu
- Center for Translational Medicine, China Medical University Hospital, Taichung 404, Taiwan.,Graduate Institute of Biomedical Science, China Medical University, Taichung 404, Taiwan.,Department of Social Work, Asia University, Taichung 413, Taiwan
| | - Shih-Yin Chen
- Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan.,School of Chinese Medicine, China Medical University, Taichung 404, Taiwan
| | - Yu-Ning Lin
- Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan
| | - Yu-Jie Lei
- Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan
| | - Huan-Ting Liu
- Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan
| | - Yu-Jen Chen
- Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan.,Department of Radiation Oncology, Mackay Memorial Hospital, Taipei 104, Taiwan.,Department of Medical Research, Mackay Memorial Hospital, New Taipei City 251, Taiwan.,Institute of Traditional Medicine, National Yang-Ming University, Taipei 112, Taiwan
| | - Fuu-Jen Tsai
- Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan.,Children's Hospital of China Medical University, Taichung 404, Taiwan.,Department of Medical Genetics, China Medical University Hospital, Taichung 404, Taiwan.,Department of Biotechnology, Asia University, Taichung 413, Taiwan
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21
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Polverino F, Celli BR, Owen CA. COPD as an endothelial disorder: endothelial injury linking lesions in the lungs and other organs? (2017 Grover Conference Series). Pulm Circ 2018; 8:2045894018758528. [PMID: 29468936 PMCID: PMC5826015 DOI: 10.1177/2045894018758528] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 01/21/2018] [Indexed: 12/27/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is characterized by chronic expiratory airflow obstruction that is not fully reversible. COPD patients develop varying degrees of emphysema, small and large airway disease, and various co-morbidities. It has not been clear whether these co-morbidities share common underlying pathogenic processes with the pulmonary lesions. Early research into the pathogenesis of COPD focused on the contributions of injury to the extracellular matrix and pulmonary epithelial cells. More recently, cigarette smoke-induced endothelial dysfunction/injury have been linked to the pulmonary lesions in COPD (especially emphysema) and systemic co-morbidities including atherosclerosis, pulmonary hypertension, and chronic renal injury. Herein, we review the evidence linking endothelial injury to COPD, and the pathways underlying endothelial injury and the "vascular COPD phenotype" including: (1) direct toxic effects of cigarette smoke on endothelial cells; (2) generation of auto-antibodies directed against endothelial cells; (3) vascular inflammation; (4) increased oxidative stress levels in vessels inducing increases in lipid peroxidation and increased activation of the receptor for advanced glycation end-products (RAGE); (5) reduced activation of the anti-oxidant pathways in endothelial cells; (6) increased endothelial cell release of mediators with vasoconstrictor, pro-inflammatory, and remodeling activities (endothelin-1) and reduced endothelial cell expression of mediators that promote vasodilation and homeostasis of endothelial cells (nitric oxide synthase and prostacyclin); and (7) increased endoplasmic reticular stress and the unfolded protein response in endothelial cells. We also review the literature on studies of drugs that inhibit RAGE signaling in other diseases (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), or vasodilators developed for idiopathic pulmonary arterial hypertension that have been tested on cell culture systems, animal models of COPD, and/or smokers and COPD patients.
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Affiliation(s)
- Francesca Polverino
- Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Lovelace Respiratory Research Institute, Albuquerque, NM, USA
| | - Bartolome R. Celli
- Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Lovelace Respiratory Research Institute, Albuquerque, NM, USA
| | - Caroline A. Owen
- Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Lovelace Respiratory Research Institute, Albuquerque, NM, USA
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22
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Sharma D, Bhattacharya P, Kalia K, Tiwari V. Diabetic nephropathy: New insights into established therapeutic paradigms and novel molecular targets. Diabetes Res Clin Pract 2017; 128:91-108. [PMID: 28453961 DOI: 10.1016/j.diabres.2017.04.010] [Citation(s) in RCA: 96] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Accepted: 04/07/2017] [Indexed: 02/06/2023]
Abstract
Diabetic nephropathy is one of the most prevalent microvascular complication in patients suffering from diabetes and is reported to be the major cause of renal failure when compared to any other kidney disease. Currently, available therapies provide only symptomatic relief and unable to treat the underlying pathophysiology of diabetic nephropathy. This review will explore new insights into the established therapeutic paradigms targeting oxidative stress, inflammation and endoplasmic reticulum stress with the focus on recent clinical developments. Apart from this, the involvement of novel cellular and molecular mechanisms including the role of endothelin-receptor antagonists, Wnt signaling pathway, epigenetics and micro RNA is also discussed so that key molecular switches involved in the pathogenesis of diabetic nephropathy can be identified. Elucidating new molecular pathways will help in the development of novel therapeutics for the prevention and treatment of diabetic nephropathy.
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Affiliation(s)
- Dilip Sharma
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar 382355, Gujarat, India
| | - Pallab Bhattacharya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar 382355, Gujarat, India
| | - Kiran Kalia
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar 382355, Gujarat, India.
| | - Vinod Tiwari
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar 382355, Gujarat, India.
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23
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Bironneau V, Goupil F, Ducluzeau PH, Le Vaillant M, Abraham P, Henni S, Dubois S, Paris A, Priou P, Meslier N, Sanguin C, Trzépizur W, Andriantsitohaina R, Martinez MC, Gagnadoux F. Association between obstructive sleep apnea severity and endothelial dysfunction in patients with type 2 diabetes. Cardiovasc Diabetol 2017; 16:39. [PMID: 28327146 PMCID: PMC5361793 DOI: 10.1186/s12933-017-0521-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Accepted: 03/15/2017] [Indexed: 12/11/2022] Open
Abstract
Background Obstructive sleep apnea (OSA) and type 2 diabetes (T2D) are associated with endothelial dysfunction a main predictor of late cardiovascular (CV) events. Despite the high prevalence of OSA in patients with T2D, the impact of OSA severity on endothelial function has not been clearly elucidated. The aim of this cross-sectional study was to determine whether increasing OSA severity is associated with poorer endothelial function in patients with T2D. Methods 140 patients with T2D and no overt CV disease underwent polysomnography, peripheral arterial tonometry, clinic blood pressure (BP) measurement, biological assessment for CV risk factors, daytime sleepiness and health related quality of life (HRQL) questionnaires. The following commonly used cut-offs for apnea-hypopnea index (AHI) were used to define 3 categories of disease severity: AHI < 15 (no OSA or mild OSA), 15 ≤ AHI < 30 (moderate OSA), and AHI ≥ 30 (severe OSA). The primary outcome was the reactive hyperemia index (RHI), a validated assessment of endothelial function. Results 21.4% of patients had moderate OSA and 47.6% had severe OSA. Increasing OSA severity and nocturnal hypoxemia were not associated with a significant decrease in RHI. Endothelial dysfunction (RHI < 1.67) was found in 47.1, 44.4 and 39.2% of patients with no OSA or mild OSA, moderate OSA and severe OSA, respectively (p = 0.76). After adjustment for confounders including body mass index, increasing OSA severity was associated with higher systolic BP (p = 0.03), lower circulating levels of adiponectin (p = 0.0009), higher levels of sP-selectin (p = 0.03), lower scores in 3 domains of HRQL including energy/vitality (p = 0.02), role functioning (p = 0.01), and social functioning (p = 0.04). Conclusions Moderate to severe OSA is very common but has no impact on digital micro-vascular endothelial function in patients with T2D.
