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Kundu S, Gairola S, Verma S, Mugale MN, Sahu BD. Chronic kidney disease activates the HDAC6-inflammatory axis in the heart and contributes to myocardial remodeling in mice: inhibition of HDAC6 alleviates chronic kidney disease-induced myocardial remodeling. Basic Res Cardiol 2024; 119:831-852. [PMID: 38771318 DOI: 10.1007/s00395-024-01056-y] [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: 01/02/2024] [Revised: 05/11/2024] [Accepted: 05/11/2024] [Indexed: 05/22/2024]
Abstract
Chronic kidney disease (CKD) adversely affects the heart. The underlying mechanism and the interplay between the kidney and the heart are still obscure. We examined the cardiac effect using the unilateral ureteral obstruction (UUO)-induced CKD pre-clinical model in mice. Echocardiography, histopathology of the heart, myocardial mRNA expression of ANP and BNP, the extent of fibrotic (TGF-β, α-SMA, and collagen I) and epigenetic (histone deacetylases, namely HDAC3, HDAC4, and HDAC6) proteins, and myocardial inflammatory response were assessed. Six weeks of post-UUO surgery, we observed a compromised left-ventricular wall thickness and signs of cardiac hypertrophy, accumulation of fibrosis associated, and inflammatory proteins in the heart. In addition, we observed a perturbation of epigenetic proteins, especially HDAC3, HDAC4, and HDAC6, in the heart. Pharmacological inhibition of HDAC6 using ricolinostat (RIC) lessened cardiac damage and improved left-ventricular wall thickness. The RIC treatment substantially restored the serum cardiac injury markers, namely creatine kinase-MB and lactate dehydrogenase (LDH) activities, ANP and BNP mRNA expression, and heart histological changes. The extent of myocardial fibrotic proteins, phospho-NF-κB (p65), and pro-inflammatory cytokines (TNF-α, IL-18, and IL-1β) were significantly decreased in the RIC treatment group. Further findings revealed the CKD-induced infiltration of CD3, CD8a, CD11c, and F4/80 positive inflammatory cells in the heart. Treatment with RIC substantially reduced the myocardial infiltration of these inflammatory cells. From these findings, we believe that CKD-induced myocardial HDAC6 perturbation has a deteriorative effect on the heart, and inhibition of HDAC6 can be a promising approach to alleviate CKD-induced myocardial remodeling.
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Affiliation(s)
- Sourav Kundu
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, Assam, 781101, India
| | - Shobhit Gairola
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, Assam, 781101, India
| | - Smriti Verma
- Department of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226 031, India
| | - Madhav Nilakanth Mugale
- Department of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226 031, India
| | - Bidya Dhar Sahu
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, Assam, 781101, India.
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Xu Z, Tang J, Xin Chen, Jin Y, Zhang H, Liang R. Associations of C-reactive protein-albumin-lymphocyte (CALLY) index with cardiorenal syndrome: Insights from a population-based study. Heliyon 2024; 10:e37197. [PMID: 39296012 PMCID: PMC11408039 DOI: 10.1016/j.heliyon.2024.e37197] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/24/2024] [Accepted: 08/29/2024] [Indexed: 09/21/2024] Open
Abstract
Background Cardiorenal syndrome (CRS) is a complex condition characterized by the interplay of immune imbalance and inflammation. The C-reactive protein-Albumin-lymphocyte (CALLY) CALLY index serves as a new immune-nutritional scoring system, but its predictive value for CRS remains to be established. Methods In this study, we analyzed data from 27,978 participants in National Health and Nutrition Examination Survey (NHANES) from 1999 to 2010. The CALLY index was calculated as the ratio of albumin to lymphocyte, divided by C-reactive protein (CRP) multiplied by 104. CRS was defined by the coexistence of cardiovascular disease and chronic kidney disease (eGFR <60 mL/min/1.73 m2). Multivariate weighted logistic regression models were employed to determine the odds ratio and 95 % confidence interval for the association between the CALLY index and CRS. Receiver operating characteristic (ROC) curves and restricted cubic spline (RCS) curves were used to assess the predictive efficacy and nonlinear relationship, respectively. Results The prevalence of CRS in the study population was 1.22 %. Our findings revealed a significant inverse relationship between the CALLY index and CRS risk, with lower CALLY index values being associated with a higher likelihood of CRS (OR = 0.95, 95 % CI = 0.94-0.96, P < 0.001). Participants in higher quartiles of the CALLY index showed a progressively reduced risk of CRS (P for trend <0.001). Moreover, the CALLY index demonstrated superior predictive performance compared to other inflammatory indicators, such as systemic immune-inflammation index (SII), neutrophil/high-density lipoprotein ratio (NHR), lymphocyte/high-density lipoprotein ratio (LHR), monocyte/high-density lipoprotein ratio (MHR), and platelet/high-density lipoprotein ratio (PHR) (AUC = 0.672, 95 % CI = 0.643-0.701). Conclusions This study underscores the significant negative correlation between the CALLY index and the risk of cardiorenal syndrome. The CALLY index emerges as a robust and independent predictor of CRS, outperforming traditional inflammatory markers. This finding highlights the potential utility of the CALLY index as a clinical tool for identifying individuals at risk for CRS.
