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Anyfanti P, Theodorakopoulou M, Iatridi F, Sarafidis P. Endothelin receptor antagonists for diabetic kidney disease: back to the future? Expert Opin Investig Drugs 2025; 34:317-327. [PMID: 40313198 DOI: 10.1080/13543784.2025.2500294] [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: 01/29/2025] [Accepted: 04/17/2025] [Indexed: 05/03/2025]
Abstract
INTRODUCTION Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease worldwide. Endothelin-1 (ET-1) is a potent vasoconstrictor secreted by vascular endothelial cells, actively involved in the pathophysiology of numerous cardiovascular diseases. Based on the differential downstream effects of ET-1 binding to its two distinct types of receptors (ETA/ETB) within the kidney, selective ETA receptor blockade has been long proposed as a promising treatment modality for DKD. AREAS COVERED This review aims to examine the available evidence base for the use of ERAs in the treatment of DKD, by critically reappraising available landmark trials and discussing their possible position in the context of current treatment of this disease. EXPERT OPINION Despite early enthusiasm and widespread expectations, endothelin receptor antagonists (ERAs) faded into obscurity following the release of the first randomized controlled trials (RCTs). More recent RCTs using different compounds have re-introduced ERAs as a promising treatment in the growing pharmaceutical armamentarium of DKD. While the future of DKD management will be based on a more personalized approach, new, robust evidence from appropriately designed RCTs is eagerly anticipated to clearly define the role of ERAs in DKD.
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Affiliation(s)
- Panagiota Anyfanti
- Third Department of Internal Medicine, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Marieta Theodorakopoulou
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Fotini Iatridi
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Pantelis Sarafidis
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Greco M, Mirabelli M, Sicilia L, Dragone F, Giuliano S, Brunetti FS, Scalise R, Chiefari E, Andreadi A, Lauro D, Foti DP, Brunetti A. Circulating Thrombospondin-1 and Endothelin-1 Levels Tend to Decline with Increasing Obesity Severity in Women: Evidence from a Pilot, Cross-Sectional Study. J Clin Med 2025; 14:2143. [PMID: 40217594 PMCID: PMC11989311 DOI: 10.3390/jcm14072143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 03/03/2025] [Accepted: 03/19/2025] [Indexed: 04/14/2025] Open
Abstract
Background: Thrombospondin-1 (TSP1) is a multimeric glycoprotein that is increasingly recognized as a mediator of metabolic, thrombotic, and inflammatory processes. Although TSP1 expression has been associated with adipose tissue dysfunction and insulin resistance, the precise relationship with obesity severity remains unclear. Endothelin-1 (ET1), another important regulator of vascular homeostasis, may also contribute to obesity-related cardiometabolic risk, with evidence suggesting sex-specific differences, including delayed onset in women. The study aimed to investigate circulating TSP1 and ET1 levels in a cohort of nondiabetic obese female adults, evaluate their associations with metabolic and inflammatory parameters, and determine whether these markers differ according to obesity severity and related disease risk. Methods: Fifty-five nondiabetic women with obesity and no history of cardiovascular events were enrolled at the Endocrinology Unit ("R. Dulbecco" Univ. Hospital, Catanzaro, Italy). Anthropometric and clinical data, together with hematological and coagulation parameters and metabolic indices (HOMA-IR, HbA1c, and lipid profile), were evaluated. TSP1 and ET1 concentrations were measured using automated enzyme immunoassays (ELISAs). The participants were stratified by BMI (30-34.9 vs. ≥35 kg/m2) into low-risk and moderate/high-risk obesity based on the WHO classification, and correlations between biomarkers and metabolic/inflammatory parameters were evaluated. Results: The median BMI was 33.7 kg/m2, with 52% of participants having moderate/high-risk obesity (WHO Class II/III). A significant proportion (69.8%) showed insulin resistance (HOMA-IR > 2.5). TSP1 was positively correlated with white blood cell count (WBC, r = 0.354, p < 0.01), platelet count (PLT, r = 0.411, p < 0.01), and glycated hemoglobin (r = 0.391, p < 0.01), suggesting an association with both inflammation and glycemic control. ET1 was positively correlated with liver enzymes and triglycerides but negatively correlated with PLT and D-dimer. Women with moderate/high-risk obesity had significantly higher HOMA-IR, D-dimer, and inflammatory markers, in addition to a lower TSP1-to-PLT ratio. Conclusions: In this pilot study, TSP1 and ET1 levels tended to decrease with increasing obesity severity in women but were associated with distinct metabolic and inflammatory profiles. The results support the potential role of TSP1 as a biomarker for obesity-related cardiometabolic risk and highlight the complex interplay between TSP1, ET1, and obesity progression. Further studies may clarify whether targeting TSP1 can ameliorate chronic inflammation and insulin resistance in obesity and the potential sex-specific influences on these mechanisms.
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Affiliation(s)
- Marta Greco
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.)
- Operative Unit of Clinical Pathology, “R. Dulbecco” Hospital, 88100 Catanzaro, Italy
| | - Maria Mirabelli
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.)
- Operative Unit of Endocrinology, “R. Dulbecco” University Hospital, 88100 Catanzaro, Italy
| | - Luciana Sicilia
- Operative Unit of Endocrinology, “R. Dulbecco” University Hospital, 88100 Catanzaro, Italy
| | - Francesco Dragone
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.)
| | - Stefania Giuliano
- Operative Unit of Endocrinology, “R. Dulbecco” University Hospital, 88100 Catanzaro, Italy
| | - Francesco S. Brunetti
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.)
| | - Rosa Scalise
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.)
| | - Eusebio Chiefari
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.)
| | - Aikaterini Andreadi
- Section of Endocrinology and Metabolic Diseases, Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy (D.L.)
| | - Davide Lauro
- Section of Endocrinology and Metabolic Diseases, Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy (D.L.)
| | - Daniela P. Foti
- Operative Unit of Clinical Pathology, “R. Dulbecco” Hospital, 88100 Catanzaro, Italy
- Department of Experimental and Clinical Medicine, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy
| | - Antonio Brunetti
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.)
- Operative Unit of Endocrinology, “R. Dulbecco” University Hospital, 88100 Catanzaro, Italy
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Zhen J, Sun L, Ji L, Zhou S, Cui Y, Li Z. EDN1 facilitates cisplatin resistance of non-small cell lung cancer cells by regulating the TNF signaling pathway. World J Surg Oncol 2025; 23:71. [PMID: 40025550 PMCID: PMC11871734 DOI: 10.1186/s12957-025-03692-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 01/28/2025] [Indexed: 03/04/2025] Open
Abstract
BACKGROUND Cisplatin (DDP) is a commonly utilized chemotherapeutic agent. Nevertheless, the development of resistance to DDP significantly diminishes the effectiveness of DDP-based chemotherapy in patients with non-small cell lung cancer (NSCLC). In this study, we investigated the impact of endothelin 1 (EDN1) on the resistance to DDP in NSCLC. METHODS The proliferation, invasion, and migration of NSCLC cells were detected by cell counting kit-8 and Transwell migration and invasion assays. ELISA was performed to analyze the inflammatory cytokines concentrations. The related protein levels of tumor necrosis factor (TNF) signaling pathway were analyzed by Western blot. Besides, a xenograft tumor mice model was established to explore the role of EDN1 in vivo. RESULTS The results showed that DDP-resistance upregulated EDN1 expression, cell viability, invasion, migration, and inflammation in NSCLC cells, while the results were reversed after EDN1 inhibition. EDN1 affected DDP-resistance of NSCLC by regulating TNF signaling pathway. Overexpression of TNF receptor-1 (TNFR1) reversed the decreased cell viability, invasion, migration, and inflammation induced by silencing EDN1 in A549/DDP cells. Moreover, silencing EDN1 inhibited tumor growth and the protein levels of EDN1 and TNFR1. CONCLUSION EDN1 promoted DDP resistance in NSCLC cells through the modulation of the TNF signaling pathway, suggesting a potential therapeutic intervention strategy for NSCLC.
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Affiliation(s)
- Jie Zhen
- Department of Thoracic Surgery, Qidong People's Hospital, Qidong Liver Cancer Institute, Affiliated Qidong Hospital of Nantong University, Qidong, China
| | - Long Sun
- Department of Pathology, Qidong People's Hospital, Qidong Liver Cancer Institute, Affiliated Qidong Hospital of Nantong University, Qidong, China
| | - Li Ji
- Department of Blood Transfusion, Qidong People's Hospital, Qidong Liver Cancer Institute, Affiliated Qidong Hospital of Nantong University, Qidong, China
| | - Shaochong Zhou
- Department of Thoracic Surgery, Qidong People's Hospital, Qidong Liver Cancer Institute, Affiliated Qidong Hospital of Nantong University, Qidong, China
| | - Yijin Cui
- Department of Neurology, Qidong People's Hospital, Qidong Liver Cancer Institute, Affiliated Qidong Hospital of Nantong University, Qidong, China
| | - Zhenwei Li
- Department of Operating Room, Qidong People's Hospital, Qidong Liver Cancer Institute, Affiliated Qidong Hospital of Nantong University, No.753, Jianghai Middle Road, Qidong, Jiangsu, 226200, China.