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Affiliation(s)
| | | | - Pierre Henri Ducluzeau
- Unité d'Endocrinologie-Diabétologie-Nutrition, Pole de Médecine, CHRU de Tours, Tours, France
| | - Marc Le Vaillant
- Centre de Recherche Médecine, Sciences, Santé, Santé mentale, Société, CNRS UMR 8211, INSERM UMR U988-EHESS, Villejuif, France
| | - Pierre Abraham
- Département de Médecine du Sport et Explorations Fonctionnelles Vasculaires, Université Bretagne Loire, CHU d'Angers, Angers, France
| | - Samir Henni
- Département de Médecine du Sport et Explorations Fonctionnelles Vasculaires, Université Bretagne Loire, CHU d'Angers, Angers, France
| | - Séverine Dubois
- Département d'Endocrinologie, Diabétologie, Nutrition, Université Bretagne Loire, CHU d'Angers, Angers, France
| | - Audrey Paris
- Service de Pneumologie, Centre Hospitalier, Le Mans, France
| | - Pascaline Priou
- Université Bretagne Loire, INSERM UMR 1063, Angers, France.,Département de Pneumologie, Université Bretagne Loire, CHU d'Angers, 4 Rue Larrey, 49100, Angers, France
| | - Nicole Meslier
- Université Bretagne Loire, INSERM UMR 1063, Angers, France.,Département de Pneumologie, Université Bretagne Loire, CHU d'Angers, 4 Rue Larrey, 49100, Angers, France
| | - Claire Sanguin
- Service d'Endocrinologie, Diabétologie, Centre Hospitalier, Le Mans, France
| | - Wojciech Trzépizur
- Université Bretagne Loire, INSERM UMR 1063, Angers, France.,Département de Pneumologie, Université Bretagne Loire, CHU d'Angers, 4 Rue Larrey, 49100, Angers, France
| | | | | | - Frédéric Gagnadoux
- Université Bretagne Loire, INSERM UMR 1063, Angers, France. .,Département de Pneumologie, Université Bretagne Loire, CHU d'Angers, 4 Rue Larrey, 49100, Angers, France.
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24
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Vanhoutte PM, Shimokawa H, Feletou M, Tang EHC. Endothelial dysfunction and vascular disease - a 30th anniversary update. Acta Physiol (Oxf) 2017; 219:22-96. [PMID: 26706498 DOI: 10.1111/apha.12646] [Citation(s) in RCA: 620] [Impact Index Per Article: 77.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Revised: 10/27/2015] [Accepted: 12/17/2015] [Indexed: 02/06/2023]
Abstract
The endothelium can evoke relaxations of the underlying vascular smooth muscle, by releasing vasodilator substances. The best-characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO) which activates soluble guanylyl cyclase in the vascular smooth muscle cells, with the production of cyclic guanosine monophosphate (cGMP) initiating relaxation. The endothelial cells also evoke hyperpolarization of the cell membrane of vascular smooth muscle (endothelium-dependent hyperpolarizations, EDH-mediated responses). As regards the latter, hydrogen peroxide (H2 O2 ) now appears to play a dominant role. Endothelium-dependent relaxations involve both pertussis toxin-sensitive Gi (e.g. responses to α2 -adrenergic agonists, serotonin, and thrombin) and pertussis toxin-insensitive Gq (e.g. adenosine diphosphate and bradykinin) coupling proteins. New stimulators (e.g. insulin, adiponectin) of the release of EDRFs have emerged. In recent years, evidence has also accumulated, confirming that the release of NO by the endothelial cell can chronically be upregulated (e.g. by oestrogens, exercise and dietary factors) and downregulated (e.g. oxidative stress, smoking, pollution and oxidized low-density lipoproteins) and that it is reduced with ageing and in the course of vascular disease (e.g. diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively lose the pertussis toxin-sensitive pathway for NO release which favours vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. In addition to the release of NO (and EDH, in particular those due to H2 O2 ), endothelial cells also can evoke contraction of the underlying vascular smooth muscle cells by releasing endothelium-derived contracting factors. Recent evidence confirms that most endothelium-dependent acute increases in contractile force are due to the formation of vasoconstrictor prostanoids (endoperoxides and prostacyclin) which activate TP receptors of the vascular smooth muscle cells and that prostacyclin plays a key role in such responses. Endothelium-dependent contractions are exacerbated when the production of nitric oxide is impaired (e.g. by oxidative stress, ageing, spontaneous hypertension and diabetes). They contribute to the blunting of endothelium-dependent vasodilatations in aged subjects and essential hypertensive and diabetic patients. In addition, recent data confirm that the release of endothelin-1 can contribute to endothelial dysfunction and that the peptide appears to be an important contributor to vascular dysfunction. Finally, it has become clear that nitric oxide itself, under certain conditions (e.g. hypoxia), can cause biased activation of soluble guanylyl cyclase leading to the production of cyclic inosine monophosphate (cIMP) rather than cGMP and hence causes contraction rather than relaxation of the underlying vascular smooth muscle.
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Affiliation(s)
- P. M. Vanhoutte
- State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy; Li Ka Shing Faculty of Medicine; The University of Hong Kong; Hong Kong City Hong Kong
| | - H. Shimokawa
- Department of Cardiovascular Medicine; Tohoku University; Sendai Japan
| | - M. Feletou
- Department of Cardiovascular Research; Institut de Recherches Servier; Suresnes France
| | - E. H. C. Tang
- State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy; Li Ka Shing Faculty of Medicine; The University of Hong Kong; Hong Kong City Hong Kong
- School of Biomedical Sciences; Li Ka Shing Faculty of Medicine; The University of Hong Kong; Hong Kong City Hong Kong
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Yuan W, Cheng G, Li B, Li Y, Lu S, Liu D, Xiao J, Zhao Z. Endothelin-receptor antagonist can reduce blood pressure in patients with hypertension: a meta-analysis. Blood Press 2016; 26:139-149. [PMID: 27808564 DOI: 10.1080/08037051.2016.1208730] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Wenming Yuan
- Renal Division, Department of Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Genyang Cheng
- Renal Division, Department of Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Bin Li
- Renal Division, Department of Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yansheng Li
- Renal Division, Department of Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shan Lu
- Renal Division, Department of Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Dong Liu
- Renal Division, Department of Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jing Xiao
- Renal Division, Department of Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhanzheng Zhao
- Renal Division, Department of Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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26
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Idris-Khodja N, Ouerd S, Mian MOR, Gornitsky J, Barhoumi T, Paradis P, Schiffrin EL. Endothelin-1 Overexpression Exaggerates Diabetes-Induced Endothelial Dysfunction by Altering Oxidative Stress. Am J Hypertens 2016; 29:1245-1251. [PMID: 27465439 DOI: 10.1093/ajh/hpw078] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2016] [Accepted: 07/06/2016] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Increased endothelin (ET)-1 expression causes endothelial dysfunction and oxidative stress. Plasma ET-1 is increased in patients with diabetes mellitus. Since endothelial dysfunction often precedes vascular complications in diabetes, we hypothesized that overexpression of ET-1 in the endothelium would exaggerate diabetes-induced endothelial dysfunction. METHODS Diabetes was induced by streptozotocin treatment (55mg/kg/day, i.p.) for 5 days in 6-week-old male wild type (WT) mice and in mice overexpressing human ET-1 restricted to the endothelium (eET-1). Mice were studied 14 weeks later. Small mesenteric artery (MA) endothelial function and vascular remodeling by pressurized myography, reactive oxygen species (ROS) production by dihydroethidium staining and mRNA expression by reverse transcription/quantitative PCR were determined. RESULTS Endothelium-dependent vasodilatory responses to acetylcholine of MA were reduced 24% by diabetes in WT ( P < 0.05), and further decreased by 12% in eET-1 ( P < 0.05). Diabetes decreased MA media/lumen in WT and eET-1 ( P < 0.05), whereas ET-1 overexpression increased MA media/lumen similarly in diabetic and nondiabetic WT mice ( P < 0.05). Vascular ROS production was increased 2-fold by diabetes in WT ( P < 0.05) and further augmented 1.7-fold in eET-1 ( P < 0.05). Diabetes reduced endothelial nitric oxide synthase (eNOS, Nos3 ) expression in eET-1 by 31% ( P < 0.05) but not in WT. Induction of diabetes caused a 52% ( P < 0.05) increase in superoxide dismutase 1 ( Sod1 ) and a 32% ( P < 0.05) increase in Sod2 expression in WT but not in eET-1. CONCLUSIONS Increased expression of ET-1 exaggerates diabetes-induced endothelial dysfunction. This may be caused by decrease in eNOS expression, increase in vascular oxidative stress, and decrease in antioxidant capacity.
