CKD Decreases Cardiac PGC-1α Through Activin A Disrupting Mitochondrial Function

Le résumé fourni par la source

Background: The CKD-MBD syndrome is a cause of cardiac risk. Our hypothesis was that a new component of the syndrome, activin A, is responsible for systemic activation of activin receptor (ActRII) signaling in kidney disease, and is a mechanism of cardiac disease. Methods: Two models of CKD were employed, Col4A5 Alport Syndrome mice and ablative CKD in Rosa26 cre ERT+/inhbafl/fl mice. Inhibition of Activin A in CKD was accomplished by either knockdown in Rosa26 cre ERT+/inhbafl/fl CKD mice or by monoclonal antibody in Alport mice. PGC-1α, mitochondrial gene expression and oxidative phosphorylation were measured by PCR and western analysis Cardiac mitochondrial respiration was measured by respirometry. Results: In two kidney disease models, we show that activin A is the responsible ligand for cardiac and aortic ActRIIA activation in CKD. In untreated CKD mice, cardiac levels of pSmad2 and inhibin βa mRNA and preprotein (activin A monomer) were increased. Activin A inhibition, accomplished by either knockdown in Rosa26 cre ERT+/inhbafl/fl CKD mice or by monoclonal antibody in Alport mice, prevents CKD-induced cardiac ActRIIA activation and loss of PGC-1α, the master regulator of mitochondrial biogenesis and fatty acid oxidative phosphorylation. Mitochondrial gene expression and oxidative phosphorylation were decreased by CKD but prevented by activin A inhibition in CKD. Cardiac hypertrophy by echocardiography and heart weight was increased by CKD and prevented by activin A inhibition in the absence of vascular stiffness and without change in FGF23 levels. Conclusions: We conclude that activation of cardiac activin/ActRIIA signaling by CKD induces mitochondrial dysfunction through decreased PGC-1α which contributes to compensated cardiac hypertrophy in the early stages of CKD associated cardiac disease. Funding: NIDDK Support, Commercial Support - Regeneron

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.