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Babcock MC, DuBose LE, Hildreth KL, Stauffer BL, Kohrt WM, Wenner MM, Moreau KL. Endothelial dysfunction in middle-aged and older men with low testosterone is associated with elevated circulating endothelin-1. Am J Physiol Regul Integr Comp Physiol 2025; 328:R253-R261. [PMID: 39887085 DOI: 10.1152/ajpregu.00218.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 10/07/2024] [Accepted: 01/26/2025] [Indexed: 02/01/2025]
Abstract
Low testosterone in middle-aged/older men contributes to accelerated vascular aging, including endothelial dysfunction. However, the mechanisms by which low testosterone affects endothelial dysfunction are not well understood. We sought to determine whether higher endothelin-1 (ET-1) levels are associated with reduced brachial artery flow-mediated dilation (FMD) in middle-aged/older men with low testosterone. Plasma ET-1 was quantified in 60 men categorized as young (n = 20, age = 30 ± 4 yr, testosterone = 510 ± 63 ng/dL), middle-aged/older with normal testosterone (n = 20, age = 59 ± 6 yr, testosterone = 512 ± 115 ng/dL), or middle-aged/older with low testosterone (n = 20, age = 60 ± 8 yr, testosterone = 265 ± 47 ng/dL). Endothelial function was determined via brachial artery FMD. Venous and arterial endothelial cells were harvested via endovascular biopsy in a subset of participants and stained for ET-1 expression. Middle-aged/older men with normal testosterone exhibited lower brachial artery FMD (5.7 ± 2.2%) compared with young men (7.3 ± 1.3%, P = 0.020), which was exaggerated in middle-aged/older men with low testosterone (4.0 ± 1.8%, P = 0.010 vs. middle-aged/older men with normal testosterone). Plasma ET-1 was not different between young (5.6 ± 0.9 ng/dL) and middle-aged/older men with normal testosterone (6.0 ± 1.4 ng/dL, P = 0.681) but was higher in middle-aged/older men with low testosterone (7.7 ± 2.8 ng/dL) compared with both groups (P < 0.001 vs. young men; P = 0.013 vs. middle-aged/older men with normal testosterone). There was no difference in venous (P = 0.616) or arterial (P = 0.222) endothelial cell ET-1 expression between groups. There was a significant inverse association between plasma ET-1 and FMD (r =-0.371, P = 0.004). These data suggest that the accelerated age-associated reduction in endothelial dysfunction in middle-aged/older men with low testosterone is related to higher circulating ET-1.NEW & NOTEWORTHY Middle-aged/older men with low testosterone have reduced vascular endothelial function compared with young and age-matched men with normal testosterone. In this manuscript, we demonstrate that men with low testosterone have higher plasma endothelin-1, which is associated with worse brachial artery flow-mediated dilation. The source of higher plasma endothelin-1 remains unknown; however, higher circulating endothelin-1 appears to be a mechanism contributing to reduced vascular endothelial function in men with low testosterone.
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Affiliation(s)
- Matthew C Babcock
- Division of Geriatric Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Lyndsey E DuBose
- Division of Geriatric Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Kerry L Hildreth
- Division of Geriatric Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Brian L Stauffer
- Division of Cardiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Division of Cardiology, Denver Health Medical Center, Denver, Colorado, United States
| | - Wendy M Kohrt
- Division of Geriatric Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Geriatric Research, Educational and Clinical Center, Veterans Affairs Eastern Colorado, Denver, Colorado, United States
| | - Megan M Wenner
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, Delaware, United States
| | - Kerrie L Moreau
- Division of Geriatric Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Geriatric Research, Educational and Clinical Center, Veterans Affairs Eastern Colorado, Denver, Colorado, United States
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Sinclair SH, Schwartz S. Diabetic retinopathy: New concepts of screening, monitoring, and interventions. Surv Ophthalmol 2024; 69:882-892. [PMID: 38964559 DOI: 10.1016/j.survophthal.2024.07.001] [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: 03/14/2024] [Revised: 06/30/2024] [Accepted: 07/01/2024] [Indexed: 07/06/2024]
Abstract
The science of diabetes care has progressed to provide a better understanding of the oxidative and inflammatory lesions and pathophysiology of the neurovascular unit within the retina (and brain) that occur early in diabetes, even prediabetes. Screening for retinal structural abnormalities, has traditionally been performed by fundus examination or color fundus photography; however, these imaging techniques detect the disease only when there are sufficient lesions, predominantly hemorrhagic, that are recognized to occur late in the disease process after significant neuronal apoptosis and atrophy, as well as microvascular occlusion with alterations in vision. Thus, interventions have been primarily oriented toward the later-detected stages, and clinical trials, while demonstrating a slowing of the disease progression, demonstrate minimal visual improvement and modest reduction in the continued loss over prolonged periods. Similarly, vision measurement utilizing charts detects only problems of visual function late, as the process begins most often parafoveally with increasing number and progressive expansion, including into the fovea. While visual acuity has long been used to define endpoints of visual function for such trials, current methods reviewed herein are found to be imprecise. We review improved methods of testing visual function and newer imaging techniques with the recommendation that these must be utilized to discover and evaluate the injury earlier in the disease process, even in the prediabetic state. This would allow earlier therapy with ocular as well as systemic pharmacologic treatments that lower the and neuro-inflammatory processes within eye and brain. This also may include newer, micropulsed laser therapy that, if applied during the earlier cascade, should result in improved and often normalized retinal function without the adverse treatment effects of standard photocoagulation therapy.
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Affiliation(s)
| | - Stan Schwartz
- University of Pennsylvania Affiliate, Main Line Health System, USA
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Gumanova NG, Vasilyev DK, Bogdanova NL, Drapkina OM. Serum Level of Cadherin-P (CDH3) Is a Novel Predictor of Cardiovascular Events Related to Atherosclerosis in a 3-Year Follow-Up Study. J Clin Med 2024; 13:6293. [PMID: 39518432 PMCID: PMC11546736 DOI: 10.3390/jcm13216293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 10/18/2024] [Accepted: 10/18/2024] [Indexed: 11/16/2024] Open
Abstract
Background: Placental cadherin (CDH3) is an adhesion molecule expressed in many malignant tumors. The role of serum CDH3 in atherosclerosis is unclear. Methods: This 3-year follow-up study measured atherosclerosis and serum CDH3 in 218 angiography inpatients. Coronary stenosis was assessed as the Gensini score. The brachiocephalic and femoral plaques were quantified by ultrasound. Microarray serum profiling was conducted in selected samples. CDH3 in the serum was measured using an indirect ELISA. The odds ratio (OR), ROC analysis, and logistic regressions were used to evaluate the associations between CDH3 content, atherosclerotic lesions, and various serum biomarkers. Results: Serum CDH3 was associated with the severity of atherosclerosis and diastolic blood pressure. The levels of CDH3 were able to discriminate patients with total subclinical and hemodynamically significant atherosclerotic lesions in all circulation pools (coronary, brachiocephalic, and femoral). Elevated serum CDH3 appeared to be a risk factor for cardiovascular outcomes after 3-year follow up with OR = 1.81 (95% CI: 1.07-3.72; p = 0.022). Endothelin-1 and NOx were associated with the content of CDH3 in the serum, suggesting the involvement of certain signal transduction pathways that may participate in plaque formation. Conclusions: CDH3 was associated with cardiovascular outcomes adjusted for coronary plaque presence, indicating a role of CDH3 in plaque biology.
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Affiliation(s)
- Nadezhda G. Gumanova
- Department of Biochemistry, National Research Center for Preventive Medicine (NRCPM), 101990 Moscow, Russia;
| | - Dmitry K. Vasilyev
- Department of Cardiovascular X-Ray Surgery, National Research Center for Preventive Medicine (NRCPM), 101990 Moscow, Russia;
| | - Natalya L. Bogdanova
- Department of Biochemistry, National Research Center for Preventive Medicine (NRCPM), 101990 Moscow, Russia;
| | - Oxana M. Drapkina
- Administrative Department, National Research Center for Preventive Medicine (NRCPM), 101990 Moscow, Russia;
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Rivera-Gonzalez O, Mills MF, Konadu BD, Wilson NA, Murphy HA, Newberry MK, Hyndman KA, Garrett MR, Webb DJ, Speed JS. Adipocyte endothelin B receptor activation inhibits adiponectin production and causes insulin resistance in obese mice. Acta Physiol (Oxf) 2024; 240:e14214. [PMID: 39096077 PMCID: PMC11421981 DOI: 10.1111/apha.14214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 07/16/2024] [Accepted: 07/17/2024] [Indexed: 08/04/2024]
Abstract
AIMS Endothelin-1 (ET-1) is elevated in patients with obesity and adipose tissue of obese mice fed high-fat diet (HFD); however, its contribution to the pathophysiology of obesity is not fully understood. Genetic loss of endothelin type B receptors (ETB) improves insulin sensitivity in rats and leads to increased circulating adiponectin, suggesting that ETB activation on adipocytes may contribute to obesity pathophysiology. We hypothesized that elevated ET-1 in obesity promotes insulin resistance by reducing the secretion of insulin sensitizing adipokines, via ETB receptor. METHODS Male adipocyte-specific ETB receptor knockout (adETBKO), overexpression (adETBOX), or control littermates were fed either normal diet (NMD) or high-fat diet (HFD) for 8 weeks. RESULTS RNA-sequencing of epididymal adipose (eWAT) indicated differential expression of over 5500 genes (p < 0.05) in HFD compared to NMD controls, and changes in 1077 of these genes were attenuated in HFD adETBKO mice. KEGG analysis indicated significant increase in metabolic signaling pathway. HFD adETBKO mice had significantly improved glucose and insulin tolerance compared to HFD control. In addition, adETBKO attenuated changes in plasma adiponectin, insulin, and leptin that is observed in HFD versus NMD control mice. Treatment of primary adipocytes with ET-1 caused a reduction in adiponectin production that was attenuated in cells pretreated with an ETB antagonist. CONCLUSION These data indicate elevated ET-1 in adipose tissue of mice fed HFD inhibits adiponectin production and causes insulin resistance through activation of the ETB receptor on adipocytes.