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Affiliation(s)
- Zhehao Xu
- Department of General Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, China
| | - Jiao Tang
- Department of Cardiovascular Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, China
| | - Xin Chen
- Department of Cardiovascular Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, China
| | - Yian Jin
- Department of General Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, China
| | - Huanji Zhang
- Department of Cardiovascular Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, China
| | - Ruiyun Liang
- Department of Respiratory Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, China
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Marchiori GN, Defagó MD, Baraquet ML, Del Rosso S, Perovic NR, Soria EA. Interleukin-6, tumor necrosis factor-α, and high-sensitivity C-reactive protein for optimal immunometabolic profiling of the lifestyle-related cardiorenal risk. Diagnosis (Berl) 2024; 11:82-90. [PMID: 38154057 DOI: 10.1515/dx-2023-0159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 12/07/2023] [Indexed: 12/30/2023]
Abstract
OBJECTIVES The present study aimed to identify optimal inflammatory biomarkers involved in cardiorenal risk in response to major lifestyle factors. METHODS One hundred and twenty-nine adults aged 35-77 years participated voluntarily from 2017 to 2019 (Córdoba, Argentina) in a cross-sectional study to collect sociodemographic, clinical, and lifestyle data. Blood biomarkers (different cytokines, monocyte chemoattractant protein-1 [MCP-1], and high-sensitivity C-reactive protein [hs-CRP]) were measured using standard methods and then evaluated by principal component analysis and structural equation modeling (SEM) according to Mediterranean diet adherence, physical activity level, and waist circumference, while cardiorenal risk involved blood diastolic pressure, HDL-cholesterol, triacylglycerols, creatinine, and glycosylated hemoglobin. RESULTS A principal component included TNF-α (tumor necrosis factor-alpha), IL-8 (interleukin-8), IL-6 (interleukin-6), hs-CRP, and MCP-1, with absolute rotated factor loadings >0.10. SEM showed that IL-6 (β=0.38, 95 % IC=0.08-0.68), hs-CRP (β=0.33, 95 % IC=0.17-0.48), and TNF-α (β=0.22, 95 % IC=0.11-0.32) were the mediators that better explained an inflammatory profile positively related to waist circumference (β=0.77, 95 % IC=0.61-0.94). Moreover, this profile was associated with an increased cardiorenal risk (β=0.78, 95 % IC=0.61-0.94), which was well-defined by the variable used. CONCLUSIONS Immune mediators are key elements in profiling the cardiorenal risk associated with lifestyle factors, for which the combination of hs-CRP, IL-6, and TNF-α has emerged as a robust indicator. This work reaffirms the need for biomarker optimization for early diagnosis and risk assessment.
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Affiliation(s)
- Georgina Noel Marchiori
- Universidad Nacional de Córdoba, Facultad de Ciencias Médicas, Escuela de Nutrición, Centro de Investigaciones en Nutrición Humana (CenINH), Córdoba, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, INICSA, Córdoba, Argentina
| | - María Daniela Defagó
- Universidad Nacional de Córdoba, Facultad de Ciencias Médicas, Escuela de Nutrición, Centro de Investigaciones en Nutrición Humana (CenINH), Córdoba, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, INICSA, Córdoba, Argentina
| | - María Lucía Baraquet
- Universidad Nacional de Córdoba, Facultad de Ciencias Médicas, Escuela de Nutrición, Centro de Investigaciones en Nutrición Humana (CenINH), Córdoba, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, INICSA, Córdoba, Argentina
| | - Sebastián Del Rosso
- Universidad Nacional de Córdoba, Facultad de Ciencias Químicas, Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Córdoba, Argentina
| | - Nilda Raquel Perovic
- Universidad Nacional de Córdoba, Facultad de Ciencias Médicas, Escuela de Nutrición, Centro de Investigaciones en Nutrición Humana (CenINH), Córdoba, Argentina
| | - Elio Andrés Soria
- Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, INICSA, Córdoba, Argentina
- Universidad Nacional de Córdoba, Facultad de Ciencias Médicas, Cátedra de Biología Celular, Histología y Embriología, Instituto de Biología Celular, Córdoba, Argentina
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Wu HHL, Rakisheva A, Ponnusamy A, Chinnadurai R. Hepatocardiorenal syndrome in liver cirrhosis: Recognition of a new entity? World J Gastroenterol 2024; 30:128-136. [PMID: 38312119 PMCID: PMC10835518 DOI: 10.3748/wjg.v30.i2.128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/05/2023] [Accepted: 12/28/2023] [Indexed: 01/12/2024] Open
Abstract
Emerging evidence and perspectives have pointed towards the heart playing an important role in hepatorenal syndrome (HRS), outside of conventional understanding that liver cirrhosis is traditionally considered the sole origin of a cascade of pathophysiological mechanisms directly affecting the kidneys in this context. In the absence of established heart disease, cirrhotic cardiomyopathy may occur more frequently in those with liver cirrhosis and kidney disease. It is a specific form of cardiac dysfunction characterized by blunted contractile responsiveness to stress stimuli and altered diastolic relaxation with electrophysiological abnormalities. Despite the clinical description of these potential cardiac-related complications of the liver, the role of the heart has traditionally been an overlooked aspect of circulatory dysfunction in HRS. Yet from a physiological sense, temporality (prior onset) of cardiorenal interactions in HRS and positive effects stemming from portosystemic shunting demonstrated an important role of the heart in the development and progression of kidney dysfunction in cirrhotic patients. In this review, we discuss current concepts surrounding how the heart may influence the development and progression of HRS, and the role of systemic inflammation and endothelial dysfunction causing circulatory dysfunction within this setting. The temporality of heart and kidney dysfunction in HRS will be discussed. For a subgroup of patients who receive portosystemic shunting, the dynamics of cardiorenal interactions following treatment is reviewed. Continued research to determine the unknowns in this topic is anticipated, hopefully to further clarify the intricacies surrounding the liver-heart-kidney connection and improve strategies for management.