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Affiliation(s)
- Noureddine Idris-Khodja
- Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research , Montréal, Québec , Canada
| | - Sofiane Ouerd
- Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research , Montréal, Québec , Canada
| | - Muhammad Oneeb Rehman Mian
- Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research , Montréal, Québec , Canada
| | - Jordan Gornitsky
- Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research , Montréal, Québec , Canada
| | - Tlili Barhoumi
- Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research , Montréal, Québec , Canada
| | - Pierre Paradis
- Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research , Montréal, Québec , Canada
| | - Ernesto L Schiffrin
- Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research, Montréal, Québec, Canada
- Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montréal, Québec, Canada
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Wils J, Favre J, Bellien J. Modulating putative endothelial progenitor cells for the treatment of endothelial dysfunction and cardiovascular complications in diabetes. Pharmacol Ther 2016; 170:98-115. [PMID: 27773788 DOI: 10.1016/j.pharmthera.2016.10.014] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Diabetes induces a decrease in the number and function of different pro-angiogenic cell types generically designated as putative endothelial progenitor cells (EPC), which encompasses cells from myeloid origin that act in a paracrine fashion to promote angiogenesis and putative "true" EPC that contribute to endothelial replacement. This not only compromises neovasculogenesis in ischemic tissues but also impairs, at an early stage, the reendotheliziation process at sites of injury, contributing to the development of endothelial dysfunction and cardiovascular complications. Hyperglycemia, insulin resistance and dyslipidemia promote putative EPC dysregulation by affecting the SDF-1/CXCR-4 and NO pathways and the p53/SIRT1/p66Shc axis that contribute to their mobilization, migration, homing and vasculogenic properties. To optimize the clinical management of patients with hypoglycemic agents, statins and renin-angiotensin system inhibitors, which display pleiotropic effects on putative EPC, is a first step to improve their number and angiogenic potential but specific strategies are needed. Among them, mobilizing therapies based on G-CSF, erythropoietin or CXCR-4 antagonism have been developed to increase putative EPC number to treat ischemic diseases with or without prior cell isolation and transplantation. Growth factors, genetic and pharmacological strategies are also evaluated to improve ex vivo cultured EPC function before transplantation. Moreover, pharmacological agents increasing in vivo the bioavailability of NO and other endothelial factors demonstrated beneficial effects on neovascularization in diabetic ischemic models but their effects on endothelial dysfunction remain poorly evaluated. More experiments are warranted to develop orally available drugs and specific agents targeting p66Shc to reverse putative EPC dysfunction in the expected goal of preventing endothelial dysfunction and diabetic cardiovascular complications.
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Affiliation(s)
- Julien Wils
- Department of Pharmacology, Rouen University Hospital, Rouen, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France
| | - Julie Favre
- MITOVASC Institute, Angers, France; Centre National de la Recherche Scientifique (CNRS) UMR 6214, Angers, France; INSERM U1083, Angers, France; University of Angers, Angers, France
| | - Jérémy Bellien
- Department of Pharmacology, Rouen University Hospital, Rouen, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France.
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Leung WK, Gao L, Siu PM, Lai CW. Diabetic nephropathy and endothelial dysfunction: Current and future therapies, and emerging of vascular imaging for preclinical renal-kinetic study. Life Sci 2016; 166:121-130. [PMID: 27765534 DOI: 10.1016/j.lfs.2016.10.015] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Revised: 10/13/2016] [Accepted: 10/14/2016] [Indexed: 02/07/2023]
Abstract
An explosion in global epidemic of type 2 diabetes mellitus poses major rise in cases with vascular endothelial dysfunction ranging from micro- (retinopathy, nephropathy and neuropathy) to macro-vascular (atherosclerosis and cardiomyopathy) conditions. Functional destruction of endothelium is regarded as an early event that lays the groundwork for the development of renal microangiopathy and subsequent clinical manifestation of nephropathic symptoms. Recent research has shed some light on the molecular mechanisms of type 2 diabetes-associated comorbidity of endothelial dysfunction and nephropathy. Stemming from currently proposed endothelium-centered therapeutic strategies for diabetic nephropathy, this review highlighted some most exploited pathways that involve the intricate coordination of vasodilators, vasoconstrictors and vaso-modulatory molecules in the pathogenesis of diabetic nephropathy. We also emphasized the emerging roles of oxidative and epigenetic modifications of microvasculature as our prospective therapeutics for diabetic renal diseases. Finally, this review in particular addressed the potential use of multispectral optoacoustic tomography in real-time, minimally-invasive vascular imaging of small experimental animals for preclinical renal-kinetic drug trials.
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Affiliation(s)
- Wilson Kc Leung
- Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hung Hom, HKSAR, China
| | - L Gao
- Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hung Hom, HKSAR, China
| | - Parco M Siu
- Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hung Hom, HKSAR, China
| | - Christopher Wk Lai
- Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hung Hom, HKSAR, China.
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Targeting the ROS-HIF-1-endothelin axis as a therapeutic approach for the treatment of obstructive sleep apnea-related cardiovascular complications. Pharmacol Ther 2016; 168:1-11. [PMID: 27492897 DOI: 10.1016/j.pharmthera.2016.07.010] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Accepted: 07/08/2016] [Indexed: 12/12/2022]
Abstract
Obstructive sleep apnea (OSA) is now recognized as an independent and important risk factor for cardiovascular diseases such as hypertension, coronary heart disease, heart failure and stroke. Clinical and experimental data have confirmed that intermittent hypoxia is a major contributor to these deleterious consequences. The repetitive occurrence of hypoxia-reoxygenation sequences generates significant amounts of free radicals, particularly in moderate to severe OSA patients. Moreover, in addition to hypoxia, reactive oxygen species (ROS) are potential inducers of the hypoxia inducible transcription factor-1 (HIF-1) that promotes the transcription of numerous adaptive genes some of which being deleterious for the cardiovascular system, such as the endothelin-1 gene. This review will focus on the involvement of the ROS-HIF-1-endothelin signaling pathway in OSA and intermittent hypoxia and discuss current and potential therapeutic approaches targeting this pathway to treat or prevent cardiovascular disease in moderate to severe OSA patients.
