Pro-oxidative priming but maintained cardiac function in a broad spectrum of murine models of chronic kidney disease
Redox Biology, vol. 56, pp. 102459
Abstract
AIMS: Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular events and exhibit myocardial changes including left ventricular (LV) hypertrophy and fibrosis, overall referred to as 'uremic cardiomyopathy'. Although different CKD animal models have been studied for cardiac effects, lack of consistent reporting on cardiac function and pathology complicates clear comparison of these models. Therefore, this study aimed at a systematic and comprehensive comparison of cardiac function and cardiac pathophysiological characteristics in eight different CKD models and mouse strains, with a main focus on adenine-induced CKD. METHODS AND RESULTS: , 129/Sv), followed by the analysis of kidney function and morphology, blood pressure, cardiac function, cardiac hypertrophy, fibrosis, myocardial calcification and inflammation using functional, histological and molecular techniques, including cardiac gene expression profiling supplemented by oxidative stress analysis. Intriguingly, despite uremia of variable degree, neither cardiac dysfunction, hypertrophy nor interstitial fibrosis were observed. However, already moderate CKD altered cardiac oxidative stress responses and enhanced oxidative stress markers in each mouse strain, with cardiac RNA sequencing revealing activation of oxidative stress signaling as well as anti-inflammatory feedback responses. CONCLUSION: This study considerably expands the knowledge on strain- and protocol-specific differences in the field of cardiorenal research and reveals that several weeks of at least moderate experimental CKD increase oxidative stress responses in the heart in a broad spectrum of mouse models. However, this was insufficient to induce relevant systolic or diastolic dysfunction, suggesting that additional "hits" are required to induce uremic cardiomyopathy. TRANSLATIONAL PERSPECTIVE: Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular adverse events and exhibit myocardial changes, overall referred to as 'uremic cardiomyopathy'. We revealed that CKD increases cardiac oxidative stress responses in the heart. Nonetheless, several weeks of at least moderate experimental CKD do not necessarily trigger cardiac dysfunction and remodeling, suggesting that additional "hits" are required to induce uremic cardiomyopathy in the clinical setting. Whether the altered cardiac oxidative stress balance in CKD may increase the risk and extent of cardiovascular damage upon additional cardiovascular risk factors and/or events will be addressed in future studies.
Authors 27
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
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Affiliation as printed
Department of Biophysics, Center for Integrative Physiology and Molecular Medicine, Medical Faculty, Saarland University, Center for Human and Molecular Biology, Homburg/Saar, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
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Science for Life Laboratory · Maastricht University · KTH Royal Institute of Technology
Affiliation as printed
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands; Science for Life Laboratory (SciLifeLab), KTH Royal Institute of Technology, Stockholm, Sweden
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
Science for Life Laboratory (SciLifeLab), KTH Royal Institute of Technology, Stockholm, Sweden
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Department of Internal Medicine I, Cardiology, University Hospital RWTH Aachen, Aachen, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
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University of Southern Denmark · Institutul National Victor Babes
Affiliation as printed
Institute for Molecular Medicine, University of South Denmark, Odense, Denmark; National Institute for Pathology "Victor Babes", Bucharest, Romania
Institute for Molecular Medicine, University of South Denmark, Odense, Denmark
National Institute for Pathology "Victor Babes", Bucharest, Romania
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Affiliation as printed
Translational Cardio-Renal Medicine, Saarland University, Homburg/Saar, Germany
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Universitätsklinikum des Saarlandes · Saarland University
Affiliation as printed
Department of Cardiology, Angiology and Intensive Care Medicine, Saarland University Medical Centre, Homburg/Saar, Germany
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Emiel P. C. van der Vorst Aachen Institute for Molecular Cardiovascular Research Interdisciplinary Center for Clinical Research (IZKF) Interdisciplinary Center for Clinical Research (IZKF)
Maastricht University · Universitätsklinikum Aachen · German Centre for Cardiovascular Research · Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten · Ludwig-Maximilians-Universität München · RWTH Aachen University
Affiliation as printed
Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands; Interdisciplinary Centre for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich, Germany
Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
Interdisciplinary Centre for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany
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Universitätsklinikum des Saarlandes · Saarland University
Affiliation as printed
Department of Cardiology, Angiology and Intensive Care Medicine, Saarland University Medical Centre, Homburg/Saar, Germany
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Universitätsklinikum des Saarlandes · Saarland University
Affiliation as printed
Department of Cardiology, Angiology and Intensive Care Medicine, Saarland University Medical Centre, Homburg/Saar, Germany
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Universitätsklinikum des Saarlandes · Saarland University
Affiliation as printed
Department of Cardiology, Angiology and Intensive Care Medicine, Saarland University Medical Centre, Homburg/Saar, Germany
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Rafael Kramann Aachen Institute of Experimental Medicine and Systems Biology Department of Nephrology and Clinical Immunology
Erasmus MC · Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute of Experimental Medicine and Systems Biology, University Hospital RWTH Aachen, Aachen, Germany; Department of Nephrology and Clinical Immunology, University Hospital RWTH Aachen, Aachen, Germany; Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, the Netherlands
Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, the Netherlands
Department of Nephrology and Clinical Immunology, University Hospital RWTH Aachen, Aachen, Germany
Institute of Experimental Medicine and Systems Biology, University Hospital RWTH Aachen, Aachen, Germany
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Affiliation as printed
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
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Universitätsklinikum des Saarlandes · Universitätsklinikum Aachen · RWTH Aachen University · Saarland University
Affiliation as printed
Department of Internal Medicine I, Cardiology, University Hospital RWTH Aachen, Aachen, Germany
Department of Cardiology, Angiology and Intensive Care Medicine, Saarland University Medical Centre, Homburg/Saar, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Department of Internal Medicine I, Cardiology, University Hospital RWTH Aachen, Aachen, Germany
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Maastricht University · Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
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Affiliation as printed
Department of Translational Research, Comprehensive Heart Failure Center (CHFC), University Hospital Würzburg, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany; Department of Nephrology and Clinical Immunology, University Hospital RWTH Aachen, Aachen, Germany
Department of Nephrology and Clinical Immunology, University Hospital RWTH Aachen, Aachen, Germany
Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
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Affiliation as printed
Department of Biophysics, Center for Integrative Physiology and Molecular Medicine, Medical Faculty, Saarland University, Center for Human and Molecular Biology, Homburg/Saar, Germany. Electronic address: leticia.prates-roma@uks.eu
Department of Biophysics, Center for Integrative Physiology and Molecular Medicine, Medical Faculty, Saarland University, Center for Human and Molecular Biology, Homburg/Saar, Germany
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Heidi Noels Aachen Institute for Molecular Cardiovascular Research Corresponding author. Institute for Molecular Cardiovascular Research (IMCAR)
Maastricht University · Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands. Electronic address: hnoels@ukaachen.de
Corresponding author. Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Pauwelsstraße 30, 52074, Germany
Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
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