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Affiliation(s)
- Henry H L Wu
- Renal Research, Kolling Institute of Medical Research, Royal North Shore Hospital & The University of Sydney, St. Leonards (Sydney) 2065, New South Wales, Australia
| | - Amina Rakisheva
- Department of Cardiology, City Cardiological Center, Almaty 050000, Kazakhstan
| | - Arvind Ponnusamy
- Department of Renal Medicine, Royal Preston Hospital, Preston PR2 9HT, United Kingdom
| | - Rajkumar Chinnadurai
- Donal O’Donoghue Renal Research Centre & Department of Renal Medicine, Northern Care Alliance National Health Service Foundation Trust, Salford M6 8HD, United Kingdom
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Zhang J, Zhao Y, Gong N. XBP1 Modulates the Aging Cardiorenal System by Regulating Oxidative Stress. Antioxidants (Basel) 2023; 12:1933. [PMID: 38001786 PMCID: PMC10669121 DOI: 10.3390/antiox12111933] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/25/2023] [Accepted: 10/27/2023] [Indexed: 11/26/2023] Open
Abstract
X-box binding protein 1 (XBP1) is a unique basic-region leucine zipper (bZIP) transcription factor. Over recent years, the powerful biological functions of XBP1 in oxidative stress have been gradually revealed. When the redox balance remains undisturbed, oxidative stress plays a role in physiological adaptations and signal transduction. However, during the aging process, increased cellular senescence and reduced levels of endogenous antioxidants cause an oxidative imbalance in the cardiorenal system. Recent studies from our laboratory and others have indicated that these age-related cardiorenal diseases caused by oxidative stress are guided and controlled by a versatile network composed of diversified XBP1 pathways. In this review, we describe the mechanisms that link XBP1 and oxidative stress in a range of cardiorenal disorders, including mitochondrial instability, inflammation, and alterations in neurohumoral drive. Furthermore, we propose that differing degrees of XBP1 activation may cause beneficial or harmful effects in the cardiorenal system. Gaining a comprehensive understanding of how XBP1 exerts influence on the aging cardiorenal system by regulating oxidative stress will enhance our ability to provide new directions and strategies for cardiovascular and renal safety outcomes.
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Affiliation(s)
- Ji Zhang
- Anhui Province Key Laboratory of Genitourinary Diseases, Department of Urology, The First Affiliated Hospital of Anhui Medical University, Institute of Urology, Anhui Medical University, Hefei 230022, China;
- Key Laboratory of Organ Transplantation of Ministry of Education, Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, National Health Commission and Chinese Academy of Medical Sciences, Huazhong University of Science and Technology, Wuhan 430030, China;
| | - Yuanyuan Zhao
- Key Laboratory of Organ Transplantation of Ministry of Education, Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, National Health Commission and Chinese Academy of Medical Sciences, Huazhong University of Science and Technology, Wuhan 430030, China;
| | - Nianqiao Gong
- Key Laboratory of Organ Transplantation of Ministry of Education, Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, National Health Commission and Chinese Academy of Medical Sciences, Huazhong University of Science and Technology, Wuhan 430030, China;
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Gallo G, Lanza O, Savoia C. New Insight in Cardiorenal Syndrome: From Biomarkers to Therapy. Int J Mol Sci 2023; 24:5089. [PMID: 36982164 PMCID: PMC10049666 DOI: 10.3390/ijms24065089] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/28/2023] [Accepted: 03/02/2023] [Indexed: 03/09/2023] Open
Abstract
Cardiorenal syndrome consists in the coexistence of acute or chronic dysfunction of heart and kidneys resulting in a cascade of feedback mechanisms and causing damage to both organs associated with high morbidity and mortality. In the last few years, different biomarkers have been investigated with the aim to achieve an early and accurate diagnosis of cardiorenal syndrome, to provide a prognostic role and to guide the development of targeted pharmacological and non-pharmacological therapies. In such a context, sodium-glucose cotransporter 2 (SGLT2) inhibitors, recommended as the first-line choice in the management of heart failure, might represent a promising strategy in the management of cardiorenal syndrome due to their efficacy in reducing both cardiac and renal outcomes. In this review, we will discuss the current knowledge on the pathophysiology of cardiorenal syndrome in adults, as well as the utility of biomarkers in cardiac and kidney dysfunction and potential insights into novel therapeutics.
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Affiliation(s)
| | | | - Carmine Savoia
- Clinical and Molecular Medicine Department, Faculty of Medicine and Psychology, Sant’Andrea Hospital, Sapienza University of Rome, 00189 Rome, Italy
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Lai W, Xie Y, Zhao X, Xu X, Yu S, Lu H, Huang H, Li Q, Xu JY, Liu J, Chen S, Liu Y. Elevated systemic immune inflammation level increases the risk of total and cause-specific mortality among patients with chronic kidney disease: a large multi-center longitudinal study. Inflamm Res 2023; 72:149-158. [PMID: 36352033 DOI: 10.1007/s00011-022-01659-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 10/13/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Chronic kidney disease (CKD) is inherently a complex immune-inflammatory condition, and heightened inflammation and immune dysfunction are closely related to an increased risk of death. However, evidence regarding the relationship between immune-inflammatory levels and all-cause, cardiovascular, and cancer mortality among patients with CKD is scarce. METHODS Patients with non-dialysis dependent CKD undergoing coronary angiography (CAG) were included from five Chinese tertiary hospitals. Systemic immune inflammation index (SII) was calculated by multiplying peripheral platelet count with neutrophil-to-lymphocyte ratio, and patients were categorized into four groups by SII quartiles. Cox regression models and competing risk Fine and Gray models were used to examining the relationships between SII levels and all-cause, cardiovascular, and cancer mortality. RESULTS A total of the 19,327 patients (68.8 ± 10.03 years, female 32.0%) were included in this study. During a median follow-up of 4.5 years, 5,174 deaths occurred, including 2,861 cardiovascular deaths and 375 cancer deaths. Controlling for confounders, all-cause mortality (Q2, Q3, Q4: hazard ratio(HR) [95 CI%] = 1.15 [1.06-1.26], 1.30 [1.19-1.42], 1.48 [1.35-1.62], respectively; p for trend < 0.001) and cardiovascular mortality (Q2, Q3, Q4: HR [95 CI%] = 1.16 [1.03-1.31], 1.40 [1.24-1.58], 1.64 [1.44-1.85], respectively; p for trend < 0.001) increased with higher SII levels, and SII levels was related to cancer mortality comparing last quartile to first quartile of SII (Q2, Q3, Q4: HR [95 CI%] = 1.12 [0.83-1.52], 1.22 [0.90-1.67], 1.50 [1.09-2.08], respectively; p for trend < 0.001). CONCLUSION Elevated immune inflammation level on admission was an independent risk factor for all-cause, cardiovascular, and cancer mortality among CKD patients. Further research is needed to validate the predictive value of SII for mortality risk among CKD patients.