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Jung C, Lichtenauer M, Wernly B, Franz M, Goebel B, Rafnsson A, Figulla HR, Pernow J. Effect of endothelin-1 and endothelin receptor blockade on the release of microparticles. Eur J Clin Invest 2016; 46:707-13. [PMID: 27322814 DOI: 10.1111/eci.12652] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 06/18/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND Increased levels of endothelial cell microparticles (EMP) are known to reflect endothelial dysfunction (ED). In diabetes mellitus type 2 (T2DM), the expression of endothelin (ET)-1 is increased. As treatment with an ET-1 antagonist significantly inhibited atherosclerosis in animal models, we sought to investigate whether treatment with ET-1 antagonists affects EMP levels in vitro and in vivo in patients with T2DM. MATERIALS AND METHODS In vitro study: Human umbilical vein endothelial cells (HUVEC) were stimulated with ET-1 alone and ET-1 in combination with a dual ET-A and ET-B endothelin receptor blocker. In vivo study: Patients with T2DM were randomized to treatment with the ET receptor antagonist bosentan or placebo. After 4 weeks, the patients were re-examined and blood samples were obtained. EMP counts in supernatants and plasma samples were determined using flow cytometry. RESULTS In vitro study: In supernatants of ET-1-stimulated HUVECs, the increased release of EMP was reduced significantly by co-incubation with an ET-1 receptor antagonist (e.g. CD31+/CD42b-EMP decreased from 37·1% ± 2·8 to 31·5% ± 2·8 SEM, P = 0·0078). In vivo study: No changes in EMP levels in blood samples of patients with T2DM were found after 4 weeks of bosentan treatment (n = 36, P = ns). CONCLUSIONS Our in vitro results suggest that ET-1 stimulates the release of EMP from HUVECs via a receptor-dependent mechanism. Co-incubation with an endothelin receptor blocker abolished ET-1-dependent EMP release. However, treatment with bosentan for 4 weeks failed to alter EMP levels in patients with T2DM. Other factors seem to have influenced EMP release in patients with T2DM independent of ET-1 receptor-mediated mechanisms.
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Affiliation(s)
- Christian Jung
- Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Duesseldorf, Duesseldorf, Germany
- Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Michael Lichtenauer
- Clinic of Internal Medicine II, Department of Cardiology, Paracelsus Medical University of Salzburg, Salzburg, Austria
| | - Bernhard Wernly
- Clinic of Internal Medicine II, Department of Cardiology, Paracelsus Medical University of Salzburg, Salzburg, Austria
| | - Marcus Franz
- Universitätsherzzentrum Thüringen, Clinic of Internal Medicine I, Department of Cardiology, Friedrich Schiller University Jena, Jena, Germany
| | - Bjoern Goebel
- Universitätsherzzentrum Thüringen, Clinic of Internal Medicine I, Department of Cardiology, Friedrich Schiller University Jena, Jena, Germany
| | - Arnar Rafnsson
- Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Hans-Reiner Figulla
- Universitätsherzzentrum Thüringen, Clinic of Internal Medicine I, Department of Cardiology, Friedrich Schiller University Jena, Jena, Germany
| | - John Pernow
- Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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Yuan W, Li Y, Wang J, Li J, Gou S, Fu P. Endothelin-receptor antagonists for diabetic nephropathy: A meta-analysis. Nephrology (Carlton) 2016; 20:459-66. [PMID: 25753148 DOI: 10.1111/nep.12442] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/06/2015] [Indexed: 02/05/2023]
Abstract
AIM Endothelin-receptor antagonists may be a novel therapeutic strategy for diabetic nephropathy, but their use remains controversial. This meta-analysis seeks to evaluate the effectiveness and safety of endothelin-receptor antagonists for patients with diabetic nephropathy. METHODS Literature reviews of the PubMed, EMBASE and CENTRAL databases were conducted to identify randomized controlled trials (RCTs) comparing endothelin-receptor antagonist treatment with placebo in patients with diabetic nephropathy. Quality assessment was performed by using the Cochrane Handbook's tools for assessing risk of bias; meta-analysis was conducted by RevMan 5.3. RESUTLS Five RCTs (n=2034 patients) were included for analysis. Compared with placebo, endothelin-receptor antagonists showed significant benefits for lowering albuminuria (five trials, n=2034 patients; SMD 0.66 95% confidence interval (CI) 0.56 to 0.76), but there was no significant difference in the risk of death (two trials, n=1674 patients; RR 1.49 95% CI 0.81 to 2.76). In addition, risk of cardiovascular events and other serious adverse events were significantly higher in the endothelin-receptor antagonists group than the placebo group (four trials, n=1956 patients; RR 1.45 95% CI 1.07 to 1.97; five trials, n=2034 patients; RR 1.32 95% CI 1.10 to 1.58). CONCLUSION Endothelin-receptor antagonists can reduce albuminuria in patients with diabetic nephropathy, although use resulted in more serious adverse events compared with placebo. There is a potential need for further RCTs, which has larger sample size and longer duration.
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Affiliation(s)
- Wenming Yuan
- Renal Division, Department of Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yi Li
- Kidney Epidemiology and Cost Center, University of Michigan, Ann Arbor, MI, USA
| | - Ji Wang
- Division of Evidence-Based Medicine and Clinical Epidemiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Jing Li
- Division of Evidence-Based Medicine and Clinical Epidemiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Shenju Gou
- Renal Division, Department of Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Ping Fu
- Renal Division, Department of Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, China
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Cayir A, Ugan RA, Albayrak A, Kose D, Akpinar E, Cayir Y, Atmaca HT, Bayraktutan Z, Kara M. The lung endothelin system: a potent therapeutic target with bosentan for the amelioration of lung alterations in a rat model of diabetes mellitus. J Endocrinol Invest 2015; 38:987-98. [PMID: 25847324 DOI: 10.1007/s40618-015-0282-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Accepted: 03/24/2015] [Indexed: 01/14/2023]
Abstract
PURPOSE The aim of this study is to show the effect of a new mechanism on endothelin (ET) receptors in the physiopathology of diabetes-related pulmonary injury. We tested the hypothesis that dual ET-1 receptor antagonism via bosentan can reverse diabetes-induced lung injury. METHODS The rats (24 male) were separated into four groups: group 1 (HEALTHY): Control group; group 2 (DM): Streptozotocin 60 mg/kg (i.p.); group 3 (DM + BOS-1): Diabetes + bosentan 50 mg/kg per-os; group 4 (DM + BOS-2): Diabetes + bosentan 100 mg/kg per-os. The bosentan treatment was initiated immediately after the onset of STZ-induced diabetes and continued for 6 weeks. RESULTS In the treatment group, SOD activity was significantly increased, although GSH and MDA levels and TNF-α and TGF-β gene expression were decreased. Bosentan 50 mg/kg and bosentan 100 mg/kg showed a significantly down-regulatory effect on ET-1, ET-A, and ET-B mRNA expression. CONCLUSIONS In conclusion, increased endothelin levels in the lung associated with diabetes may be one cause of endothelial dysfunction, cytokine increase, and oxidant/antioxidant imbalance in the pathogenesis of complications that may develop during diabetes. With its multiple effects, bosentan therapy may be an effective option against complications that may develop in association with diabetes.
