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Abstract: TH-OR047

Novel Mechanism of Cardiac Hypertrophy Within the CKD-MBD

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic


  • Williams, Matthew, Washington University in St. Louis, St Louis, Missouri, United States
  • Hruska, Keith A., Washington University in St. Louis, St Louis, Missouri, United States

Cardiac Hypertrophy is a predecessor of cardiac morbidity associated with CKD and caused by factors that are components of the CKD - MBD syndrome: vascular calcification (VC) and elevated levels of FGF23. In a murine model of Alport syndrome, we show that CKD causes cardiac hypertophy due to mechanisms independent of VC and FGF23 due to signaling through activin receptor type 2A (ActRIIA).


Cardiac size and function were determined by heart weight/tibial length (HW/TL) and echocardiography in 200 day old (do) Col4a5 deficient male mice on the C57Bl6J background. BUN, inulin clearance were used to measure kidney function. Aortic compliance was determined by pressure - diameter relationship. FGF23 levels were by Elisa. Mitochondrial morphometry was by electron microscopy, and OXPHOS was by respirometry. ActRIIA signaling was inhibited by an ActRIIA-Fc ligand trap.


200 do Alport mice had BUNs of 50 -90 and 70-85 % reduction in inulin clearance. Cardiac levels of psmad 2 and inhibin βa were increased in Alport mice and cardiac PGC1α levels were decreased. These effects of CKD were reversed by ActRIIA signaling inhibition. Aortic compliance was unchanged compared to WT mice, and elevated FGF23 levels were not altered by the ActRII-Fc treatment. HW/TL was 6.2 mg/mm in 200do Alport mice compared to 4.7 in WT control mice, and 4.9 in ActRIIA-Fc treated Alport mice, p<0.01 (Fig.1). Cardiac hypertrophy was confirmed by echocardiography, but function was not significantly altered. Mitochondrial OXPHOS and morphology were significantly altered in 200do Alport mice indicating a metabolic cause for the compensated hypertrophy.


Compensated cardiac hypertrophy in 200 do Alport mice was due in part to cardiac activation of ActRIIA signaling and prevented by its inhibition in the absence of vascular stiffness and without change in FGF23 levels.


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