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Affiliation(s)
- Wenguang Lai
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- Department of Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Yun Xie
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- Department of Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Xiaoli Zhao
- Department of Cardiology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xiayan Xu
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- Department of Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Sijia Yu
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- Department of Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Hongyu Lu
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- Department of Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Haozhang Huang
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- Department of Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Qiang Li
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- Department of Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Jun-Yan Xu
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- Department of Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- Ministry of Education, Key Laboratory of Hainan Trauma and Disaster Rescue, College of Emergency and Trauma, Hainan Medical University, Haikou, 571199, China
| | - Jin Liu
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
- Department of Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
| | - Shiqun Chen
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
- Department of Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
| | - Yong Liu
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China.
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
- Department of Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
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Matsui M, Onoue K, Saito Y. sFlt-1 in Chronic Kidney Disease: Friend or Foe? Int J Mol Sci 2022; 23:ijms232214187. [PMID: 36430665 PMCID: PMC9697971 DOI: 10.3390/ijms232214187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/08/2022] [Accepted: 11/14/2022] [Indexed: 11/18/2022] Open
Abstract
Placental growth factor (PlGF) and its receptor, fms-like tyrosine kinase-1 (Flt-1), are important regulators involved in angiogenesis, atherogenesis, and inflammation. This review article focuses on the function of PlGF/Flt-1 signaling and its regulation by soluble Flt-1 (sFlt-1) in chronic kidney disease (CKD). Elevation of circulating sFlt-1 and downregulation of sFlt-1 in the vascular endothelium by uremic toxins and oxidative stress both exacerbate heart failure and atherosclerosis. Circulating sFlt-1 is inconsistent with sFlt-1 synthesis, because levels of matrix-bound sFlt-1 are much higher than those of circulating sFlt-1, as verified by a heparin loading test, and are drastically reduced in CKD.
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Affiliation(s)
- Masaru Matsui
- Department of Nephrology, Nara Prefecture General Medical Center, 2-897-5 Shichijo-Nishimachi, Nara 630-8581, Japan
- Department of Nephrology, Nara Medical University, 840 Shijo-Cho, Kashihara 634-8521, Japan
- Correspondence: ; Tel./Fax: +81-742-46-6001
| | - Kenji Onoue
- Department of Cardiology, Nara Medical University, 840 Shijo-Cho, Kashihara 634-8521, Japan
| | - Yoshihiko Saito
- Nara Prefecture Seiwa Medical Center, 1-14-16, Mimuro, Sango-Cho, Ikoma-Gun 636-0802, Japan
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Giri M, He L, Hu T, Puri A, Zheng X, Dai H, Guo S. Blood Urea Nitrogen Is Associated with In-Hospital Mortality in Critically Ill Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease: A Propensity Score Matching Analysis. J Clin Med 2022; 11:jcm11226709. [PMID: 36431186 PMCID: PMC9699438 DOI: 10.3390/jcm11226709] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/28/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Elevated blood urea nitrogen (BUN) level is associated with a higher risk of mortality in various diseases; however, the association between BUN level and in-hospital mortality in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) admitted to the intensive care unit (ICU) is not known. This study aimed to investigate the relationship between BUN level and in-hospital mortality in patients with AECOPD admitted to the ICU. Methods: In this retrospective cohort study, AECOPD patients were identified from the Medical Information Mart for Intensive Care (MIMIC-IV) database. Multivariate regression was used to elucidate the relationship between BUN level and in-hospital mortality, and propensity score matching (PSM) was used to adjust confounders. Receiver operating characteristics and Kaplan−Meier curves were used to evaluate the relationship between BUN level and in-hospital mortality. Results: Data from 1201 patients were analyzed. The all-cause in-hospital mortality was 13.7%. BUN levels were significantly higher in non-survivors compared to the survival group before (p < 0.001) and after (p = 0.005) PSM. Multivariate analysis indicated that elevated BUN levels were independently associated with increased risk of in-hospital mortality both before (p = 0.002) and after (p = 0.015) PSM. The optimal BUN cut-off value for in-hospital mortality in critical patients with AECOPD before (>23 mg/dL) and after (>22 mg/dL) PSM was comparable. Compared with the low BUN group, the hazard ratio (HR) of the high BUN group was 1.8987 (before PSM) and 1.7358 (after PSM). Conclusions: Higher BUN levels were significantly associated with an increased risk of in-hospital mortality in critically ill patients with AECOPD. As a widely available and rapidly measured biomarker, BUN may be useful in the risk stratification of critically ill AECOPD patients. The results need to be verified in prospective studies.
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Affiliation(s)
- Mohan Giri
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, No 1 Youyi Road, Yuzhong, Chongqing 400016, China
| | - Lin He
- Department of Respiratory and Critical Care Medicine, Chongqing University Fuling Hospital, Chongqing 408000, China
| | - Tianyang Hu
- Precision Medicine Center, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
| | - Anju Puri
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, No 1 Youyi Road, Yuzhong, Chongqing 400016, China
| | - Xiaozhuo Zheng
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, No 1 Youyi Road, Yuzhong, Chongqing 400016, China
| | - Haiyun Dai
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, No 1 Youyi Road, Yuzhong, Chongqing 400016, China
| | - Shuliang Guo
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, No 1 Youyi Road, Yuzhong, Chongqing 400016, China
- Correspondence:
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Li X, Yuan F, Zhou L. Organ Crosstalk in Acute Kidney Injury: Evidence and Mechanisms. J Clin Med 2022; 11:jcm11226637. [PMID: 36431113 PMCID: PMC9693488 DOI: 10.3390/jcm11226637] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/31/2022] [Accepted: 11/03/2022] [Indexed: 11/11/2022] Open
Abstract
Acute kidney injury (AKI) is becoming a public health problem worldwide. AKI is usually considered a complication of lung, heart, liver, gut, and brain disease, but recent findings have supported that injured kidney can also cause dysfunction of other organs, suggesting organ crosstalk existence in AKI. However, the organ crosstalk in AKI and the underlying mechanisms have not been broadly reviewed or fully investigated. In this review, we summarize recent clinical and laboratory findings of organ crosstalk in AKI and highlight the related molecular mechanisms. Moreover, their crosstalk involves inflammatory and immune responses, hemodynamic change, fluid homeostasis, hormone secretion, nerve reflex regulation, uremic toxin, and oxidative stress. Our review provides important clues for the intervention for AKI and investigates important therapeutic potential from a new perspective.