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Affiliation(s)
- A Cayir
- Department of Pediatric Endocrinology, Erzurum Regional Education and Research Hospital, 25100, Erzurum, Turkey,
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Sánchez A, Martínez P, Muñoz M, Benedito S, García-Sacristán A, Hernández M, Prieto D. Endothelin-1 contributes to endothelial dysfunction and enhanced vasoconstriction through augmented superoxide production in penile arteries from insulin-resistant obese rats: role of ET(A) and ET(B) receptors. Br J Pharmacol 2015; 171:5682-95. [PMID: 25091502 DOI: 10.1111/bph.12870] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Revised: 07/21/2014] [Accepted: 07/26/2014] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND AND PURPOSE We assessed whether endothelin-1 (ET-1) inhibits NO and contributes to endothelial dysfunction in penile arteries in a model of insulin resistance-associated erectile dysfunction (ED). EXPERIMENTAL APPROACH Vascular function was assessed in penile arteries, from obese (OZR) and lean (LZR) Zucker rats, mounted in microvascular myographs. Changes in basal and stimulated levels of superoxide (O2 (-) ) were detected by lucigenin-enhanced chemiluminescence and ET receptor expression was determined by immunohistochemistry. KEY RESULTS ET-1 stimulated acute O2 (-) production that was blunted by tempol and the NADPH oxidase inhibitor, apocynin, but markedly enhanced in obese animals. ET-1 inhibited the vasorelaxant effects of ACh and of the NO donor S-nitroso-N-acetyl-DL-penicillamine in arteries from both LZR and OZR. Selective ETA (BQ123) or ETB receptor (BQ788) antagonists reduced both basal and ET-1-stimulated superoxide generation and reversed ET-1-induced inhibition of NO-mediated relaxations in OZR, while only BQ-123 antagonized ET-1 actions in LZR. ET-1-induced vasoconstriction was markedly enhanced by NO synthase blockade and reduced by endothelium removal and apocynin. In endothelium-denuded penile arteries, apocynin blunted augmented ET-1-induced contractions in OZR. Both ETA and ETB receptors were expressed in smooth muscle and the endothelial layer and up-regulated in arteries from OZR. CONCLUSIONS AND IMPLICATIONS ET-1 stimulates ETA -mediated NADPH oxidase-dependent ROS generation, which inhibits endothelial NO bioavailability and contributes to ET-1-induced contraction in healthy penile arteries. Enhanced vascular expression of ETB receptors contributes to augmented ROS production, endothelial dysfunction and increased vasoconstriction in erectile tissue from insulin-resistant obese rats. Hence, antagonism of ETB receptors might improve the ED associated with insulin-resistant states.
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Affiliation(s)
- A Sánchez
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain
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Tobe S, Kohan DE, Singarayer R. Endothelin Receptor Antagonists: New Hope for Renal Protection? Curr Hypertens Rep 2015; 17:57. [DOI: 10.1007/s11906-015-0568-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Abstract
Diabetic kidney disease (DKD) remains the most common cause of chronic kidney disease and multiple therapeutic agents, primarily targeted at the renin-angiotensin system, have been assessed. Their only partial effectiveness in slowing down progression to end-stage renal disease, points out an evident need for additional effective therapies. In the context of diabetes, endothelin-1 (ET-1) has been implicated in vasoconstriction, renal injury, mesangial proliferation, glomerulosclerosis, fibrosis and inflammation, largely through activation of its endothelin A (ETA) receptor. Therefore, endothelin receptor antagonists have been proposed as potential drug targets. In experimental models of DKD, endothelin receptor antagonists have been described to improve renal injury and fibrosis, whereas clinical trials in DKD patients have shown an antiproteinuric effect. Currently, its renoprotective effect in a long-time clinical trial is being tested. This review focuses on the localization of endothelin receptors (ETA and ETB) within the kidney, as well as the ET-1 functions through them. In addition, we summarize the therapeutic benefit of endothelin receptor antagonists in experimental and human studies and the adverse effects that have been described.
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Wang C, Luo Z, Kohan D, Wellstein A, Jose PA, Welch WJ, Wilcox CS, Wang D. Thromboxane prostanoid receptors enhance contractions, endothelin-1, and oxidative stress in microvessels from mice with chronic kidney disease. Hypertension 2015; 65:1055-63. [PMID: 25733239 DOI: 10.1161/hypertensionaha.115.05244] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 02/10/2015] [Indexed: 02/06/2023]
Abstract
Cardiovascular disease is frequent in chronic kidney disease and has been related to angiotensin II, endothelin-1 (ET-1), thromboxane A2, and reactive oxygen species (ROS). Because activation of thromboxane prostanoid receptors (TP-Rs) can generate ROS, which can generate ET-1, we tested the hypothesis that chronic kidney disease induces cyclooxygenase-2 whose products activate TP-Rs to enhance ET-1 and ROS generation and contractions. Mesenteric resistance arterioles were isolated from C57/BL6 or TP-R+/+ and TP-R-/- mice 3 months after SHAM-operation (SHAM) or surgical reduced renal mass (RRM, n=6/group). Microvascular contractions were studied on a wire myograph. Cellular (ethidium: dihydroethidium) and mitochondrial (mitoSOX) ROS were measured by fluorescence microscopy. Mice with RRM had increased excretion of markers of oxidative stress, thromboxane, and microalbumin; increased plasma ET-1; and increased microvascular expression of p22(phox), cyclooxygenase-2, TP-Rs, preproendothelin and endothelin-A receptors, and increased arteriolar remodeling. They had increased contractions to U-46,619 (118 ± 3 versus 87 ± 6, P<0.05) and ET-1 (108 ± 5 versus 89 ± 4, P<0.05), which were dependent on cellular and mitochondrial ROS, cyclooxygenase-2, and TP-Rs. RRM doubled the ET-1-induced cellular and mitochondrial ROS generation (P<0.05). TP-R-/- mice with RRM lacked these abnormal structural and functional microvascular responses and lacked the increased systemic and the increased microvascular oxidative stress and circulating ET-1. In conclusion, RRM leads to microvascular remodeling and enhanced ET-1-induced cellular and mitochondrial ROS and contractions that are mediated by cyclooxygenase-2 products activating TP-Rs. Thus, TP-Rs can be upstream from enhanced ROS, ET-1, microvascular remodeling, and contractility and may thereby coordinate vascular dysfunction in chronic kidney disease.
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Affiliation(s)
- Cheng Wang
- From the Hypertension, Kidney and Vascular Research Center and Division of Nephrology and Hypertension, Department of Medicine (C.W., Z.L., W.J.W., C.S.W., D.W.) and Department of Oncology, Lombardi Cancer Center (A.W.), Georgetown University, Washington, DC; Department of Nephrology, The Third Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China (C.W.); Division of Nephrology, Department of Medicine, University of Utah, Salt Lake City (D.K.); and Division of Nephrology, Department of Medicine and Department of Physiology, University of Maryland, Baltimore, MD (P.A.J.)
| | - Zaiming Luo
- From the Hypertension, Kidney and Vascular Research Center and Division of Nephrology and Hypertension, Department of Medicine (C.W., Z.L., W.J.W., C.S.W., D.W.) and Department of Oncology, Lombardi Cancer Center (A.W.), Georgetown University, Washington, DC; Department of Nephrology, The Third Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China (C.W.); Division of Nephrology, Department of Medicine, University of Utah, Salt Lake City (D.K.); and Division of Nephrology, Department of Medicine and Department of Physiology, University of Maryland, Baltimore, MD (P.A.J.)
| | - Donald Kohan
- From the Hypertension, Kidney and Vascular Research Center and Division of Nephrology and Hypertension, Department of Medicine (C.W., Z.L., W.J.W., C.S.W., D.W.) and Department of Oncology, Lombardi Cancer Center (A.W.), Georgetown University, Washington, DC; Department of Nephrology, The Third Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China (C.W.); Division of Nephrology, Department of Medicine, University of Utah, Salt Lake City (D.K.); and Division of Nephrology, Department of Medicine and Department of Physiology, University of Maryland, Baltimore, MD (P.A.J.)
