In the CKD-MBD Absent Vascular Disease, CKD Decreases Cardiac Mitochondrial Function and Activin A Is an Activator of Skeletal Activin Receptor Signaling

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Background: The CKD-MBD is an important factor in the cardiovascular mortality associated with CKD. The cardiac component of the CKD-MBD has not been studied in the absence of vascular disease. Methods: We developed an animal model of the CKD-MBD without associated vascular disease. We randomized CKD Alport mice into two groups - treatment with a monoclonal Ab to activin A (CKD-AB) or an isotype matched IgG (CKD-IgG). Results: The Alport- AB and IgG mice had CKD equivalent to human stage 4-5 CKD. PTH and FGF23 levels were one log order elevated, and circulating sclerostin was elevated. Activin A was strongly induced in the kidneys. Aortic Ca levels were not increased in the CKD mice. The CKD mice were not hypertensive, and there was no cardiac hypertrophy. Freshly excised cardiac tissue respirometry (Oroboros) revealed that ADP minus Palmitoyl Carnitine stimulated O2 flux was diminished from 52 to 22 pmol/mg (p<0.05) (Figure 1). RNA seq of cardiac tissue from CKD-IgG mice showed significantly decreased levels of cardiac mitochondrial oxidative phosphorylation genes. In the skeleton, the Activin A antibody decreased the effect of CKD to stimulate osteoclast number and eroded surfaces along with a decrease in the stimulation of osteoclast driven remodeling. Immunohistochemical detection of osteocytic sclerostin was increased in the CKD-IgG mice, and the antibody treatment had no effect. Conclusions: Two important advances in the pathophysiology of the CKD-MBD are reported here. The first, that cardiac mitochondrial respiration is impaired in CKD of Alport mice in the absence of vascular disease. This is the first report of the direct effect of CKD on cardiac respiration. Secondly, we demonstrate the role of activin A in renal osteodystrophy pathogenesis. Activin A becomes the third renal produced factor after the Wnt inhibitors and klotho to contribute to the CKD-MBD. Funding: NIDDK Support

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