Mapping cardiac remodeling in chronic kidney disease
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Mapping cardiac remodeling in chronic kidney disease. / 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.
In: Science Advances, Vol. 9, No. 47, eadj4846, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Mapping cardiac remodeling in chronic kidney disease
AU - Kaesler, Nadine
AU - Cheng, Mingbo
AU - Nagai, James
AU - O'Sullivan, James
AU - Peisker, Fabian
AU - Bindels, Eric M.J.
AU - Babler, Anne
AU - Moellmann, Julia
AU - Droste, Patrick
AU - Franciosa, Giulia
AU - Dugourd, Aurelien
AU - Saez-Rodriguez, Julio
AU - Neuss, Sabine
AU - Lehrke, Michael
AU - Boor, Peter
AU - Goettsch, Claudia
AU - Olsen, Jesper V.
AU - Speer, Thimoteus
AU - Lu, Tzong Shi
AU - Lim, Kenneth
AU - Floege, Jürgen
AU - Denby, Laura
AU - Costa, Ivan
AU - Kramann, Rafael
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
U2 - 10.1126/sciadv.adj4846
DO - 10.1126/sciadv.adj4846
M3 - Journal article
C2 - 38000021
AN - SCOPUS:85177759470
VL - 9
JO - Science advances
JF - Science advances
SN - 2375-2548
IS - 47
M1 - eadj4846
ER -
ID: 375308976