| | - Anton Wellstein
- From the Hypertension, Kidney and Vascular Research Center and Division of Nephrology and Hypertension, Department of Medicine (C.W., Z.L., W.J.W., C.S.W., D.W.) and Department of Oncology, Lombardi Cancer Center (A.W.), Georgetown University, Washington, DC; Department of Nephrology, The Third Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China (C.W.); Division of Nephrology, Department of Medicine, University of Utah, Salt Lake City (D.K.); and Division of Nephrology, Department of Medicine and Department of Physiology, University of Maryland, Baltimore, MD (P.A.J.)
| | - Pedro A Jose
- From the Hypertension, Kidney and Vascular Research Center and Division of Nephrology and Hypertension, Department of Medicine (C.W., Z.L., W.J.W., C.S.W., D.W.) and Department of Oncology, Lombardi Cancer Center (A.W.), Georgetown University, Washington, DC; Department of Nephrology, The Third Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China (C.W.); Division of Nephrology, Department of Medicine, University of Utah, Salt Lake City (D.K.); and Division of Nephrology, Department of Medicine and Department of Physiology, University of Maryland, Baltimore, MD (P.A.J.)
| | - William J Welch
- From the Hypertension, Kidney and Vascular Research Center and Division of Nephrology and Hypertension, Department of Medicine (C.W., Z.L., W.J.W., C.S.W., D.W.) and Department of Oncology, Lombardi Cancer Center (A.W.), Georgetown University, Washington, DC; Department of Nephrology, The Third Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China (C.W.); Division of Nephrology, Department of Medicine, University of Utah, Salt Lake City (D.K.); and Division of Nephrology, Department of Medicine and Department of Physiology, University of Maryland, Baltimore, MD (P.A.J.)
| | - Christopher S Wilcox
- From the Hypertension, Kidney and Vascular Research Center and Division of Nephrology and Hypertension, Department of Medicine (C.W., Z.L., W.J.W., C.S.W., D.W.) and Department of Oncology, Lombardi Cancer Center (A.W.), Georgetown University, Washington, DC; Department of Nephrology, The Third Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China (C.W.); Division of Nephrology, Department of Medicine, University of Utah, Salt Lake City (D.K.); and Division of Nephrology, Department of Medicine and Department of Physiology, University of Maryland, Baltimore, MD (P.A.J.)
| | - Dan Wang
- From the Hypertension, Kidney and Vascular Research Center and Division of Nephrology and Hypertension, Department of Medicine (C.W., Z.L., W.J.W., C.S.W., D.W.) and Department of Oncology, Lombardi Cancer Center (A.W.), Georgetown University, Washington, DC; Department of Nephrology, The Third Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China (C.W.); Division of Nephrology, Department of Medicine, University of Utah, Salt Lake City (D.K.); and Division of Nephrology, Department of Medicine and Department of Physiology, University of Maryland, Baltimore, MD (P.A.J.).
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Campia U, Tesauro M, Di Daniele N, Cardillo C. The vascular endothelin system in obesity and type 2 diabetes: Pathophysiology and therapeutic implications. Life Sci 2014; 118:149-55. [DOI: 10.1016/j.lfs.2014.02.028] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2013] [Revised: 02/05/2014] [Accepted: 02/20/2014] [Indexed: 12/29/2022]
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Reichetzeder C, Tsuprykov O, Hocher B. Endothelin receptor antagonists in clinical research — Lessons learned from preclinical and clinical kidney studies. Life Sci 2014; 118:141-8. [DOI: 10.1016/j.lfs.2014.02.025] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2013] [Revised: 01/18/2014] [Accepted: 02/19/2014] [Indexed: 11/25/2022]
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Selective endothelin ETA and dual ETA/ETB receptor blockade improve endothelium-dependent vasodilatation in patients with type 2 diabetes and coronary artery disease. Life Sci 2014; 118:435-9. [DOI: 10.1016/j.lfs.2014.02.026] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Revised: 02/10/2014] [Accepted: 02/18/2014] [Indexed: 11/17/2022]
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Ladeia AM, Sampaio RR, Hita MC, Adan LF. Prognostic value of endothelial dysfunction in type 1 diabetes mellitus. World J Diabetes 2014; 5:601-605. [PMID: 25317238 PMCID: PMC4138584 DOI: 10.4239/wjd.v5.i5.601] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 06/30/2014] [Accepted: 07/18/2014] [Indexed: 02/05/2023] Open
Abstract
Patients with diabetes mellitus are at high risk of developing atherosclerosis, associated with higher rates of micro and macro vascular involvement such as coronary artery disease and renal disease. The role of hyperglycemia to induce synthesis of reactive oxygen species by the oxidation of glucose, leading to an increased production of advanced glycosylation end products, as well as inflammation and oxidative stress has been proposed as a possible mechanism in the pathogenesis of endothelial dysfunction (ED). The interaction between C-peptide - the connecting segment of pro-insulin-and nitric oxide in vasodilation is also discussed. Therefore, endothelial dysfunction has been identified as an early marker of vascular disorder in type 1 and type 2 diabetes mellitus. In some other diseases, ED has been considered an independent predictor of vascular disease, regardless of the method used. Studies have demonstrated the importance of endothelial dysfunction as an useful tool for identifying the risk of vascular complications in patients with type 1 diabetes mellitus, particularly as regards to renal impairment. The aim of this review is to clarify the prognostic value of endothelial dysfunction as a marker of vascular disease in these subjects.
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Peng XH, Liang PY, Ou SJ, Zu XB. Protective effect of pioglitazone on kidney injury in diabetic rats. ASIAN PAC J TROP MED 2014; 7:819-22. [DOI: 10.1016/s1995-7645(14)60143-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Revised: 08/15/2014] [Accepted: 09/15/2014] [Indexed: 10/24/2022] Open
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Singh G, Sharma B, Jaggi AS, Singh N. Efficacy of bosentan, a dual ETA and ETB endothelin receptor antagonist, in experimental diabetes induced vascular endothelial dysfunction and associated dementia in rats. Pharmacol Biochem Behav 2014; 124:27-35. [DOI: 10.1016/j.pbb.2014.05.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Revised: 05/01/2014] [Accepted: 05/08/2014] [Indexed: 01/17/2023]
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Kövamees O, Shemyakin A, Pernow J. Effect of arginase inhibition on ischemia-reperfusion injury in patients with coronary artery disease with and without diabetes mellitus. PLoS One 2014; 9:e103260. [PMID: 25072937 PMCID: PMC4114552 DOI: 10.1371/journal.pone.0103260] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Accepted: 06/30/2014] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND Arginase competes with nitric oxide synthase for their common substrate L-arginine. Up-regulation of arginase in coronary artery disease (CAD) and diabetes mellitus may reduce nitric oxide bioavailability contributing to endothelial dysfunction and ischemia-reperfusion injury. Arginase inhibition reduces infarct size in animal models. Therefore the aim of the current study was to investigate if arginase inhibition protects from endothelial dysfunction induced by ischemia-reperfusion in patients with CAD with or without type 2 diabetes ( CLINICAL TRIAL REGISTRATION NUMBER NCT02009527). METHODS Male patients with CAD (n = 12) or CAD + type 2 diabetes (n = 12), were included in this cross-over study with blinded evaluation. Endothelium-dependent vasodilatation was assessed by flow-mediated dilatation (FMD) of the radial artery before and after 20 min ischemia-reperfusion during intra-arterial infusion of the arginase inhibitor (Nω-hydroxy-nor-L-arginine, 0.1 mg/min) or saline. RESULTS The forearm ischemia-reperfusion was well tolerated. Endothelium-independent vasodilatation was assessed by sublingual nitroglycerin. Ischemia-reperfusion decreased FMD in patients with CAD from 12.7±5.2% to 7.9±4.0% during saline administration (P<0.05). Nω-hydroxy-nor-L-arginine administration prevented the decrease in FMD in the CAD group (10.3±4.3% at baseline vs. 11.5±3.6% at reperfusion). Ischemia-reperfusion did not significantly reduce FMD in patients with CAD + type 2 diabetes. However, FMD at reperfusion was higher following nor-NOHA than following saline administration in both groups (P<0.01). Endothelium-independent vasodilatation did not differ between the occasions. CONCLUSIONS Inhibition of arginase protects against endothelial dysfunction caused by ischemia-reperfusion in patients with CAD. Arginase inhibition may thereby be a promising therapeutic strategy in the treatment of ischemia-reperfusion injury.