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11
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Chen W, Fan Z, Huang C, Liu J. Poricoic Acid A Inhibits the NF- κB/MAPK Pathway to Alleviate Renal Fibrosis in Rats with Cardiorenal Syndrome. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:8644353. [PMID: 35754696 PMCID: PMC9217574 DOI: 10.1155/2022/8644353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/18/2022] [Accepted: 05/25/2022] [Indexed: 11/17/2022]
Abstract
Objective To explore the potential and mechanism of action of poricoic acid A (PAA) in treatment of cardiorenal injury and fibrosis due to cardiorenal syndrome (CRS). Materials and Methods A CRS rat model was established by transabdominal subtotal nephrectomy (STNx). The experimental group was treated by gavage of PAA (10 mg/kg/day). After 8 weeks of treatment, echocardiography was utilized for detecting heart-related indexes in rats. HE and Masson staining were conducted to detect the degree of pathological damage and fibrosis in rat kidney tissue, respectively. In addition, serum blood urea nitrogen (BUN), serum creatinine (SCr), and 24-hour urine protein were measured biochemically. Also, the levels of inflammatory factors (IL-1β, IL-6, and IL-10) in rat kidneys were measured using ELISA. Western blot was used to examine the expression of NF-κB/MAPK pathway-related proteins. Results In this study, a CRS rat model was successfully established by STNx surgery. PAA treatment could significantly alleviate the damage of heart and kidney function in CRS rats and reduce the pathological damage of kidney tissue and renal fibrosis. Meanwhile, PAA could also inhibit the renal inflammatory response through downregulating IL-1β and IL-6 levels in the kidney tissue and upregulating IL-10 level. Further mechanism exploration showed that the NF-κB/MAPK signaling pathway was significantly activated in CRS rats, while PAA treatment could markedly inhibit the NF-κB/MAPK signaling pathway activity in CRS rats. Conclusion PAA can obviously improve the pathological damage and fibrosis of renal tissue in CRS rats and maintain the function of the heart and kidney. The above functions of PAA may be achieved by inhibiting the NF-κB/MAPK signaling pathway activity. Briefly speaking, PAA can serve as a potential drug for CRS treatment.
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Affiliation(s)
- Wenzhong Chen
- Department of Cardiovascular Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, China
| | - Zhiwen Fan
- Department of Cardiology, The PLA 74th Group Army Hospital, Guangzhou, Guangdong 510300, China
| | - Canhui Huang
- Department of Cardiovascular Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, China
| | - Junying Liu
- Department of Endocrinology, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518000, China
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12
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Buliga-Finis ON, Ouatu A, Badescu MC, Dima N, Tanase DM, Richter P, Rezus C. Beyond the Cardiorenal Syndrome: Pathophysiological Approaches and Biomarkers for Renal and Cardiac Crosstalk. Diagnostics (Basel) 2022; 12:diagnostics12040773. [PMID: 35453821 PMCID: PMC9028970 DOI: 10.3390/diagnostics12040773] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/17/2022] [Accepted: 03/19/2022] [Indexed: 02/04/2023] Open
Abstract
Cardiorenal syndrome encompasses complex multifactorial facets and carries significant morbidity and mortality worldwide. The bi-directional relationship between the heart and kidneys, where dysfunction in one organ worsens the function of the other, has been the leading motor for research in the last few years. In the pathophysiological process, small noncoding RNAs, epigenetics, vascular growth factors, oxidative stress, hemodynamic factors, and biomarkers play a pivotal role in the development of cardiorenal syndrome. It is therefore important to elucidate all the mechanisms in order to provide diagnostic and treatments tools. This review summarizes the hemodynamic and non-hemodynamic pathways along with biomarkers that could be the next target for diagnosis, treatment, and prognosis in cardiorenal syndrome.
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Affiliation(s)
- Oana Nicoleta Buliga-Finis
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (O.N.B.-F.); (M.C.B.); (N.D.); (D.M.T.); (C.R.)
- Internal Medicine Clinic, “Sf. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Anca Ouatu
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (O.N.B.-F.); (M.C.B.); (N.D.); (D.M.T.); (C.R.)
- Internal Medicine Clinic, “Sf. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
- Correspondence: ; Tel.: +40-722899045
| | - Minerva Codruta Badescu
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (O.N.B.-F.); (M.C.B.); (N.D.); (D.M.T.); (C.R.)
- Internal Medicine Clinic, “Sf. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Nicoleta Dima
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (O.N.B.-F.); (M.C.B.); (N.D.); (D.M.T.); (C.R.)
- Internal Medicine Clinic, “Sf. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Daniela Maria Tanase
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (O.N.B.-F.); (M.C.B.); (N.D.); (D.M.T.); (C.R.)
- Internal Medicine Clinic, “Sf. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Patricia Richter
- Department of Rheumatology and Physiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Rheumatology Clinic, Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| | - Ciprian Rezus
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (O.N.B.-F.); (M.C.B.); (N.D.); (D.M.T.); (C.R.)
