Pro-oxidative priming but maintained cardiac function in a broad spectrum of murine models of chronic kidney disease

Julia Wollenhaupt, Janina Frisch, Eva Harlacher, Dickson W.L. Wong, Han Jin, Corinna Schulte, Sonja Vondenhoff, Julia Moellmann, Barbara Mara Klinkhammer, Li Zhang, Adelina Baleanu-Curaj, Elisa A. Liehn, Thimoteus Speer, Andrey Kazakov, Christian Werner, Emiel P.C. van der Vorst, Simina Ramona Selejan, Mathias Hohl, Michael Böhm, Rafael KramannErik A.L. Biessen, Michael Lehrke, Nikolaus Marx, Joachim Jankowski, Christoph Maack, Peter Boor, Leticia Prates Roma, Heidi Noels*

*Corresponding author for this work

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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: CKD of different severity and duration was induced by subtotal nephrectomy or adenine-rich diet in various strains (C57BL/6J, C57BL/6 N, hyperlipidemic C57BL/6J ApoE−/−, 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.

Original languageEnglish
Article number102459
JournalRedox Biology
Publication statusPublished - Oct 2022

Bibliographical note

Funding Information:
This research was supported by the German Research Foundation (DFG SFB/TRR219 Project-ID 322900939). H.N. was furthermore supported by the Else Kröner-Fresenius-Stiftung (Project 2020_EKEA.60). H.N. and J.J. also received support of DFG SFB 1382 (project-ID 403224013) and from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 764474 (CaReSyAn). E.P.C.v.d.V. was supported by a grant from the Interdisciplinary Center for Clinical Research within the faculty of Medicine at the RWTH Aachen University, the DZHK (German Centre for Cardiovascular Research) and the BMBF (German Ministry of Education and Research), and NWO-ZonMw Veni (91619053). P.B. was also supported by the DFG (Project-ID 454024652, 432698239 and 445703531), the European Research Council (ERC; Consolidator Grant AIM.imaging.CKD, No 101001791) and the BMBF (STOP-FSGS-01GM1901A). C.M. was and is supported by DFG SFB 894 and Ma2528/7-1, the Corona Foundation and the Barth Syndrome Foundation. Transgenic mice (roGFP2-Orp1) were originally imported and kindly provided by Dr. Tobias Dick (German Cancer Research Center – DKFZ, Germany). Scanning of histological slides was performed by Dr. Anja Scheller (Department of Physiology, Saarland University, Germany). We thank Josefin Soppert for support with the animal experiment application and Ellen Becker, Julia Weber, Sandra Janku, Ivo Sluijsmans, Melanie Garbe, Stefanie Elbin, Yuan Kong and Roya Soltan for their technical support.

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