There is a current major focus on the newly recognized cardiovascular risk associated with kidney disease. Recent studies have discovered new principles of pathophysiology linking chronic kidney disease (CKD) to the skeleton, the vasculature and the heart. Important advances arising from pathophysiology will be pursued in this application, and the efficacy of new renal therapeutic agents will be determined in novel translational models to approach the cardiovascular risk. New pathophysiologic discoveries for which mechanisms must be discovered are: first, in early CKD causing the CKD-MBD how does the skeleton contribute to vascular calcification (VC);and how calcitriol blocks CKD stimulated VC and inhibits the actions of hyperphosphatemia. These will be sought in the studies of the first aim. In the second aim, the mechanism of impaired cardiovascular function produced by kidney injury through the skeleton will be determined. In the third aim, the mechanism of phosphorus (Pi) stimulation of vascular calcification through the heterotopic vascular osteogenic program activated by BMP-2 in atherosclerosis will be sought. CKD decreases the differentiated phenotype of vascular smooth muscle cells, osteoblasts, and podocytes. CKD stimulates a heterotopic osteoblast program in cells migrating into atherosclerotic plaques leading to mineralization. Hyperphosphatemia is one of the factors driving the effects of CKD, and its mechanism of action is stimulation of osteoblast specific transcription factor activity in the vasculature. However, suppression of the action of hyperphosphatemia decreased the osteogenic program proximal to osterix. The long-range objective of this application is to pursue treatment of chronic kidney disease complications through attacking the mechanisms of pathophysiology. The studies in this application will address the central hypothesis that the skeleton is a critical organ in the multisystem failure associated with CKD, and that treatment of the CKD-MBD will decrease cardiovascular mortality. The hypothesis will be tested in early CKD which causes disordered regulation of two new hormonal systems and stimulation of vascular calcification. One of the new hormones regulates energy utilization and the effects of changes in osteocalcin on cardiac energy utilization will be studied in aim 2.
In aim three, how reduction in the serum Pi suppresses osteoblastic transition of vascular smooth muscle cells will be determined.
The specific aims of the application are to: 1) Determine the mechanism of stimulation of vascular calcification in early CKD. 2) Analyze the effect of osteocalcin on cardiac energy utilization and vascular smooth muscle cell differentiation. 3) Determine the molecular basis for the interaction of skeleton with BMP-2/4 stimulated VSMC osteoblastic transition in CKD.

Public Health Relevance

Patients with hardening of the arteries get heart attacks or heart failure because their blood vessels get calcium deposits. Patients with kidney disease have a higher risk of having heart attacks or heart failure than the general population because their blood vessels get more calcium deposits. We have shown that these calcium deposits are like bone being formed in blood vessels, and that they are stimulated in kidney failure by high levels of blood phosphorus. The research proposed in this application demonstrates that the effect of kidney disease to cause vascular and heart disease is more than just phosphorus and occurs before phosphorus is abnormal. The mechanism of the early actions of kidney disease are studied with attention to novel therapies for prevention of the effect of kidney disease to cause heart attacks or heart failure.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MOSS-A (03))
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Kimmel, Paul
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Washington University
Schools of Medicine
Saint Louis
United States
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Hruska, Keith A; Lanske, Beate; Moe, Orson W (2017) Crosstalk between kidney and bone - Bench to bedside. Bone 100:1-3
Sugatani, Toshifumi; Agapova, Olga A; Fang, Yifu et al. (2017) Ligand trap of the activin receptor type IIA inhibits osteoclast stimulation of bone remodeling in diabetic mice with chronic kidney disease. Kidney Int 91:86-95
Hruska, Keith A; Sugatani, Toshifumi; Agapova, Olga et al. (2017) The chronic kidney disease - Mineral bone disorder (CKD-MBD): Advances in pathophysiology. Bone 100:80-86
Agapova, Olga A; Fang, Yifu; Sugatani, Toshifumi et al. (2016) Ligand trap for the activin type IIA receptor protects against vascular disease and renal fibrosis in mice with chronic kidney disease. Kidney Int 89:1231-43
Seifert, Michael E; Hruska, Keith A (2016) The Kidney-Vascular-Bone Axis in the Chronic Kidney Disease-Mineral Bone Disorder. Transplantation 100:497-505
Seifert, Michael E; Ashoor, Isa F; Chiang, Myra L et al. (2016) Fibroblast growth factor-23 and chronic allograft injury in pediatric renal transplant recipients: a Midwest Pediatric Nephrology Consortium study. Pediatr Transplant 20:378-87
Sugatani, Toshifumi; Agapova, Olga; Malluche, Hartmut H et al. (2015) SIRT6 deficiency culminates in low-turnover osteopenia. Bone 81:168-77
Freedman, Barry I; Divers, Jasmin; Russell, Gregory B et al. (2015) Plasma FGF23 and Calcified Atherosclerotic Plaque in African Americans with Type 2 Diabetes Mellitus. Am J Nephrol 42:391-401
Hruska, Keith A; Seifert, Michael; Sugatani, Toshifumi (2015) Pathophysiology of the chronic kidney disease-mineral bone disorder. Curr Opin Nephrol Hypertens 24:303-9
Anyaegbu, Elizabeth I; Shaw, Andrey S; Hruska, Keith A et al. (2015) Clinical phenotype of APOL1 nephropathy in young relatives of patients with end-stage renal disease. Pediatr Nephrol 30:983-9

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