- Internal Medicine Clinic, “Sf. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
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Safiriyu I, Nagraj S, Otulana R, Saralidze T, Kokkinidis DG, Faillace R. Prognostic impact of pre- and post- procedural renal dysfunction on late all-cause mortality outcome following transcatheter edge-to-edge repair of the Mitral Valve: A systematic review and Meta-analysis. CARDIOVASCULAR REVASCULARIZATION MEDICINE 2022; 42:6-14. [DOI: 10.1016/j.carrev.2022.03.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/21/2022] [Accepted: 03/23/2022] [Indexed: 12/20/2022]
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Abstract
Almost 200 years ago, the first evidence described by Robert Bright (1836) showed the strong interaction between the kidneys and heart and, since then, the scientific community has dedicated itself to better understanding the mechanisms involved in the kidney-heart relationship, known in recent decades as cardiorenal syndrome (CRS). This syndrome includes a wide clinical variety that affects the kidneys and heart, in an acute or chronic manner. Moreover, it is well established in the literature that the immune system, the sympathetic nervous system, the renin-angiotensin-aldosterone, and the oxidative stress actively play a strong role in the cellular and molecular processes present in CRS. More recently, uremic molecules and epigenetic factors have been also shown to be key mediators in the development of syndrome. The present review intends to present the state of the art regarding CRS and to show the paths known, until now, in the long road between the kidneys and heart.
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15
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Role and Mechanism of the Renin-Angiotensin-Aldosterone System in the Onset and Development of Cardiorenal Syndrome. J Renin Angiotensin Aldosterone Syst 2022; 2022:3239057. [PMID: 35111237 PMCID: PMC8803448 DOI: 10.1155/2022/3239057] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 12/03/2021] [Accepted: 01/04/2022] [Indexed: 02/06/2023] Open
Abstract
Cardiorenal syndrome (CRS), a clinical syndrome involving multiple pathological mechanisms, exhibits high morbidity and mortality. According to the primary activity of the disease, CRS can be divided into cardiorenal syndrome (type I and type II), renal heart syndrome (type III and type IV), and secondary heart and kidney disease (type V). The renin-angiotensin-aldosterone system (RAAS) is an important humoral regulatory system of the body that exists widely in various tissues and organs. As a compensatory mechanism, the RAAS is typically activated to participate in the regulation of target organ function. RAAS activation plays a key role in the pathogenesis of CRS. The RAAS induces the onset and development of CRS by mediating oxidative stress, uremic toxin overload, and asymmetric dimethylarginine production. Research on the mechanism of RAAS-induced CRS can provide multiple intervention methods that are of great significance for reducing end-stage organ damage and further improving the quality of life of patients with CRS.
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Fu K, Hu Y, Zhang H, Wang C, Lin Z, Lu H, Ji X. Insights of Worsening Renal Function in Type 1 Cardiorenal Syndrome: From the Pathogenesis, Biomarkers to Treatment. Front Cardiovasc Med 2022; 8:760152. [PMID: 34970606 PMCID: PMC8712491 DOI: 10.3389/fcvm.2021.760152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 11/11/2021] [Indexed: 12/16/2022] Open
Abstract
Type-1 cardiorenal syndrome refers to acute kidney injury induced by acute worsening cardiac function. Worsening renal function is a strong and independent predictive factor for poor prognosis. Currently, several problems of the type-1 cardiorenal syndrome have not been fully elucidated. The pathogenesis mechanism of renal dysfunction is unclear. Besides, the diagnostic efficiency, sensitivity, and specificity of the existing biomarkers are doubtful. Furthermore, the renal safety of the therapeutic strategies for acute heart failure (AHF) is still ambiguous. Based on these issues, we systematically summarized and depicted the research actualities and predicaments of the pathogenesis, diagnostic markers, and therapeutic strategies of worsening renal function in type-1 cardiorenal syndrome.
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Affiliation(s)
- Kang Fu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Yue Hu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Hui Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Chen Wang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Zongwei Lin
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Huixia Lu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Xiaoping Ji
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
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Jin L, Li Q, Li J, Pan Y, Zou J, Wu X, Wang Z. Apela inhibits systemic and renal inflammatory reactions in mice with type I cardiorenal syndrome. FASEB J 2021; 35:e21907. [PMID: 34516679 DOI: 10.1096/fj.202101030r] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 08/19/2021] [Accepted: 08/24/2021] [Indexed: 12/29/2022]
Abstract
This study investigated the effect of apela on renal function and anti-inflammatory effect on whole body and kidney tissue in mice with type I cardiorenal syndrome (CRS). The murine type I CRS model was established and apela was subcutaneously infused for two weeks. Cardiac and renal functions were evaluated by echocardiography and blood biochemistry, respectively. The systemic and renal inflammatory responses were examined with molecular biological and histological methods. Human renal glomerular endothelial cells (RGECs) were used to evaluate the adhesion effect of monocytes in vitro. Compared to mice from the control group (CRS + vehicle), the plasma levels of N-terminal pro-brain natriuretic peptide, blood urea nitrogen and creatinine were significantly decreased, while the mean left ventricular ejection fraction was increased in apela-treated CRS mice at the 4th week. The expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) in the circulation and kidney was decreased in apela-treated mice compared with control mice, and apela improved cardio-renal pathology in mice with type I CRS. Additionally, Apela significantly suppressed the expression of MCP-1, TNF-α, intercellular adhesion molecule-1 and vascular intercellular adhesion molecule-1 in RGECs induced by angiotensin II (Ang II), and inhibited the promoting effect of Ang II on the adhesion of THP-1 cells to RGECs. Western blot results showed that the expression of phosphorylated nuclear factor kappa B (phospho-NFκB) in CRS mice was increased, but the expression of phospho-NFκB was down-regulated after apela treatment. Furthermore, apela significantly inhibited the Ang II-mediated increase in phospho-NFκB expression in RGECs in vitro, but the administration of an apelin peptide jejunum receptor (APJ) inhibitor blocked the inhibitory effect of apela. This study revealed that apela improves cardiorenal function and reduces systemic and renal inflammatory response in type I CRS mice and the apela/APJ system may alleviate renal inflammatory responses by inhibiting the NFκB signalling pathway.
