Hruska Lab

Our laboratory's focus is the pathogenesis and pathophysiologic mechanisms of the chronic kidney disease-bone and mineral disorder. We have discovered that renal injury and chronic kidney disease directly impair vascular, cardiac and skeletal function by production of factors involved in renal repair that are released into the circulation (Fang, Y et al JASN 2014). The consequent effects on the skeleton are loss of osteoblast function, decreased bone formation, less of an inhibiton of bone resorption. As a result, renal osteodystrophy contributes to the serum phosphorus levels in chronic kidney disease through excess osteoclast activity. Furthermore, we have shown that hyperphosphatemia is a direct stimulus to a heterotopic osteogenic program in the vasculature. This program is activated in atherosclerosis by stimulation of expression of osteoblastic transcription factors including RUNX2, Msx2 and osterix in neointimal cells leading to plaque calcification. When atherosclerosis is complicated by CKD, hyperphosphatemia stimulates expression of osterix completing the RUNX2 and Msx2 induced osteoblast transcriptome and inducing vascular mineralization (see figure, B). The mechanism of hyperphosphatemia action is direct stimulation of signal transduction in the vascular cells expressing the osteoblastic phenotype. Thus, in chronic kidney disease, we have discovered that the serum phosphorus is a cardiovascular risk factor. Correcting hyperphosphatemia causes loss of vascular calcium accumulation (Mathew,S et al JASN, 2008). The actions of hyperphosphatemia are inhibited by BMP-7. The mechanisms of BMP-7 action in vascular calcification, renal osteodystrophy,and as a novel new renal therapeutic are active investigations in the laboratory (Hruska et al, Kid. Int., 2008). The actions of BMP-7 therapy include opposing the pathologic reactivation of the WNT pathway in tubulointerstitial nephritis through loss of the sFRP4 inhibitor (Surendran et al JASN, 2005), Activation of the Wnt pathway in kidney disease produces increased Wnt inhibitors, including Dkk1 in the circulation. Circulating Wnt inhibitors stimulate endothelial to mesenchymal transition and oteoblastic differentiation in the neointimal plaques. We have shown Dkk1 neutralization stimulates vascular smooth muscle differentiation and inhibits vascular calcification (Fang et al JASN 2014). We have characterized the early CKD-MBD syndrome showing that it consists of decreased renal klotho, decreased bone formation, increased FGF23, and stimulated vascular calcification, which occurs in the presence of normal Ca, Pi, PTH and calcitriol (Fang et al Kid. Int. 2013).

Stimulation of vascular calcification by Chronic Kidney Disease (CKD) in mice with the metabolic syndrome (low density lipoprotein receptor deficient (LDLR-/-) fed high fat diets) and treatment with BMP-7. Panels A, B, and C are sections of the proximal aorta demonstrating large calcified atherosclerotic plaques in the LDLR-/- high fat fed mice. A) Large lipid laden plaque (between arrows) in proximal aorta of a sham-operated high fat fed LDLR-/- mouse. Thick arrows identify focal calcifications in the base of the plaque. (B) A large calcified plaque (between arrows) in the proximal aorta of a CKD high fat fed LDLR-/- mouse. (C) A large lipid laden plaque (between arrows) in the proximal aorta of a BMP-7 treated CKD high fat fed LDLR-/- mouse. The stain is alizarin red. Magnification is 400x in A-C. 

Contact Information

Keith A. Hruska, M.D.
Professor of Pediatrics, Medicine, Cell Biology
Department of Pediatrics
5th Fl MPRB
Campus Box 8208
660 S. Euclid Avenue
St. Louis, MO 63110
(314) 286-2772
(314) 286-2894 (fax)
hruska_k@wustl.edu

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