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Affiliation(s)
- Oskar Kövamees
- Department of Medicine, Karolinska Institutet, Stockholm, Sweden
- * E-mail:
| | - Alexey Shemyakin
- Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - John Pernow
- Department of Medicine, Karolinska Institutet, Stockholm, Sweden
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Schreuder THA, van Lotringen JH, Hopman MTE, Thijssen DHJ. Impact of endothelin blockade on acute exercise-induced changes in blood flow and endothelial function in type 2 diabetes mellitus. Exp Physiol 2014; 99:1253-64. [DOI: 10.1113/expphysiol.2013.077297] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Tim H. A. Schreuder
- Department of Physiology; Radboud University Nijmegen Medical Centre; Nijmegen The Netherlands
| | - Jaap H. van Lotringen
- Department of Physiology; Radboud University Nijmegen Medical Centre; Nijmegen The Netherlands
| | - Maria T. E. Hopman
- Department of Physiology; Radboud University Nijmegen Medical Centre; Nijmegen The Netherlands
| | - Dick H. J. Thijssen
- Department of Physiology; Radboud University Nijmegen Medical Centre; Nijmegen The Netherlands
- Research Institute for Sports and Exercise Sciences; Liverpool John Moores University; Liverpool UK
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Lenoir O, Milon M, Virsolvy A, Hénique C, Schmitt A, Massé JM, Kotelevtsev Y, Yanagisawa M, Webb DJ, Richard S, Tharaux PL. Direct action of endothelin-1 on podocytes promotes diabetic glomerulosclerosis. J Am Soc Nephrol 2014; 25:1050-62. [PMID: 24722437 DOI: 10.1681/asn.2013020195] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The endothelin system has emerged as a novel target for the treatment of diabetic nephropathy. Endothelin-1 promotes mesangial cell proliferation and sclerosis. However, no direct pathogenic effect of endothelin-1 on podocytes has been shown in vivo and endothelin-1 signaling in podocytes has not been investigated. This study investigated endothelin effects in podocytes during experimental diabetic nephropathy. Stimulation of primary mouse podocytes with endothelin-1 elicited rapid calcium transients mediated by endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs). We then generated mice with a podocyte-specific double deletion of ETAR and ETBR (NPHS2-Cre×Ednra(lox/lox)×Ednrb(lox/lox) [Pod-ETRKO]). In vitro, treatment with endothelin-1 increased total β-catenin and phospho-NF-κB expression in wild-type glomeruli, but this effect was attenuated in Pod-ETRKO glomeruli. After streptozotocin injection to induce diabetes, wild-type mice developed mild diabetic nephropathy with microalbuminuria, mesangial matrix expansion, glomerular basement membrane thickening, and podocyte loss, whereas Pod-ETRKO mice presented less albuminuria and were completely protected from glomerulosclerosis and podocyte loss, even when uninephrectomized. Moreover, glomeruli from normal and diabetic Pod-ETRKO mice expressed substantially less total β-catenin and phospho-NF-κB compared with glomeruli from counterpart wild-type mice. This evidence suggests that endothelin-1 drives development of glomerulosclerosis and podocyte loss through direct activation of endothelin receptors and NF-κB and β-catenin pathways in podocytes. Notably, both the expression and function of the ETBR subtype were found to be important. Furthermore, these results indicate that activation of the endothelin-1 pathways selectively in podocytes mediates pathophysiologic crosstalk that influences mesangial architecture and sclerosis.
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Affiliation(s)
- Olivia Lenoir
- Paris Cardiovascular Research Centre, Institut National de la Santé et de la Recherche Médicale, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Marine Milon
- Paris Cardiovascular Research Centre, Institut National de la Santé et de la Recherche Médicale, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Anne Virsolvy
- Physiologie et Médecine expérimentale du Cœur et des Muscles, Institut National de la Santé et de la Recherche Médicale U1046, Université Montpellier 1, Université Montpellier 2, Montpellier, France
| | - Carole Hénique
- Paris Cardiovascular Research Centre, Institut National de la Santé et de la Recherche Médicale, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Alain Schmitt
- Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Transmission Electron Microscopy Platform, Institut National de la Santé et de la Recherche Médicale U1016, Cochin Institut, Paris, France; Centre National de la Recherche Scientifique UMR81044, Paris, France
| | - Jean-Marc Massé
- Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Transmission Electron Microscopy Platform, Institut National de la Santé et de la Recherche Médicale U1016, Cochin Institut, Paris, France; Centre National de la Recherche Scientifique UMR81044, Paris, France
| | - Yuri Kotelevtsev
- The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom; Pushchino State Institute for Natural Sciences, Pushchino, Moscow Region, Russian Federation
| | | | - David J Webb
- The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Sylvain Richard
- Physiologie et Médecine expérimentale du Cœur et des Muscles, Institut National de la Santé et de la Recherche Médicale U1046, Université Montpellier 1, Université Montpellier 2, Montpellier, France
| | - Pierre-Louis Tharaux
- Paris Cardiovascular Research Centre, Institut National de la Santé et de la Recherche Médicale, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Nephrology Service, Georges Pompidou European Hospital, Assistance Publique Hopitaux de Paris, Paris, France
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Howangyin KY, Silvestre JS. Diabetes mellitus and ischemic diseases: molecular mechanisms of vascular repair dysfunction. Arterioscler Thromb Vasc Biol 2014; 34:1126-35. [PMID: 24675660 DOI: 10.1161/atvbaha.114.303090] [Citation(s) in RCA: 101] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In patients with diabetes mellitus, the ability of ischemic tissue to synchronize the molecular and cellular events leading to restoration of tissue perfusion in response to the atherosclerotic occlusion of a patent artery is markedly impaired. As a consequence, adverse tissue remodeling and the extent of ischemic injury are intensified, leading to increased morbidity and mortality. Growing evidence from preclinical and clinical studies has implicated alterations in hypoxia-inducible factor 1 levels in the abrogation of proangiogenic pathways, including vascular endothelial growth factor A/phosphoinositide 3' kinase/AKT/endothelial nitric oxide synthase and in the activation of antiangiogenic signals characterized by accumulation of advanced glycation end products, reactive oxygen species overproduction, and endoplasmic reticulum stress. In addition, the diabetic milieu shows a switch toward proinflammatory antiregenerative pathways. Finally, the mobilization, subsequent recruitment, and the proangiogenic potential of the different subsets of angiogenesis-promoting bone marrow-derived cells are markedly impaired in the diabetic environment. In this review, we will give an overview of the current understanding on the signaling molecules contributing to the diabetes mellitus-induced impairment of postischemic revascularization mainly in the setting of myocardial infarction or critical limb ischemia.