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Affiliation(s)
- Liangli Jin
- Department of Cardiovascular Medicine, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China
| | - Quanyi Li
- Department of Cardiovascular Medicine, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China
| | - Jing Li
- Department of Cardiovascular Medicine, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China
| | - Yang Pan
- Department of Cardiovascular Medicine, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China
| | - Jue Zou
- Department of Pathology, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China
| | - Xiaoyuan Wu
- Department of Central Laboratory, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China
| | - Zhi Wang
- Department of Cardiovascular Medicine, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China
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18
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Aquilani R, Maestri R, Dossena M, La Rovere MT, Buonocore D, Boschi F, Verri M. Altered Amino Acid Metabolism in Patients with Cardiorenal Syndrome Type 2: Is It a Problem for Protein and Exercise Prescriptions? Nutrients 2021; 13:nu13051632. [PMID: 34067952 PMCID: PMC8152258 DOI: 10.3390/nu13051632] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/05/2021] [Accepted: 05/10/2021] [Indexed: 11/23/2022] Open
Abstract
The goal of this retrospective study was to document any alterations in plasma amino acids (AAs) in subjects with cardiorenal syndrome type 2 (CRS 2). We analyzed data from sixteen patients with CRS 2 and eight healthy subjects (control group, C), whose plasma arterial (A) and venous (V) AA concentrations had been measured. Compared to C, the group of CRS 2 patients showed significant reductions by more than 90% in A (p < 0.01) and V (p < 0.01) individual AAs, whereas negative A-V differences that indicated a net muscle AA release (muscle hypercatabolism) were found in 59% of CRS 2 patients (p < 0.03). No significant differences in plasma A and V AA concentrations nor in A-V differences were found between patients with mild kidney damage (N = 5; estimated glomerular filtration rate, eGFR ≥ 60 mL/min/1.73 m2) and patients with moderate-severe kidney damage (N = 11; eGFR < 60 mL/min/1.73 m2). Several plasma arterial AAs correlated with hemodynamic variables, but not with GFR. The study showed that patients with CRS 2 had very low concentrations of circulating AAs, independent of the degree of GFR damage.
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Affiliation(s)
- Roberto Aquilani
- Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, 27100 Pavia, Italy; (R.A.); (M.D.); (D.B.)
| | - Roberto Maestri
- Department of Biomedical Engineering of the Montescano Institute, Istituti Clinici Scientifici Maugeri IRCCS, 27040 Montescano, Italy;
| | - Maurizia Dossena
- Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, 27100 Pavia, Italy; (R.A.); (M.D.); (D.B.)
| | - Maria Teresa La Rovere
- Department of Cardiac Rehabilitation of the Montescano Institute, Istituti Clinici Scientifici Maugeri IRCCS, 27040 Montescano, Italy;
| | - Daniela Buonocore
- Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, 27100 Pavia, Italy; (R.A.); (M.D.); (D.B.)
| | - Federica Boschi
- Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy;
| | - Manuela Verri
- Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, 27100 Pavia, Italy; (R.A.); (M.D.); (D.B.)
- Correspondence: ; Tel.: +39-0382-986423
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Wang J, Sun X, Wang X, Cui S, Liu R, Liu J, Fu B, Gong M, Wang C, Shi Y, Chen Q, Cai G, Chen X. Grb2 Induces Cardiorenal Syndrome Type 3: Roles of IL-6, Cardiomyocyte Bioenergetics, and Akt/mTOR Pathway. Front Cell Dev Biol 2021; 9:630412. [PMID: 33829014 PMCID: PMC8019825 DOI: 10.3389/fcell.2021.630412] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 02/22/2021] [Indexed: 12/26/2022] Open
Abstract
Cardiorenal syndrome type 3 (CRS-3) is damage to the heart following acute kidney injury (AKI). Although many experiments have found that inflammation, oxidative stress, and cardiomyocyte death are involved in cardiomyocyte pathophysiological alterations during CRS-3, they lack a non-bias analysis to figure out the primary mediator of cardiac dysfunction. Herein proteomic analysis was operated in CRS-3 and growth factor receptor-bound protein 2 (Grb2) was identified as a regulator involving AKI-related myocardial damage. Increased Grb2 was associated with cardiac diastolic dysfunction and mitochondrial bioenergetics impairment; these pathological changes could be reversed through the administration of a Grb2-specific inhibitor during AKI. Molecular investigation illustrated that augmented Grb2 promoted cardiomyocyte mitochondrial metabolism disorder through inhibiting the Akt/mTOR signaling pathway. Besides that, Mouse Inflammation Array Q1 further identified IL-6 as the upstream stimulator of Grb2 upregulation after AKI. Exogenous administration of IL-6 induced cardiomyocyte damage and mitochondrial bioenergetics impairment, whereas these effects were nullified in cardiomyocytes pretreated with Grb2 inhibitor. Our results altogether identify CRS-3 to be caused by the upregulations of IL-6/Grb2 which contribute to cardiac dysfunction through inhibiting the Akt/mTOR signaling pathway and inducing cardiomyocyte mitochondrial bioenergetics impairment. This finding provides a potential target for the clinical treatment of patients with CRS-3.
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Affiliation(s)
- Jin Wang
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, China
| | - Xuefeng Sun
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, China
| | - Xu Wang
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, China
| | - Shaoyuan Cui
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, China
| | - Ran Liu
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, China
| | - Jiaona Liu
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, China
| | - Bo Fu
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, China
| | - Ming Gong
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, China
| | - Conghui Wang
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, China
| | - Yushen Shi
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, China
| | - Qianqian Chen
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, China
| | - Guangyan Cai
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, China
| | - Xiangmei Chen
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, China
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Peterson SJ, Choudhary A, Kalsi AK, Zhao S, Alex R, Abraham NG. OX-HDL: A Starring Role in Cardiorenal Syndrome and the Effects of Heme Oxygenase-1 Intervention. Diagnostics (Basel) 2020; 10:E976. [PMID: 33233550 PMCID: PMC7699797 DOI: 10.3390/diagnostics10110976] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 11/17/2020] [Accepted: 11/19/2020] [Indexed: 12/14/2022] Open
Abstract
In this review, we will evaluate how high-density lipoprotein (HDL) and the reverse cholesterol transport (RCT) pathway are critical for proper cardiovascular-renal physiology. We will begin by reviewing the basic concepts of HDL cholesterol synthesis and pathway regulation, followed by cardiorenal syndrome (CRS) pathophysiology. After explaining how the HDL and RCT pathways become dysfunctional through oxidative processes, we will elaborate on the potential role of HDL dysfunction in CRS. We will then present findings on how HDL function and the inducible antioxidant gene heme oxygenase-1 (HO-1) are interconnected and how induction of HO-1 is protective against HDL dysfunction and important for the proper functioning of the cardiovascular-renal system. This will substantiate the proposal of HO-1 as a novel therapeutic target to prevent HDL dysfunction and, consequently, cardiovascular disease, renal dysfunction, and the onset of CRS.
