Loading…

Mapping cardiac remodeling in chronic kidney disease

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 ventricu...

Full description

Saved in:
Bibliographic Details
Published in:Science advances 2023-11, Vol.9 (47), p.eadj4846-eadj4846
Main Authors: Kaesler, Nadine, Cheng, Mingbo, Nagai, James, O'Sullivan, James, Peisker, Fabian, Bindels, Eric M J, Babler, Anne, Moellmann, Julia, Droste, Patrick, Franciosa, Giulia, Dugourd, Aurelien, Saez-Rodriguez, Julio, Neuss, Sabine, Lehrke, Michael, Boor, Peter, Goettsch, Claudia, Olsen, Jesper V, Speer, Thimoteus, Lu, Tzong-Shi, Lim, Kenneth, Floege, Jürgen, Denby, Laura, Costa, Ivan, Kramann, Rafael
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2375-2548
2375-2548
DOI:10.1126/SCIADV.ADJ4846