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Affiliation(s)
- Kiave Yune Howangyin
- From the INSERM UMRS 970, Paris Descartes University, Sorbonne Paris Cité, Paris, France
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Daehn I, Casalena G, Zhang T, Shi S, Fenninger F, Barasch N, Yu L, D'Agati V, Schlondorff D, Kriz W, Haraldsson B, Bottinger EP. Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis. J Clin Invest 2014; 124:1608-21. [PMID: 24590287 DOI: 10.1172/jci71195] [Citation(s) in RCA: 237] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Accepted: 01/02/2014] [Indexed: 01/08/2023] Open
Abstract
Focal segmental glomerular sclerosis (FSGS) is a primary kidney disease that is commonly associated with proteinuria and progressive loss of glomerular function, leading to development of chronic kidney disease (CKD). FSGS is characterized by podocyte injury and depletion and collapse of glomerular capillary segments. Progression of FSGS is associated with TGF-β activation in podocytes; however, it is not clear how TGF-β signaling promotes disease. Here, we determined that podocyte-specific activation of TGF-β signaling in transgenic mice and BALB/c mice with Adriamycin-induced glomerulosclerosis is associated with endothelin-1 (EDN1) release by podocytes, which mediates mitochondrial oxidative stress and dysfunction in adjacent endothelial cells via paracrine EDN1 receptor type A (EDNRA) activation. Endothelial dysfunction promoted podocyte apoptosis, and inhibition of EDNRA or scavenging of mitochondrial-targeted ROS prevented podocyte loss, albuminuria, glomerulosclerosis, and renal failure. We confirmed reciprocal crosstalk between podocytes and endothelial cells in a coculture system. Biopsies from patients with FSGS exhibited increased mitochondrial DNA damage, consistent with EDNRA-mediated glomerular endothelial mitochondrial oxidative stress. Our studies indicate that segmental glomerulosclerosis develops as a result of podocyte-endothelial crosstalk mediated by EDN1/EDNRA-dependent mitochondrial dysfunction and suggest that targeting the reciprocal interaction between podocytes and endothelia may provide opportunities for therapeutic intervention in FSGS.
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MESH Headings
- Animals
- Cell Line
- Disease Models, Animal
- Endothelin-1/genetics
- Endothelin-1/metabolism
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/pathology
- Glomerulosclerosis, Focal Segmental/genetics
- Glomerulosclerosis, Focal Segmental/metabolism
- Glomerulosclerosis, Focal Segmental/pathology
- Humans
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Transgenic
- Mitochondria/metabolism
- Models, Biological
- Oxidative Stress
- Podocytes/metabolism
- Podocytes/pathology
- Protein Serine-Threonine Kinases/genetics
- Protein Serine-Threonine Kinases/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptor, Endothelin A/genetics
- Receptor, Endothelin A/metabolism
- Receptor, Transforming Growth Factor-beta Type I
- Receptors, Transforming Growth Factor beta/genetics
- Receptors, Transforming Growth Factor beta/metabolism
- Signal Transduction
- Transforming Growth Factor beta/metabolism
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Matsumoto T, Lopes RAM, Taguchi K, Kobayashi T, Tostes RC. Linking the beneficial effects of current therapeutic approaches in diabetes to the vascular endothelin system. Life Sci 2014; 118:129-35. [PMID: 24418002 DOI: 10.1016/j.lfs.2013.12.216] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 12/04/2013] [Accepted: 12/24/2013] [Indexed: 12/19/2022]
Abstract
The rising epidemic of diabetes worldwide is of significant concern. Although the ultimate objective is to prevent the development and find a cure for the disease, prevention and treatment of diabetic complications is very important. Vascular complications in diabetes, or diabetic vasculopathy, include macro- and microvascular dysfunction and represent the principal cause of morbidity and mortality in diabetic patients. Endothelial dysfunction plays a pivotal role in the development and progression of diabetic vasculopathy. Endothelin-1 (ET-1), an endothelial cell-derived peptide, is a potent vasoconstrictor with mitogenic, pro-oxidative and pro-inflammatory properties that are particularly relevant to the pathophysiology of diabetic vasculopathy. Overproduction of ET-1 is reported in patients and animal models of diabetes and the functional effects of ET-1 and its receptors are also greatly altered in diabetic conditions. The current therapeutic approaches in diabetes include glucose lowering, sensitization to insulin, reduction of fatty acids and vasculoprotective therapies. However, whether and how these therapeutic approaches affect the ET-1 system remain poorly understood. Accordingly, in the present review, we will focus on experimental and clinical evidence that indicates a role for ET-1 in diabetic vasculopathy and on the effects of current therapeutic approaches in diabetes on the vascular ET-1 system.
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Affiliation(s)
- Takayuki Matsumoto
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
| | - Rheure A M Lopes
- Department of Pharmacology, Medical School of Ribeirao Preto, University of Sao Paulo, Av Bandeirantes 3900, Ribeirao Preto, SP 14049-900, Brazil
| | - Kumiko Taguchi
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
| | - Tsuneo Kobayashi
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
| | - Rita C Tostes
- Department of Pharmacology, Medical School of Ribeirao Preto, University of Sao Paulo, Av Bandeirantes 3900, Ribeirao Preto, SP 14049-900, Brazil
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Urinary leukotriene E4 is associated with renal function but not with endothelial function in type 2 diabetes. DISEASE MARKERS 2013; 35:475-80. [PMID: 24198444 PMCID: PMC3809968 DOI: 10.1155/2013/370461] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/29/2013] [Revised: 09/19/2013] [Accepted: 09/19/2013] [Indexed: 11/17/2022]
Abstract
Leukotrienes are inflammatory and vasoactive mediators implicated in endothelium-dependent relaxations and atherosclerosis. Urinary leukotriene E4 (U-LTE4) is a validated disease marker of asthma and increases also in diabetes and acute coronary syndromes. The aim of the present study was to evaluate the association of U-LTE4 and CRP with endothelial function. Urine samples were obtained from 30 subjects (80% males; median age 65) with type 2 diabetes of at least two years duration and a median glomerular filtration rate (eGFR) of 71 (14–129) mL/min. Reactive hyperemia index (RHI) was used as a measure of microvascular endothelial function, whereas macrovascular endothelial function was determined be means of flow-mediated dilatation of the brachial artery (FMD). Decreased renal function was associated with lower concentrations of U-LTE4. In addition, U-LTE4 was correlated with serum creatinine (R = −0.572; P = 0.001) and eGFR (R = 0.517; P = 0.0036). A stepwise multiple linear regression analysis identified eGFR as an independent predictor of U-LTE4 concentrations. In conclusion, the present results did not establish an association of U-LTE4 with endothelial dysfunction. However, eGFR was an independent predictor of U-LTE4, but not CRP, in this cohort, suggesting that GFR should be considered in biomarker studies of U-LTE4.
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Contreras C, Sánchez A, Martínez P, Climent B, Benedito S, García-Sacristán A, Hernández M, Prieto D. Impaired Endothelin Calcium Signaling Coupled to Endothelin Type B Receptors in Penile Arteries from Insulin-Resistant Obese Zucker Rats. J Sex Med 2013; 10:2141-53. [DOI: 10.1111/jsm.12234] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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