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Affiliation(s)
- Stephen J. Peterson
- Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA;
- Department of Medicine, New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY 11215, USA; (A.C.); (A.K.K.); (S.Z.)
| | - Abu Choudhary
- Department of Medicine, New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY 11215, USA; (A.C.); (A.K.K.); (S.Z.)
| | - Amardeep K. Kalsi
- Department of Medicine, New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY 11215, USA; (A.C.); (A.K.K.); (S.Z.)
| | - Shuyang Zhao
- Department of Medicine, New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY 11215, USA; (A.C.); (A.K.K.); (S.Z.)
| | - Ragin Alex
- Department of Medicine, New York Medical College, Valhalla, NY 10595, USA;
| | - Nader G. Abraham
- Department of Medicine, New York Medical College, Valhalla, NY 10595, USA;
- Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA
- Department of Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA
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21
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Saito Y. The role of the PlGF/Flt-1 signaling pathway in the cardiorenal connection. J Mol Cell Cardiol 2020; 151:106-112. [PMID: 33045252 DOI: 10.1016/j.yjmcc.2020.10.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 09/29/2020] [Accepted: 10/02/2020] [Indexed: 02/07/2023]
Abstract
Although the concept of the cardiorenal connection is widely accepted, athe underlying molecular mechanism has not been clearly defined. Nevertheless, accumulating evidence indicates that the nervous system and both the humoral and cellular immune systems are all involved. This review article focuses on the roles of the signaling pathway of placental growth factor (PlGF) and its receptor, fms-like tyrosine kinase-1 (Flt-1), in the development of the cardiorenal connection. PlGF, a member of the vascular endothelial cell growth factor family, is a specific ligand for Flt-1 and plays roles in the development of atherosclerosis, wound healing after ischemia injury, and angiogenesis through Flt-1 signaling. Flt-1, a tyrosine-kinase type receptor with a single transmembrane domain, has a soluble isoform (sFlt-1) consisting of only extracellular domains, and is an intrinsic antagonist of PlGF. In renal dysfunction, PlGF is upregulated and sFlt-1 is downregulated by oxidative stress or uremic toxins, leading to activation of the PlGF/Flt-1 signaling pathway, which in turn plays a role in the worsening of atherosclerosis and heart failure, both of which are frequently associated with renal dysfunction. Monocyte chemotactic protein-1 (MCP-1) is involved in the process downstream of the Flt-1 signaling pathway. Plasma levels of sFlt-1 correlate with the severity of renal dysfunction in patients with heart failure or myocardial infarction, and are associated with the incidence of cardiovascular events. This is inconsistent with the concept of relative activation of the PlGF/Flt-1 pathway in renal dysfunction. However, the level of circulating sFlt-1 does not always parallel sFlt-1 synthesis, probably because sFlt-1 is stored on cell surfaces through its heparin-binding domains and its quantity is regulated differently in renal dysfunction. This review summarizes a novel concept wherein noninfectious inflammation via PlGF/Flt-1 signaling is involved in the development of renal dysfunction-related cardiovascular complications.
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Affiliation(s)
- Yoshihiko Saito
- Department of Cardiovascular Medicine, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Japan.
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Peesapati VSR, Sadik M, Verma S, Attallah MA, Khan S. Panoramic Dominance of the Immune System in Cardiorenal Syndrome Type I. Cureus 2020; 12:e9869. [PMID: 32963910 PMCID: PMC7500732 DOI: 10.7759/cureus.9869] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 08/19/2020] [Indexed: 12/18/2022] Open
Abstract
Physiological organ cross-talk is necessary to maintain equilibrium and homeostasis. Heart and kidney are the essences of this equilibrium. Organ failure in either of these organs can perturb the bidirectional communication between them, impinging this unpleasant vascular and cellular milieu on other distant organs. Cardiorenal syndrome (CRS) type I occurs due to acute deterioration of cardiac function, ultimately causing acute kidney injury (AKI). This syndrome is an intricate condition with neurohormonal and inflammatory aspects. Inflammation creates a vicious circle filled with the innate and adaptive immune systems, pro-inflammatory cytokines, chemokines to actuate hemodynamic compromise in CRS type I patients. Pro-inflammatory cytokines not only aggravate fluid retention and venous congestion but also initiate apoptosis and oxidative stress. The immune response's primary motive is to elicit the heart and kidney to produce cytokines, intensifying the inflammatory process. Despite the possible standard of care, patient mortality, treatment cost, readmissions are extreme in CRS type I, and inflammation certainly has critical inferences warranting future research in humans.
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Affiliation(s)
| | - Mohammad Sadik
- Research, California Institute of Behavorial Neurosciences and Psychology, Fairfield, USA
| | - Sadhika Verma
- Research, California Institute of Behavorial Neurosciences and Psychology, Fairfield, USA
- Internal Medicine, Manipal College of Medical Sciences, Pokhara, NPL
| | - Marline A Attallah
- Research, California Institute of Behavorial Neurosciences and Psychology, Fairfield, USA
| | - Safeera Khan
- Internal Medicine, California Institute of Behavorial Neurosciences and Psychology, Fairfield, USA
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