Abstract Our recent studies have established a new paradigm that the chronic kidney disease – mineral bone disorder (CKD-MBD) syndrome is partly caused by release of factors that are induced during attempted kidney repair into the circulation. These studies have shown systemic activation of activin receptor type IIA (ActRIIA) in CKD and identified ActRIIA signaling as a potential therapeutic target for the CKD-MBD and renal fibrosis. Chronic Kidney Disease (CKD) is a pandemic associated with high cardiovascular mortality rates. The causes of the high cardiovascular mortality risk include CKD-MBD components. The CKD-MBD syndrome is a uniform complication of CKD beginning after significant kidney injury reduces GFR by 10% or more. The available therapeutic options attacking the CKD-MBD - phosphate binders, vitamin D analogs, and calcimimetics, target late stages of the syndrome and not its pathogenesis or the cardiovascular complications directly, and have failed to show cardiovascular benefit in clinical trials. Thus, there is great need for discoveries related to CKD-MBD pathogenesis and identification of therapeutic targets for the CKD-MBD cardiovascular components. CKD modulates ActRIIA signaling in the vasculature, heart, skeleton and kidney. ActRIIA signaling contributes to vascular, skeletal, and cardiac complications of kidney disease. The studies in this application propose to identify the mechanism by which ActRIIA is activated in CKD focusing on ligand stimulation by Activin A. Inducible knockdown strategies and monoclonal antibody to activin A will be used to determine the role of activin A in ActRIIA activation in CKD. Vascular, skeletal and cardiac tissues will be studied for mechanism of disease and mechanism of ActRIIA activation. The vascular aim 1 studies will validate ActRIIA as a therapeutic target in the vascular calcification of the CKD-MBD. In skeletal aim 2 studies, the mechanism of CKD stimulated osteoblast dysfunction and bone resorption and abnormal remodeling is sought. In the cardiac aim 3 studies, the mechanism of CKD stimulated cardiac hypertrophy will be sought focusing on cardiac energetics and the regulation by perioxosome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) confirming the role of ActRIIA and validating it as a therapeutic target. Successful completion of the proposed studies will establish that the vascular, skeletal and cardiac components of the CKD-MBD are caused by activin A as an ActRIIA ligand, establishing it as a therapeutic target in the CKD-MBD and CKD, and support new clinical trials in the CKD-MBD and in the progression of CKD.