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Affiliation(s)
- Osvaldo Rivera-Gonzalez
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216
| | - Megumi F. Mills
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216
| | - Bridget D. Konadu
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216
| | - Natalie A. Wilson
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216
| | - Hayley A. Murphy
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216
| | - Madison K. Newberry
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216
| | - Kelly A. Hyndman
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham
| | - Michael R. Garrett
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216
| | - David J. Webb
- University/British Heart Foundation Centre for Cardiovascular Science|Queen’s Medical Research Institute, University of Edinburgh, UK
| | - Joshua S. Speed
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216
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Sági B, Vas T, Gál C, Horváth-Szalai Z, Kőszegi T, Nagy J, Csiky B, Kovács TJ. The Relationship between Vascular Biomarkers (Serum Endocan and Endothelin-1), NT-proBNP, and Renal Function in Chronic Kidney Disease, IgA Nephropathy: A Cross-Sectional Study. Int J Mol Sci 2024; 25:10552. [PMID: 39408883 PMCID: PMC11476882 DOI: 10.3390/ijms251910552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 09/25/2024] [Accepted: 09/29/2024] [Indexed: 10/20/2024] Open
Abstract
IgA nephropathy (IgAN) is the most common primary glomerular disease. Endothelin-1 (ET-1) is one of the strongest vasoconstrictor materials in the blood. The N-terminal prohormone of brain natriuretic peptide (NT-proBNP) is associated with renal function and poor outcomes in chronic kidney disease (CKD). Serum endocan is a biomarker associated with proinflammatory cytokines, and the increase in the serum level plays a critical role in inflammatory, proliferative, and neovascularization processes and is associated with poor cardiovascular outcomes in patients with CKD too. Identifying high-risk patients using biomarkers could help to optimize their treatment. Ninety patients with biopsy-confirmed IgAN were included in the study (50 males/40 females, mean age: 54.9 ± 14.4 years). Serum endocan, ET-1, and NT-proBNP were measured by enzyme-linked immunosorbent assay kits. Echocardiography was performed, and carotid-femoral pulse wave velocity (cfPWV) was measured by SphygmoCor in this cross-sectional study. Patients were divided into two groups based on serum endocan median level (cut-off: 44 ug/L). There was significantly higher aorta systolic blood pressure (SBPao) (p = 0.013), NT-proBNP (p = 0.028), albumin/creatinine ratio (p = 0.036), and uric acid (p = 0.045) in the case of the higher endocan group compared to the lower. There was also significantly higher SBPao (p = 0.037) and NT-proBNP (p = 0.038) in the case of higher endothelin-1 (ET-1) levels compared to the lower (cut-off: 231 pg/mL) group by the two-sample t-test. Then, we divided the patients into two groups based on the eGFR (CKD 1-2 vs. CKD 3-5). The levels of serum endocan, NT-proBNP, cfPWV, SBPao, left ventricular mass index (LVMI), uric acid, and albuminuria were significantly higher in the CKD 3-5 group compared to the CKD 1-2 group. The serum endocan and NT-proBNP levels were significantly higher in the diastolic dysfunction group (p = 0.047, p = 0.015). There was a significant increase in serum endocan levels (CKD 1 vs. CKD 5; p = 0.008) with decreasing renal function. In IgAN, vascular biomarkers (endocan, ET-1) may play a role in endothelial dysfunction through vascular damage and elevation of SBPao. Serum endocan, ET-1, and NT-proBNP biomarkers may help to identify IgAN patients at high risk.
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Affiliation(s)
- Balázs Sági
- 2nd Department of Internal Medicine and Nephrology, Diabetes Center, Clinical Centre, Medical School, University of Pécs, 7624 Pécs, Hungary; (T.V.); (J.N.); (B.C.); (T.J.K.)
- National Dialysis Center Pécs, 7624 Pécs, Hungary
| | - Tibor Vas
- 2nd Department of Internal Medicine and Nephrology, Diabetes Center, Clinical Centre, Medical School, University of Pécs, 7624 Pécs, Hungary; (T.V.); (J.N.); (B.C.); (T.J.K.)
| | - Csenge Gál
- Department of Laboratory Medicine, Medical School, University of Pécs, 7624 Pécs, Hungary; (C.G.); (Z.H.-S.); (T.K.)
- Molecular Medicine Research Group, Szentágothai Research Center, University of Pécs, 7624 Pécs, Hungary
| | - Zoltán Horváth-Szalai
- Department of Laboratory Medicine, Medical School, University of Pécs, 7624 Pécs, Hungary; (C.G.); (Z.H.-S.); (T.K.)
- Molecular Medicine Research Group, Szentágothai Research Center, University of Pécs, 7624 Pécs, Hungary
| | - Tamás Kőszegi
- Department of Laboratory Medicine, Medical School, University of Pécs, 7624 Pécs, Hungary; (C.G.); (Z.H.-S.); (T.K.)
- Molecular Medicine Research Group, Szentágothai Research Center, University of Pécs, 7624 Pécs, Hungary
| | - Judit Nagy
- 2nd Department of Internal Medicine and Nephrology, Diabetes Center, Clinical Centre, Medical School, University of Pécs, 7624 Pécs, Hungary; (T.V.); (J.N.); (B.C.); (T.J.K.)
| | - Botond Csiky
- 2nd Department of Internal Medicine and Nephrology, Diabetes Center, Clinical Centre, Medical School, University of Pécs, 7624 Pécs, Hungary; (T.V.); (J.N.); (B.C.); (T.J.K.)
- National Dialysis Center Pécs, 7624 Pécs, Hungary
| | - Tibor József Kovács
- 2nd Department of Internal Medicine and Nephrology, Diabetes Center, Clinical Centre, Medical School, University of Pécs, 7624 Pécs, Hungary; (T.V.); (J.N.); (B.C.); (T.J.K.)
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Lima AFR, Rodrigues D, Machado MR, Oliveira-Neto JT, Bressan AFM, Pedersoli CA, Alves JV, Silva-Neto JA, Barros PR, Dias TB, Garcia LV, Bruder-Nascimento A, Bruder-Nascimento T, Carneiro FS, Leiria LOS, Tostes RC, Costa RM. Endothelin-1 down-regulates nuclear factor erythroid 2-related factor-2 and contributes to perivascular adipose tissue dysfunction in obesity. Clin Sci (Lond) 2024; 138:1071-1087. [PMID: 39136472 DOI: 10.1042/cs20240624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 08/08/2024] [Accepted: 08/09/2024] [Indexed: 09/01/2024]
Abstract
Perivascular adipose tissue (PVAT) negatively regulates vascular muscle contraction. However, in the context of obesity, the PVAT releases vasoconstrictor substances that detrimentally affect vascular function. A pivotal player in this scenario is the peptide endothelin-1 (ET-1), which induces oxidative stress and disrupts vascular function. The present study postulates that obesity augments ET-1 production in the PVAT, decreases the function of the nuclear factor erythroid 2-related factor-2 (Nrf2) transcription factor, further increasing reactive oxygen species (ROS) generation, culminating in PVAT dysfunction. Male C57BL/6 mice were fed either a standard or a high-fat diet for 16 weeks. Mice were also treated with saline or a daily dose of 100 mg·kg-1 of the ETA and ETB receptor antagonist Bosentan, for 7 days. Vascular function was evaluated in thoracic aortic rings, with and without PVAT. Mechanistic studies utilized PVAT from all groups and cultured WT-1 mouse brown adipocytes. PVAT from obese mice exhibited increased ET-1 production, increased ECE1 and ETA gene expression, loss of the anticontractile effect, as well as increased ROS production, decreased Nrf2 activity, and downregulated expression of Nrf2-targeted antioxidant genes. PVAT of obese mice also exhibited increased expression of Tyr216-phosphorylated-GSK3β and KEAP1, but not BACH1 - negative Nrf2 regulators. Bosentan treatment reversed all these effects. Similarly, ET-1 increased ROS generation and decreased Nrf2 activity in brown adipocytes, events mitigated by BQ123 (ETA receptor antagonist). These findings place ET-1 as a major contributor to PVAT dysfunction in obesity and highlight that pharmacological control of ET-1 effects restores PVAT's cardiovascular protective role.
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Affiliation(s)
- Anna Flavia R Lima
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | - Daniel Rodrigues
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | - Mirele R Machado
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | - José Teles Oliveira-Neto
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | - Alecsander F M Bressan
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | - Carina A Pedersoli
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | - Juliano V Alves
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | - Júlio A Silva-Neto
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | - Paula R Barros
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | - Thiago B Dias
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | - Luis V Garcia
- Department of Biomechanics, Medicine and Locomotive Apparatus Rehabilitation, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | | | | | - Fernando S Carneiro
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | - Luiz Osório S Leiria
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | - Rita C Tostes
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | - Rafael M Costa
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
- Department of Physiology and Cell Biology, University of South Alabama, Mobile, AL, U.S.A
- Institute of Health Sciences, Federal University of Jatai, Jatai, GO, Brazil
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10
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Treister-Goltzman Y. An Ecological Association Between Air Pollution and Adolescent Obesity Study. J Occup Environ Med 2024; 66:542-547. [PMID: 38595273 DOI: 10.1097/jom.0000000000003111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2024]
Abstract
OBJECTIVES The purposes of this study were to assess the association between exposure to particulate matter (PM 2.5 ) and adolescent obesity and to identify and visualize the world areas where the problems of adolescent obesity and air pollution by fine PM are more severe. METHODS This is an ecological study, based on publicly available data from a World Health Organization site. RESULTS For each increase in air pollution there was an increase in the probability of being in the higher prevalence obesity group (OR = 1.18 (95% CI, 1.06-1.31). High prevalence rates for both adolescent obesity and air pollution by PM 2.5 were identified in several countries, including Venezuela, Algeria, Libya, Saudi Arabia, Iraq, and Oceania islands. CONCLUSIONS Efforts by local authorities and world organizations should be focused on the countries with the highest prevalence rates for both conditions.
