Mapping cardiac remodeling in chronic kidney disease
Nadine Kaesler, Mingbo Cheng, James S. Nagai, James O’Sullivan, Fabian Peisker, Eric M. Bindels, Anne Babler, Julia Moellmann, Patrick Droste, Giulia Franciosa, Aurélien Dugourd, Julio Sáez-Rodríguez, Sabine Neuß, Michael Lehrke, Peter Boor, Claudia Goettsch, Jesper V. Olsen, Thimoteus Speer, Tzongshi Lu, Kenneth Lim, Jürgen Floege, Laura Denby, Ivan G. Costa, Rafael Kramann
Abstract
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.