Mapping cardiac remodeling in chronic kidney disease.

Autor: Kaesler N; Clinic for Renal and Hypertensive Disorders, Rheumatological and Immunological Disease, University Hospital of the RWTH Aachen, Aachen, Germany.; Institute of Experimental Medicine and Systems Biology, University Hospital of the RWTH Aachen, Aachen, Germany., Cheng M; Institute for Computational Genomics, University Hospital of the RWTH Aachen, Aachen, Germany., Nagai J; Institute for Computational Genomics, University Hospital of the RWTH Aachen, Aachen, Germany., O'Sullivan J; Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK., Peisker F; Institute of Experimental Medicine and Systems Biology, University Hospital of the RWTH Aachen, Aachen, Germany., Bindels EMJ; Department of Hematology, Erasmus Medical Center, Rotterdam, Netherlands., Babler A; Institute of Experimental Medicine and Systems Biology, University Hospital of the RWTH Aachen, Aachen, Germany., Moellmann J; Department of Internal Medicine I, University Hospital of the RWTH Aachen, Aachen, Germany., Droste P; Clinic for Renal and Hypertensive Disorders, Rheumatological and Immunological Disease, University Hospital of the RWTH Aachen, Aachen, Germany.; Institute of Pathology, University Hospital of the RWTH Aachen, Aachen, Germany., Franciosa G; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark., Dugourd A; Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Bioquant, Heidelberg, Germany., Saez-Rodriguez J; Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Bioquant, Heidelberg, Germany., Neuss S; Institute of Pathology, University Hospital of the RWTH Aachen, Aachen, Germany.; Helmholtz Institute for Biomedical Engineering, Biointerface Laboratory, RWTH Aachen University, Aachen, Germany., Lehrke M; Department of Internal Medicine I, University Hospital of the RWTH Aachen, Aachen, Germany., Boor P; Clinic for Renal and Hypertensive Disorders, Rheumatological and Immunological Disease, University Hospital of the RWTH Aachen, Aachen, Germany.; Institute of Pathology, University Hospital of the RWTH Aachen, Aachen, Germany., Goettsch C; Department of Internal Medicine I, University Hospital of the RWTH Aachen, Aachen, Germany., Olsen JV; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark., Speer T; Department of Medicine (Nephrology), Goethe University Frankfurt, Frankfurt, Germany., Lu TS; Brigham and Women's Hospital, Renal Division, Boston, MA, USA., Lim K; Division of Nephrology and Hypertension, Indiana University School of Medicine, Indianapolis, IN, USA., Floege J; Clinic for Renal and Hypertensive Disorders, Rheumatological and Immunological Disease, University Hospital of the RWTH Aachen, Aachen, Germany., Denby L; Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK., Costa I; Institute for Computational Genomics, University Hospital of the RWTH Aachen, Aachen, Germany., Kramann R; Clinic for Renal and Hypertensive Disorders, Rheumatological and Immunological Disease, University Hospital of the RWTH Aachen, Aachen, Germany.; Institute of Experimental Medicine and Systems Biology, University Hospital of the RWTH Aachen, Aachen, Germany.; Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, Netherlands.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2023 Nov 24; Vol. 9 (47), pp. eadj4846. Date of Electronic Publication: 2023 Nov 24.
DOI: 10.1126/sciadv.adj4846
Abstrakt: Patients with advanced chronic kidney disease (CKD) mostly die from sudden cardiac death and recurrent heart failure. The mechanisms of cardiac remodeling are largely unclear. To dissect molecular and cellular mechanisms of cardiac remodeling in CKD in an unbiased fashion, we performed left ventricular single-nuclear RNA sequencing in two mouse models of CKD. Our data showed a hypertrophic response trajectory of cardiomyocytes with stress signaling and metabolic changes driven by soluble uremia-related factors. We mapped fibroblast to myofibroblast differentiation in this process and identified notable changes in the cardiac vasculature, suggesting inflammation and dysfunction. An integrated analysis of cardiac cellular responses to uremic toxins pointed toward endothelin-1 and methylglyoxal being involved in capillary dysfunction and TNFα driving cardiomyocyte hypertrophy in CKD, which was validated in vitro and in vivo. TNFα inhibition in vivo ameliorated the cardiac phenotype in CKD. Thus, interventional approaches directed against uremic toxins, such as TNFα, hold promise to ameliorate cardiac remodeling in CKD.
Databáze: MEDLINE