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Affiliation(s)
- Yulia Treister-Goltzman
- From the Department of Family Medicine and Siaal Research Center for Family Practice and Primary Care, The Haim Doron Division of Community Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel (Y.T.-G.); and Clalit Health Services, Southern District, Beer-Sheva, Israel (Y.T.-G.)
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11
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Hezam AAM, Shaghdar HBM, Chen L. The connection between hypertension and diabetes and their role in heart and kidney disease development. JOURNAL OF RESEARCH IN MEDICAL SCIENCES : THE OFFICIAL JOURNAL OF ISFAHAN UNIVERSITY OF MEDICAL SCIENCES 2024; 29:22. [PMID: 38855561 PMCID: PMC11162087 DOI: 10.4103/jrms.jrms_470_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 11/24/2023] [Accepted: 01/25/2024] [Indexed: 06/11/2024]
Abstract
Hypertension and diabetes are two common metabolic disorders that often coexist in the same individual. Their concurrence increases the risk of cardiovascular disease, renal dysfunction, and other complications. Cardiovascular disease is the primary cause of morbidity and mortality in individuals with diabetes, and hypertension further aggravates this condition. Interestingly, hypertension and diabetes share several common pathophysiological mechanisms including insulin resistance, vascular inflammation, endothelial dysfunction, obesity, and oxidative stress suggesting a cross-talk between these two conditions that could potentially contribute to the development of other human diseases. Effective management of diabetes should include a multifaceted approach that addresses not only glycemic control but also blood pressure (BP) and lipid control. Treatment plans should be individualized to each patient's needs and should involve a combination of lifestyle modifications and medications to achieve optimal control. With the availability of newer antidiabetic medications such as SGLT inhibitors and GLP1 receptor agonists, it is crucial to consider their potential to reduce BP, enhance kidney function, and lower the risk of cardiovascular diseases when initiating treatment for glycemic control. A more profound comprehension of the shared underlying mechanisms between these conditions could pave the way for the development of innovative therapeutic approaches to tackle them. Our review offers an in-depth analysis of the literature, providing a holistic view of the mechanisms underlying diabetes-hypertension comorbidity and its implications on heart and kidney diseases. The present article concludes by discussing current approaches for managing hypertensive diabetic patients to create a set of comprehensive individualized recommendations.
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Affiliation(s)
- Ali Ahmed Mohammed Hezam
- Department of General Practice, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | | | - Liying Chen
- School of Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
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12
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Zhang X, Perry RJ. Metabolic underpinnings of cancer-related fatigue. Am J Physiol Endocrinol Metab 2024; 326:E290-E307. [PMID: 38294698 PMCID: PMC11901342 DOI: 10.1152/ajpendo.00378.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 01/23/2024] [Accepted: 01/23/2024] [Indexed: 02/01/2024]
Abstract
Cancer-related fatigue (CRF) is one of the most prevalent and detrimental complications of cancer. Emerging evidence suggests that obesity and insulin resistance are associated with CRF occurrence and severity in cancer patients and survivors. In this narrative review, we analyzed recent studies including both preclinical and clinical research on the relationship between obesity and/or insulin resistance and CRF. We also describe potential mechanisms for these relationships, though with the caveat that because the mechanisms underlying CRF are incompletely understood, the mechanisms mediating the association between obesity/insulin resistance and CRF are similarly incompletely delineated. The data suggest that, in addition to their effects to worsen CRF by directly promoting tumor growth and metastasis, obesity and insulin resistance may also contribute to CRF by inducing chronic inflammation, neuroendocrinological disturbance, and metabolic alterations. Furthermore, studies suggest that patients with obesity and insulin resistance experience more cancer-induced pain and are at more risk of emotional and behavioral disruptions correlated with CRF. However, other studies implied a potentially paradoxical impact of obesity and insulin resistance to reduce CRF symptoms. Despite the need for further investigation utilizing interventions to directly elucidate the mechanisms of cancer-related fatigue, current evidence demonstrates a correlation between obesity and/or insulin resistance and CRF, and suggests potential therapeutics for CRF by targeting obesity and/or obesity-related mediators.
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Affiliation(s)
- Xinyi Zhang
- Departments of Cellular & Molecular Physiology and Medicine (Endocrinology), Yale University School of Medicine, New Haven, Connecticut, United States
| | - Rachel J Perry
- Departments of Cellular & Molecular Physiology and Medicine (Endocrinology), Yale University School of Medicine, New Haven, Connecticut, United States
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13
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Romano A, Sollazzo F, Rivetti S, Morra L, Servidei T, Lucchetti D, Attinà G, Maurizi P, Mastrangelo S, Zovatto IC, Monti R, Bianco M, Palmieri V, Ruggiero A. Evaluation of Metabolic and Cardiovascular Risk Measured by Laboratory Biomarkers and Cardiopulmonary Exercise Test in Children and Adolescents Recovered from Brain Tumors: The CARMEP Study. Cancers (Basel) 2024; 16:324. [PMID: 38254811 PMCID: PMC10813808 DOI: 10.3390/cancers16020324] [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: 11/30/2023] [Revised: 12/21/2023] [Accepted: 01/09/2024] [Indexed: 01/24/2024] Open
Abstract
In recent decades, the improvement of treatments and the adoption of therapeutic protocols of international cooperation has led to an improvement in the survival of children affected by brain tumors. However, in parallel with the increase in survival, long-term side effects related to treatments have been observed over time, including the activation of chronic inflammatory processes and metabolic alterations, which can facilitate the onset of metabolic syndrome and increased cardiovascular risk. The aim of this study was to find possible statistically significant differences in the serum concentrations of early biomarkers of metabolic syndrome and in the results of cardiopulmonary exercise testing between survivors of childhood brain tumors and healthy controls. This is a prospective and observational study conducted on a group of 14 male patients who survived childhood brain tumors compared with the same number of healthy controls. The concentrations of early metabolic syndrome biomarkers [adiponectin, leptin, TNF-α, IL-1, IL-6, IL-10, endothelin-1, apolipoprotein B, and lipoprotein (a)] were measured and a cardiopulmonary exercise test (CPET) was performed. Results: Childhood brain tumor survivors performed worse on average than controls on the CPET. Furthermore, they showed higher endothelin-1 values than controls (p = 0.025). The CPET results showed an inverse correlation with leptin. The differences found highlight the greater cardiovascular risk of brain tumor survivors, and radiotherapy could be implicated in the genesis of this greater cardiovascular risk.
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Affiliation(s)
- Alberto Romano
- Pediatric Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (S.R.); (T.S.); (G.A.); (P.M.); (S.M.); (A.R.)
| | - Fabrizio Sollazzo
- Sports Medicine Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (F.S.); (L.M.); (I.C.Z.); (R.M.); (M.B.); (V.P.)
| | - Serena Rivetti
- Pediatric Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (S.R.); (T.S.); (G.A.); (P.M.); (S.M.); (A.R.)
| | - Lorenzo Morra
- Sports Medicine Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (F.S.); (L.M.); (I.C.Z.); (R.M.); (M.B.); (V.P.)
| | - Tiziana Servidei
- Pediatric Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (S.R.); (T.S.); (G.A.); (P.M.); (S.M.); (A.R.)
| | - Donatella Lucchetti
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy;
| | - Giorgio Attinà
- Pediatric Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (S.R.); (T.S.); (G.A.); (P.M.); (S.M.); (A.R.)
| | - Palma Maurizi
- Pediatric Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (S.R.); (T.S.); (G.A.); (P.M.); (S.M.); (A.R.)
- Department of Woman and Child Health and Public Health, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Stefano Mastrangelo
- Pediatric Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (S.R.); (T.S.); (G.A.); (P.M.); (S.M.); (A.R.)
- Department of Woman and Child Health and Public Health, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Isabella Carlotta Zovatto
- Sports Medicine Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (F.S.); (L.M.); (I.C.Z.); (R.M.); (M.B.); (V.P.)
| | - Riccardo Monti
- Sports Medicine Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (F.S.); (L.M.); (I.C.Z.); (R.M.); (M.B.); (V.P.)
| | - Massimiliano Bianco
- Sports Medicine Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (F.S.); (L.M.); (I.C.Z.); (R.M.); (M.B.); (V.P.)
| | - Vincenzo Palmieri
- Sports Medicine Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (F.S.); (L.M.); (I.C.Z.); (R.M.); (M.B.); (V.P.)
| | - Antonio Ruggiero
- Pediatric Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (S.R.); (T.S.); (G.A.); (P.M.); (S.M.); (A.R.)
- Department of Woman and Child Health and Public Health, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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14
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Sági B, Kun S, Jakabfi-Csepregi RK, Sulyok E, Csiky B. Acute Vascular Response to Hemodialysis as Measured by Serum Syndecan-1 and Endothelin-1 Levels as Well as Vascular Stiffness. J Clin Med 2023; 12:7384. [PMID: 38068435 PMCID: PMC10707344 DOI: 10.3390/jcm12237384] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 11/25/2023] [Accepted: 11/27/2023] [Indexed: 10/08/2024] Open
Abstract
Background: Chronic hemodialysis (HD) patients have a very high cardiovascular risk. Acute vascular changes during dialysis mediated by factors of the endothelium may have a crucial role in this. The aim of this article is to study the acute vascular changes during HD. Methods: In 29 consecutive chronic HD patients (age: 65.6 ± 10.4 years), their pre-, mid-, and post-HD plasma syndecan-1 (SDC-1) and endothelin-1 (ET-1) levels were measured. Applanation tonometry was performed before HD. Results: Their SDC-1 levels increased during HD (p = 0.004). Males had higher ET-1 levels. The patients were divided into two groups based on their pre-HD pulse wave velocity (PWV): PWV ≥ 12 m/s and PWV < 12 m/s. The pre-HD and mid-HD SDC-1 levels were higher in the group with a PWV ≥ 12 m/s (10.174 ± 2.568 vs. 7.928 ± 1.794 ng/mL, p = 0.013, and 10.319 ± 3.482 vs. 8.248 ± 1.793 ng/mL, p = 0.044, respectively). The post-HD ET-1 levels were higher in the patient group with a PWV ≥ 12 m/s (10.88 ± 3.00 vs. 8.05 ± 3.48 pg/l, p = 0.027). Patients with a PWV ≥ 12 m/s had higher pre-HD peripheral and aortic systolic blood pressures (p < 0.05). The total cholesterol correlated with the SDC-1 decrease during HD (r = 0.539; p = 0.008). The pre-, mid-, and post-HD SDC-1 correlated with ultrafiltration (r = 0.432, p = 0.019; r = 0.377, p = 0.044; and r = 0.401, p = 0.012, respectively). Conclusion: SDC-1 and ET-1 contribute to the vascular changes observed during HD, and they have correlations with some cardiovascular risk factors.
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Affiliation(s)
- Balázs Sági
- 2nd Department of Internal Medicine and Nephrology, Diabetes Center, Clinical Center, Medical School, University of Pécs, 7624 Pécs, Hungary; (B.S.)
- Fresenius Medical Care Dialysis Centers, 7624 Pécs, Hungary
| | - Szilárd Kun
- 2nd Department of Internal Medicine and Nephrology, Diabetes Center, Clinical Center, Medical School, University of Pécs, 7624 Pécs, Hungary; (B.S.)
| | | | - Endre Sulyok
- Doctoral School of Health Sciences, University of Pécs, 7624 Pécs, Hungary;
| | - Botond Csiky
- 2nd Department of Internal Medicine and Nephrology, Diabetes Center, Clinical Center, Medical School, University of Pécs, 7624 Pécs, Hungary; (B.S.)
- Fresenius Medical Care Dialysis Centers, 7624 Pécs, Hungary
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15
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Jain A, Jain I. ET-traps: Potential therapeutics for preeclampsia. Drug Discov Today 2023; 28:103787. [PMID: 37742912 DOI: 10.1016/j.drudis.2023.103787] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 09/05/2023] [Accepted: 09/19/2023] [Indexed: 09/26/2023]
Abstract
Elevated endothelin-1 (ET-1) has been implicated in several diseases including preeclampsia, where it causes the induction of hypertension, oxidative stress, endoplasmic reticulum stress, microvascular dysfunction and tissue damage in different organs. ET-traps are Fc-fusion proteins with a design based on the physiological receptors of ET-1. This paper discusses the potential use of ET-traps as a therapeutic for preeclampsia. ET-traps potently bind and sequester pathologically elevated ET-1 to significantly reduce different markers of pathology to non-disease levels with no toxicity.
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Affiliation(s)
- Arjun Jain
- ET-traps, Cambridge, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, UK; Accelerate Cambridge, Judge Business School, University of Cambridge, UK; Imperial College London, UK
| | - Ira Jain
- ET-traps, Cambridge, UK; Indian Institute of Management, Ahmedabad, India; National University of Singapore, Singapore.
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16
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Błaszkiewicz M, Walulik A, Florek K, Górecki I, Sławatyniec O, Gomułka K. Advances and Perspectives in Relation to the Molecular Basis of Diabetic Retinopathy-A Review. Biomedicines 2023; 11:2951. [PMID: 38001952 PMCID: PMC10669459 DOI: 10.3390/biomedicines11112951] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 10/26/2023] [Accepted: 10/27/2023] [Indexed: 11/26/2023] Open
Abstract
Diabetes mellitus (DM) is a growing problem nowadays, and diabetic retinopathy (DR) is its predominant complication. Currently, DR diagnosis primarily relies on fundoscopic examination; however, novel biomarkers may facilitate that process and make it widely available. In this current review, we delve into the intricate roles of various factors and mechanisms in DR development, progression, prediction, and their association with therapeutic approaches linked to the underlying pathogenic pathways. Specifically, we focus on advanced glycation end products, vascular endothelial growth factor (VEGF), asymmetric dimethylarginine, endothelin-1, and the epigenetic regulation mediated by microRNAs (miRNAs) in the context of DR.
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Affiliation(s)
- Michał Błaszkiewicz
- Student Scientific Group of Adult Allergology, Wroclaw Medical University, 50-369 Wroclaw, Poland
| | - Agata Walulik
- Student Scientific Group of Adult Allergology, Wroclaw Medical University, 50-369 Wroclaw, Poland
| | - Kamila Florek
- Student Scientific Group of Adult Allergology, Wroclaw Medical University, 50-369 Wroclaw, Poland
| | - Ignacy Górecki
- Student Scientific Group of Adult Allergology, Wroclaw Medical University, 50-369 Wroclaw, Poland
| | - Olga Sławatyniec
- Student Scientific Group of Adult Allergology, Wroclaw Medical University, 50-369 Wroclaw, Poland
| | - Krzysztof Gomułka
- Clinical Department of Internal Medicine, Pneumology and Allergology, Wroclaw Medical University, 50-369 Wroclaw, Poland
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17
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Lin WR, Liu KH, Ling TC, Wang MC, Lin WH. Role of antidiabetic agents in type 2 diabetes patients with chronic kidney disease. World J Diabetes 2023; 14:352-363. [PMID: 37122432 PMCID: PMC10130897 DOI: 10.4239/wjd.v14.i4.352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 01/10/2023] [Accepted: 04/04/2023] [Indexed: 04/12/2023] Open
Abstract
Insulin resistance is a condition in which the target tissues have a decreased response to insulin signaling, resulting in glucose uptake defect, and an increased blood sugar level. Pancreatic beta cells thus enhance insulin production to compensate. This situation may cause further beta cell dysfunction and failure, which can lead diabetes mellitus (DM). Insulin resistance is thus an important cause of the development of type 2 DM. Insulin resistance has also been found to have a strong relationship with cardiovascular disease and is common in chronic kidney disease (CKD) patients. The mechanisms of insulin resistance in CKD are complex and multifactorial. They include physical inactivity, inflammation and oxidative stress, metabolic acidosis, vitamin D deficiency, adipose tissue dysfunction, uremic toxins, and renin-angiotensin-aldosterone system activation. Currently, available anti-diabetic agents, such as biguanides, sulfonylureas, thiazolidinediones, alfa-glucosidase inhibitors, glucagon-like peptide-1-based agents, and sodium-glucose co-transporter-2 inhibitors, have different effects on insulin resistance. In this short review, we describe the potential mechanisms of insulin resistance in CKD patients. We also review the interaction of currently available anti-diabetic medications with insulin resistance.
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Affiliation(s)
- Wei-Ren Lin
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Kuan-Hung Liu
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Tsai-Chieh Ling
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Ming-Cheng Wang
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Wei-Hung Lin
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
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18
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Rivera-Gonzalez O, Case CT, Wilson NA, Speed JS, Taylor EB. Endothelin receptor antagonism improves glucose tolerance and adipose tissue inflammation in an experimental model of systemic lupus erythematosus. Am J Physiol Endocrinol Metab 2023; 324:E73-E84. [PMID: 36476039 PMCID: PMC9870584 DOI: 10.1152/ajpendo.00274.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/30/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022]
Abstract
Endothelin-1 (ET-1) is elevated in patients with systemic lupus erythematosus (SLE), an autoimmune disease characterized by high rates of hypertension, renal injury, and cardiovascular disease. SLE is also associated with an increased prevalence of obesity and insulin resistance compared to the general population. In the present study, we tested the hypothesis that elevated ET-1 in SLE contributes to obesity and insulin resistance. For these studies, we used the NZBWF1 mouse model of SLE, which develops obesity and insulin resistance on a normal chow diet. To test this hypothesis, we treated control (NZW) and SLE (NZBWF1) mice with vehicle, atrasentan (ETA receptor antagonist, 10 mg/kg/day), or bosentan (ETA/ETB receptor antagonist, 100 mg/kg/day) for 4 wk. Neither treatment impacted circulating immunoglobulin levels, but treatment with bosentan lowered anti-dsDNA IgG levels, a marker of SLE disease activity. Treatment with atrasentan and bosentan decreased glomerulosclerosis, and atrasentan lowered renal T-cell infiltration. Body weight was lower in SLE mice treated with atrasentan or bosentan. Endothelin receptor antagonism also improved hyperinsulinemia, homeostatic model assessment for insulin resistance, and glucose tolerance in SLE mice. Adipose tissue inflammation was also improved by endothelin receptor blockade. Taken together, these data suggest a potential therapeutic benefit for SLE patients with obesity and insulin resistance.NEW & NOTEWORTHY SLE is an autoimmune disease that is associated with obesity, insulin resistance, and elevated endothelin-1. The present study demonstrated that pharmacological inhibition of endothelin receptors decreased body weight, insulin resistance, and adipose tissue inflammation in a murine model of SLE. The therapeutic potential of endothelin receptor antagonists to treat obesity-related diseases and pathophysiological conditions, such as autoimmune diseases and insulin resistance, has become increasingly clear.
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Affiliation(s)
- Osvaldo Rivera-Gonzalez
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi
| | - Clinton T Case
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi
| | - Natalie A Wilson
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi
| | - Joshua S Speed
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi
| | - Erin B Taylor
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi
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Heimbürger SMN, Hoe B, Nielsen CN, Bergman NC, Skov-Jeppesen K, Hartmann B, Holst JJ, Dela F, Overgaard J, Størling J, Vilsbøll T, Dejgaard TF, Havelund JF, Gorshkov V, Kjeldsen F, Færgeman NJ, Madsen MR, Christensen MB, Knop FK. GIP Affects Hepatic Fat and Brown Adipose Tissue Thermogenesis but Not White Adipose Tissue Transcriptome in Type 1 Diabetes. J Clin Endocrinol Metab 2022; 107:3261-3274. [PMID: 36111559 DOI: 10.1210/clinem/dgac542] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Indexed: 02/13/2023]
Abstract
CONTEXT Glucose-dependent insulinotropic polypeptide (GIP) has been proposed to exert insulin-independent effects on lipid and bone metabolism. OBJECTIVE We investigated the effects of a 6-day subcutaneous GIP infusion on circulating lipids, white adipose tissue (WAT), brown adipose tissue (BAT), hepatic fat content, inflammatory markers, respiratory exchange ratio (RER), and bone homeostasis in patients with type 1 diabetes. METHODS In a randomized, placebo-controlled, double-blind, crossover study, 20 men with type 1 diabetes underwent a 6-day continuous subcutaneous infusion with GIP (6 pmol/kg/min) and placebo (saline), with an interposed 7-day washout period. RESULTS During GIP infusion, participants (26 ± 8 years [mean ± SD]; BMI 23.8 ± 1.8 kg/m2; glycated hemoglobin A1c 51 ± 10 mmol/mol [6.8 ± 3.1%]) experienced transiently increased circulating concentrations of nonesterified fatty acid (NEFA) (P = 0.0005), decreased RER (P = 0.009), indication of increased fatty acid β-oxidation, and decreased levels of the bone resorption marker C-terminal telopeptide (P = 0.000072) compared with placebo. After 6 days of GIP infusion, hepatic fat content was increased by 12.6% (P = 0.007) and supraclavicular skin temperature, a surrogate indicator of BAT activity, was increased by 0.29 °C (P < 0.000001) compared with placebo infusion. WAT transcriptomic profile as well as circulating lipid species, proteome, markers of inflammation, and bone homeostasis were unaffected. CONCLUSION Six days of subcutaneous GIP infusion in men with type 1 diabetes transiently decreased bone resorption and increased NEFA and β-oxidation. Further, hepatic fat content, and supraclavicular skin temperature were increased without affecting WAT transcriptomics, the circulating proteome, lipids, or inflammatory markers.
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Affiliation(s)
- Sebastian Møller Nguyen Heimbürger
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark
- Department of Clinical Research, Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark
- Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Department of Translational Pharmacology, Zealand Pharma A/S, 2860 Søborg, Denmark
| | - Bjørn Hoe
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Chris Neumann Nielsen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark
| | - Natasha Chidekel Bergman
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark
| | - Kirsa Skov-Jeppesen
- Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Bolette Hartmann
- Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Jens Juul Holst
- Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Flemming Dela
- Xlab, Center for Healthy Ageing, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Department of Geriatrics, Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen, Denmark
| | - Julie Overgaard
- Department of Clinical Research, Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark
| | - Joachim Størling
- Department of Clinical Research, Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark
- Department of Clinical Research, Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Thomas Fremming Dejgaard
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark
- Department of Clinical Research, Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark
| | - Jesper Foged Havelund
- Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark
| | - Vladimir Gorshkov
- Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark
| | - Frank Kjeldsen
- Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark
| | - Nils Joakim Færgeman
- Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark
| | | | - Mikkel B Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, 2400 Copenhagen, Denmark
- Copenhagen Center for Translational Research, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, 2400 Copenhagen, Denmark
| | - Filip Krag Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark
- Department of Clinical Research, Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark
- Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
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20
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Sujana C, Salomaa V, Kee F, Seissler J, Jousilahti P, Neville C, Then C, Koenig W, Kuulasmaa K, Reinikainen J, Blankenberg S, Zeller T, Herder C, Mansmann U, Peters A, Thorand B. Associations of the vasoactive peptides CT-proET-1 and MR-proADM with incident type 2 diabetes: results from the BiomarCaRE Consortium. Cardiovasc Diabetol 2022; 21:99. [PMID: 35681200 PMCID: PMC9185875 DOI: 10.1186/s12933-022-01513-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 04/28/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Endothelin-1 (ET-1) and adrenomedullin (ADM) are commonly known as vasoactive peptides that regulate vascular homeostasis. Less recognised is the fact that both peptides could affect glucose metabolism. Here, we investigated whether ET-1 and ADM, measured as C-terminal-proET-1 (CT-proET-1) and mid-regional-proADM (MR-proADM), respectively, were associated with incident type 2 diabetes. METHODS Based on the population-based Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium data, we performed a prospective cohort study to examine associations of CT-proET-1 and MR-proADM with incident type 2 diabetes in 12,006 participants. During a median follow-up time of 13.8 years, 862 participants developed type 2 diabetes. The associations were examined in Cox proportional hazard models. Additionally, we performed two-sample Mendelian randomisation analyses using published data. RESULTS CT-proET-1 and MR-proADM were positively associated with incident type 2 diabetes. The multivariable hazard ratios (HRs) [95% confidence intervals (CI)] were 1.10 [1.03; 1.18], P = 0.008 per 1-SD increase of CT-proET-1 and 1.11 [1.02; 1.21], P = 0.016 per 1-SD increase of log MR-proADM, respectively. We observed a stronger association of MR-proADM with incident type 2 diabetes in obese than in non-obese individuals (P-interaction with BMI < 0.001). The HRs [95%CIs] were 1.19 [1.05; 1.34], P = 0.005 and 1.02 [0.90; 1.15], P = 0.741 in obese and non-obese individuals, respectively. Our Mendelian randomisation analyses yielded a significant association of CT-proET-1, but not of MR-proADM with type 2 diabetes risk. CONCLUSIONS Higher concentrations of CT-proET-1 and MR-proADM are associated with incident type 2 diabetes, but our Mendelian randomisation analysis suggests a probable causal link for CT-proET-1 only. The association of MR-proADM seems to be modified by body composition.
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Affiliation(s)
- Chaterina Sujana
- Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany
- Institute for Medical Information Processing, Biometry, and Epidemiology (IBE), Pettenkofer School of Public Health, Ludwig-Maximilians-Universität München, Munich, Germany
- German Center for Diabetes Research (DZD), Partner München-Neuherberg, Neuherberg, Germany
| | - Veikko Salomaa
- Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Frank Kee
- Centre for Public Health, Queens University of Belfast, Belfast, Northern Ireland, UK
| | - Jochen Seissler
- Diabetes Zentrum, Medizinische Klinik Und Poliklinik IV, Klinikum Der Ludwig-Maximilians-Universität München, Munich, Germany
| | - Pekka Jousilahti
- Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Charlotte Neville
- Centre for Public Health, Queens University of Belfast, Belfast, Northern Ireland, UK
| | - Cornelia Then
- Diabetes Zentrum, Medizinische Klinik Und Poliklinik IV, Klinikum Der Ludwig-Maximilians-Universität München, Munich, Germany
| | - Wolfgang Koenig
- Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany
- Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
- German Centre for Cardiovascular Research (DZHK E.V.), Partner Site Munich Heart Alliance, Munich, Germany
| | - Kari Kuulasmaa
- Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Jaakko Reinikainen
- Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Stefan Blankenberg
- Department for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
- German Centre for Cardiovascular Research (DZHK E.V.), Partner site Hamburg, Lübeck, Kiel, Hamburg, Germany
| | - Tanja Zeller
- Department for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
- German Centre for Cardiovascular Research (DZHK E.V.), Partner site Hamburg, Lübeck, Kiel, Hamburg, Germany
| | - Christian Herder
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
- Division of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Ulrich Mansmann
- Institute for Medical Information Processing, Biometry, and Epidemiology (IBE), Pettenkofer School of Public Health, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Annette Peters
- Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Partner München-Neuherberg, Neuherberg, Germany
- German Centre for Cardiovascular Research (DZHK E.V.), Partner Site Munich Heart Alliance, Munich, Germany
| | - Barbara Thorand
- Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany.
- German Center for Diabetes Research (DZD), Partner München-Neuherberg, Neuherberg, Germany.
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21
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Derella CC, Blanks AM, Nguyen A, Looney J, Tucker MA, Jeong J, Rodriguez-Miguelez P, Thomas J, Lyon M, Pollock DM, Harris RA. Dual endothelin receptor antagonism increases resting energy expenditure in people with increased adiposity. Am J Physiol Endocrinol Metab 2022; 322:E508-E516. [PMID: 35373585 PMCID: PMC9126219 DOI: 10.1152/ajpendo.00349.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 03/22/2022] [Accepted: 03/29/2022] [Indexed: 01/18/2023]
Abstract
Increased adiposity is associated with dysregulation of the endothelin system, both of which increase the risk of cardiovascular disease (CVD). Preclinical data indicate that endothelin dysregulation also reduces resting energy expenditure (REE). The objective was to test the hypothesis that endothelin receptor antagonism will increase REE in people with obesity compared with healthy weight individuals. Using a double blind, placebo-controlled, crossover design, 32 participants [healthy weight (HW): n = 16, BMI: 21.3 ± 2.8 kg/m2, age: 26 ± 7 yr and overweight/obese (OB): n = 16, BMI: 33.5 ± 9.5 kg/m2, age: 31 ± 6 yr] were randomized to receive either 125 mg of bosentan (ETA/B antagonism) or placebo twice per day for 3 days. Breath-by-breath gas exchange data were collected and REE was assessed by indirect calorimetry. Venous blood samples were analyzed for concentrations of endothelin-1 (ET-1). Treatment with bosentan increased plasma ET-1 in both OB and HW groups. Within the OB group, the changes in absolute REE (PLA: -77.6 ± 127.6 vs. BOS: 72.2 ± 146.6 kcal/day; P = 0.046). The change in REE was not different following either treatment in the HW group. Overall, absolute plasma concentrations of ET-1 following treatment with bosentan were significantly associated with kcal/day of fat (r = 0.488, P = 0.005), percentage of fat utilization (r = 0.415, P = 0.020), and inversely associated with the percentage of carbohydrates (r = -0.419, P = 0.019), and respiratory exchange ratio (r = -0.407, P = 0.023). Taken together, these results suggest that modulation of the endothelin system may represent a novel therapeutic approach to increase both resting metabolism and caloric expenditure, and reduce CVD risk in people with increased adiposity.NEW & NOTEWORTHY Findings from our current translational investigation demonstrate that dual endothelin A/B receptor antagonism increases total REE in overweight/obese individuals. These results suggest that modulation of the endothelin system may represent a novel therapeutic target to increase both resting metabolism and caloric expenditure, enhance weight loss, and reduce CVD risk in seemingly healthy individuals with elevated adiposity.
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Affiliation(s)
- Cassandra C Derella
- Department of Medicine, Georgia Prevention Institute, Augusta University, Augusta, Georgia
| | - Anson M Blanks
- Department of Medicine, Georgia Prevention Institute, Augusta University, Augusta, Georgia
| | - Andy Nguyen
- Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Jacob Looney
- Department of Medicine, Georgia Prevention Institute, Augusta University, Augusta, Georgia
| | - Matthew A Tucker
- Department of Medicine, Georgia Prevention Institute, Augusta University, Augusta, Georgia
| | - Jinhee Jeong
- Department of Medicine, Georgia Prevention Institute, Augusta University, Augusta, Georgia
| | - Paula Rodriguez-Miguelez
- Department of Medicine, Georgia Prevention Institute, Augusta University, Augusta, Georgia
- Department of Kinesiology and Health Sciences, Virginia Commonwealth University, Richmond, Virginia
| | - Jeffrey Thomas
- Department of Medicine, Georgia Prevention Institute, Augusta University, Augusta, Georgia
| | - Matthew Lyon
- Medical College of Georgia, Augusta University, Augusta, Georgia
| | - David M Pollock
- Cardio-Renal Physiology and Medicine Section, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Ryan A Harris
- Department of Medicine, Georgia Prevention Institute, Augusta University, Augusta, Georgia
- Sport and Exercise Science Research Institute, Ulster University, Jordanstown, United Kingdom
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22
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Proteostasis Response to Protein Misfolding in Controlled Hypertension. Cells 2022; 11:cells11101686. [PMID: 35626723 PMCID: PMC9139827 DOI: 10.3390/cells11101686] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 05/14/2022] [Accepted: 05/16/2022] [Indexed: 12/04/2022] Open
Abstract
Hypertension is the most determinant risk factor for cardiovascular diseases. Early intervention and future therapies targeting hypertension mechanisms may improve the quality of life and clinical outcomes. Hypertension has a complex multifactorial aetiology and was recently associated with protein homeostasis (proteostasis). This work aimed to characterize proteostasis in easy-to-access plasma samples from 40 individuals, 20 with controlled hypertension and 20 age- and gender-matched normotensive individuals. Proteostasis was evaluated by quantifying the levels of protein aggregates through different techniques, including fluorescent probes, slot blot immunoassays and Fourier-transform infrared spectroscopy (FTIR). No significant between-group differences were observed in the absolute levels of various protein aggregates (Proteostat or Thioflavin T-stained aggregates; prefibrillar oligomers and fibrils) or total levels of proteostasis-related proteins (Ubiquitin and Clusterin). However, significant positive associations between Endothelin 1 and protein aggregation or proteostasis biomarkers (such as fibrils and ubiquitin) were only observed in the hypertension group. The same is true for the association between the proteins involved in quality control and protein aggregates. These results suggest that proteostasis mechanisms are actively engaged in hypertension as a coping mechanism to counteract its pathological effects in proteome stability, even when individuals are chronically medicated and presenting controlled blood pressure levels.
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23
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Li Y, Lu H, Sun Y. Correlation of NO and ET-1 Levels with Blood Pressure Changes in Hemodialysis Patients after Arteriovenous Fistula Surgery. Front Surg 2022; 9:905372. [PMID: 35651688 PMCID: PMC9149304 DOI: 10.3389/fsurg.2022.905372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 04/15/2022] [Indexed: 11/13/2022] Open
Abstract
Hemodialysis (HD) is the most common renal replacement therapy for patients with end-stage renal disease (ESRD) and can significantly reduce mortality and improve the quality of life of patients. The occurrence of intradialytic hypotension and intradialytic hypertension are important risk factors for death and disability during dialysis in patients with ESRD, yet their etiology remains unclear, and some studies suggest that nitric oxide (NO) and endothelin-1 (ET-1) may play an important role in these hemodynamic alterations. For this purpose we examined the changes in NO and ET-1 levels during hemodialysis in 30 patients on maintenance hemodialysis (MHD) after arteriovenous fistula surgery. Thirty dialysis patients were divided into group I (stable blood pressure during dialysis), group II (Intradialytic hypotension) and group III (Intradialytic hypertension) according to the change of blood pressure (BP) during hemodialysis, with 10 cases in each group. BP of MHD patients were measured Pre-dialysis (Pre-D), at 1 h of dialysis (1h-D), at 2 h of dialysis (Mid-D, 2h-D), at 3 h of dialysis (3h-D), and at the end of dialysis (Post-D); and blood samples were taken from the arterial end at Pre-D, Mid-D, and Post-D to measure NO and ET-1 levels. The results of the analysis showed that as dialysis proceeded and ended, the NO levels in the three groups gradually decreased, with significant differences compared with those before dialysis (p < 0.05); the ET-1 levels in group III gradually increased, with significant differences compared with those before dialysis (p < 0.05), while the increasing trend of ET-1 levels in group I and group II was not significant. The increasing trend of MAP in group I was not significant (p > 0.05); MAP in group II showed a gradual decrease and MAP in group III showed an increasing trend, and the difference between MAP after dialysis and before dialysis was significant (p < 0.05). Correlation analysis showed a significant positive correlation between ET-1 levels and MAP in Group III at Mid-D (r = 0.847, p = 0.002). This shows that serum ET-1 and NO levels are significantly higher than normal in MHD patients after arteriovenous endovascular fistula surgery, and both ET-1 and NO levels are changing during dialysis, and there may be a link between their changes and blood pressure changes. It is suggested that the blood pressure fluctuations that occur during dialysis in MHD patients may be related to endothelial cell dysfunction.
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Effect of Resistance Exercise on the Lipolysis Pathway in Obese Pre- and Postmenopausal Women. J Pers Med 2021; 11:jpm11090874. [PMID: 34575649 PMCID: PMC8471631 DOI: 10.3390/jpm11090874] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 08/27/2021] [Accepted: 08/28/2021] [Indexed: 11/24/2022] Open
Abstract
Physical exercise may stimulate lipolytic activity within adipose tissue. Furthermore, resistance exercise may contribute to the more efficient reduction in adipose tissue mass and prevent the accumulation thereof in obese women. The purpose of this study was to examine the effects of regular resistance exercise for 12 weeks on the lipolysis pathway in women with obesity. Twenty-three pre- and postmenopausal women with body fat percentages of 30% or more were divided into the premenopausal group (n = 9) and the postmenopausal group (n = 14). All subjects participated in resistance exercise training for 12 weeks. Anthropometric and physical fitness tests were performed on all participants. Protein analyses were performed on extracted subcutaneous fatty tissue, and changes in the relevant protein levels in the samples were analyzed by Western blotting. All serum samples were submitted for enzyme-linked immunosorbent assay measurements of adipocyte factors. After 12 weeks, the adipose triglyceride lipase, monoacylglycerol lipase, and perilipin1 protein levels were significantly lower in the postmenopausal group than in the premenopausal group. The hormone-sensitive lipase protein levels were significantly higher in the postmenopausal group than in the premenopausal group. In addition, leptin concentrations were significantly decreased after resistance exercise in the postmenopausal group. Adiponectin concentrations were significantly increased after resistance exercise in both groups. These findings indicate that regular resistance exercise is effective in reducing the weight and body fat of obese premenopausal women, and in the secretion of adiponectin. On the other hand, postmenopausal women were found to have redeced weight and body fat, and were found to be positive for the secretion of adipokine factors. In addition, positive changes in lipolysis pathway factors in adipose tissue promote lipid degradation and reduce fat mass. Thus, regular resistance exercise shows positive changes in the lipolysis pathway more effectively in weight and body fat reduction in postmenopausal women than in premenopausal women.
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Guo X, Zhu Y, Li X, Lu Z, Cao Z, Yi X, Zhu X. Increased insulin resistance is associated with vascular cognitive impairment in Chinese patients with cerebral small vessel disease. Psychogeriatrics 2021; 21:342-349. [PMID: 33641231 DOI: 10.1111/psyg.12675] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/30/2021] [Accepted: 02/14/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND The aim of this study was to investigate the association between insulin resistance (IR) and vascular cognitive impairment (VCI) in patients with cerebral small vessel disease (CSVD). METHODS A total of 275 CSVD patients were enrolled in this retrospective case-control study. The homeostatic model assessment of insulin resistance (HOMA-IR) was used to measure the index of insulin resistance. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Spearman's correlation coefficient was used to evaluate the correlation between HOMA-IR and MoCA score. The variance inflation factor (VIF) was used to detect collinearity between variables. Multivariate logistic regression analysis was employed to confirm whether HOMA-IR is an independent risk factor for VCI in CVSD. Finally, receiver operating characteristic (ROC) curve analysis was conducted to assess the diagnostic value of HOMA-IR in VCI. RESULTS Of the 275 patients, 164 displayed VCI. VCI patients showed a significantly higher level of HOMA-IR compared to non-VCI patients (P < 0.001). HOMA-IR was negatively correlated with the MoCA score (r = -0.593, P < 0.001). After adjusting for potential confounding variables, using HOMA-IR quartile 1 (<1.11) as the reference, HOMA-IR quartile 3 (1.71-2.50) and quartile 4 (≥2.50) were independently associated with the occurrence of VCI; for each one unit increase in the HOMA-IR, the risk of VCI increased by 177.3% (odds ratio 2.773, 95% confidence interval: 1.050-7.324, P = 0.040) and 444.3% (odds ratio 5.443, 95% confidence interval: 2.109-14.050, P < 0.001), respectively. According to the ROC curve, the optimal cut-off point of HOMA-IR in predicting VCI was 1.55, and the area under the curve was 0.744, with a sensitivity of 71.3% and a specificity of 69.4%. CONCLUSION This study demonstrated that increased IR is significantly associated with VCI in CSVD patients.
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Affiliation(s)
- Xiaoming Guo
- Department of Neurology, Second Affiliated Hospital of Nantong University, Nantong, China
| | - Yuting Zhu
- Department of Neurology, Second Affiliated Hospital of Nantong University, Nantong, China
| | - Xinling Li
- Department of Neurology, Second Affiliated Hospital of Nantong University, Nantong, China
| | - Zhenhui Lu
- Department of Neurology, Second Affiliated Hospital of Nantong University, Nantong, China
| | - Zhiyong Cao
- Department of Neurology, Second Affiliated Hospital of Nantong University, Nantong, China
| | - Xiaoyi Yi
- Department of Neurology, Second Affiliated Hospital of Nantong University, Nantong, China
| | - Xiangyang Zhu
- Department of Neurology, Second Affiliated Hospital of Nantong University, Nantong, China
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Feng L, Wang S, Chen F, Zhang C, Wang Q, Zhao Y, Zhang Z. Hepatic Knockdown of Endothelin Type A Receptor (ETAR) Ameliorates Hepatic Insulin Resistance and Hyperglycemia Through Suppressing p66Shc-Mediated Mitochondrial Fragmentation in High-Fat Diet-Fed Mice. Diabetes Metab Syndr Obes 2021; 14:963-981. [PMID: 33688230 PMCID: PMC7936928 DOI: 10.2147/dmso.s299570] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 02/23/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Emerging evidence from animal studies and clinical trials indicates that systemic inhibition of endothelin1 (ET1) signaling by endothelin receptor antagonists improves pathological features of diabetes and its complications. It is indicated that endothelin type A receptor (ETAR) plays a major role in ET1-mediated pathophysiological actions including diabetic pathology. However, the effects as well as the mechanistic targets of hepatic ET1/ETAR signaling inhibition on the pathology of metabolic diseases remain unclear. This study aimed to investigate the beneficial effects as well as the underlying mechanisms of hepatic ETAR knockdown on metabolism abnormalities in high-fat diet (HFD)-fed mice. METHODS Mice were fed a HFD to induce insulin resistance and metabolism abnormalities. L02 cells were treated with ET1 to assess the action of ET1/ETAR signaling in vitro. Liver-selective knockdown of ETAR was achieved by tail vein injection of adeno-associated virus 8 (AAV8). Systemic and peripheral metabolism abnormalities were determined in vivo and in vitro. Mitochondrial fragmentation was observed by transmission electron microscope (TEM) and mitoTracker red staining. RESULTS Here we provided in vivo and in vitro evidence to demonstrate that liver-selective knockdown of ETAR effectively ameliorated hepatic insulin resistance and hyperglycemia in HFD-fed mice. Mechanistically, hepatic ETAR knockdown alleviated mitochondrial fragmentation and dysfunction via inactivating 66-kDa Src homology 2 domain-containing protein (p66Shc) to recover mitochondrial dynamics, which was mediated by inhibiting protein kinase Cδ (PKCδ), in the livers of HFD-fed mice. Ultimately, hepatic ETAR knockdown attenuated mitochondria-derived oxidative stress and related liver injuries in HFD-fed mice. These ETAR knockdown-mediated actions were confirmed in ET1-treated L02 cells. CONCLUSION This study defined an ameliorative role of hepatic ETAR knockdown in HFD-induced metabolism abnormalities by alleviating p66Shc-mediated mitochondrial fragmentation and consequent oxidative stress-related disorders and indicated that hepatic ETAR knockdown may be a promising therapeutic strategy for metabolic diseases.
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Affiliation(s)
- Li Feng
- School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People’s Republic of China
| | - Songhua Wang
- School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People’s Republic of China
| | - Feng Chen
- School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People’s Republic of China
| | - Cheng Zhang
- School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People’s Republic of China
| | - Qiao Wang
- School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People’s Republic of China
| | - Yuting Zhao
- School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People’s Republic of China
| | - Zifeng Zhang
- School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People’s Republic of China
- Correspondence: Zifeng Zhang 101 Shanghai Road, Xuzhou, Jiangsu Province, 221116, People’s Republic of ChinaTel + 86 516 83403729 Email
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Liu R, Guan S, Gao Z, Wang J, Xu J, Hao Z, Zhang Y, Yang S, Guo Z, Yang J, Shao H, Chang B. Pathological Hyperinsulinemia and Hyperglycemia in the Impaired Glucose Tolerance Stage Mediate Endothelial Dysfunction Through miR-21, PTEN/AKT/eNOS, and MARK/ET-1 Pathways. Front Endocrinol (Lausanne) 2021; 12:644159. [PMID: 33967958 PMCID: PMC8104127 DOI: 10.3389/fendo.2021.644159] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 04/06/2021] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Impaired glucose tolerance (IGT) is an important prediabetic stage characterized by elevated concentrations of glucose and insulin in the blood. The pathological hyperglycemia and hyperinsulinemia in IGT may regulate the expression of microRNA-21 (miR-21) and affect the downstream insulin signaling pathways, leading to endothelial cell dysfunction and early renal damage. METHODS The individual and combined effects of insulin and glucose were investigated using human glomerular endothelial cells (HGECs). The expression levels of miR-21, and PTEN/AKT/eNOS and MAPK/ET-1 pathway proteins in the treated cells were measured. The levels of nitric oxide (NO) and endothelin-1 (ET-1) secreted by the cells were also measured. The role of miR-21 in mediating the regulatory effects of insulin and glucose was assessed by overexpression/inhibition of this miRNA using mimics/inhibitor. RESULTS High (>16.7 mmol/L) concentration of glucose upregulated the expression of miR-21, leading to the activation and inhibition of the PTEN/AKT/eNOS and MAPK/ET-1 pathways, and upregulation of NO and downregulation of ET-1 secretion, respectively. High (>25 ng/mL) concentration of insulin downregulated the expression of miR-21, and lead to the activation of the MAPK/ET-1 and inhibition of the PTEN/AKT/eNOS pathway, thereby upregulating the expression of ET-1 and downregulating the secretion of NO. MiR-21 was observed to play a key role by directly controlling the activation of the insulin signaling pathways when the cells were cotreated with different concentrations of insulin and glucose. The expression of miR-21 was found to be dependent on the relative concentration of insulin and glucose. Under simulated conditions of the IGT stage (8.3 mmol/L glucose + 50 ng/mL insulin), the inhibitory effect of high insulin concentration on miR-21 expression in the cells attenuated the activation by high glucose concentration, resulting in the downregulation of miR-21, upregulation of ET-1 and downregulation of NO secretion. CONCLUSION Taken together, these results indicate that high insulin and glucose concentrations regulate the secretory function of glomerular endothelial cells in opposite ways by regulating the expression of miRNA-21. Pathological concentrations of insulin and glucose in the IGT stage may lead to a decrease in miR-21 expression, thereby disordering the secretion of vasoactive factors, resulting in renal tubule ischemia.
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Affiliation(s)
- Ran Liu
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Disease, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
- Tianjin Fourth Central Hospital, The Fourth Central Hospital Affiliated to Nankai University, The Fourth Central Clinical College, Tianjin Medical University, Tianjin, China
| | - Shilin Guan
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Disease, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Zhongai Gao
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Disease, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Jingyu Wang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Disease, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Jie Xu
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Disease, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Zhaohu Hao
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Disease, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
- Tianjin Fourth Central Hospital, The Fourth Central Hospital Affiliated to Nankai University, The Fourth Central Clinical College, Tianjin Medical University, Tianjin, China
| | - Yi Zhang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Disease, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Shaohua Yang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Disease, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Zhenhong Guo
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Disease, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Juhong Yang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Disease, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Hailin Shao
- Tianjin Fourth Central Hospital, The Fourth Central Hospital Affiliated to Nankai University, The Fourth Central Clinical College, Tianjin Medical University, Tianjin, China
- *Correspondence: Hailin Shao, ; Baocheng Chang,
| | - Baocheng Chang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Disease, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
- *Correspondence: Hailin Shao, ; Baocheng Chang,
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