Research Abstract:
We study cardiovascular disease mechanisms in chronic kidney failure. We have discovered that kidney injury decreases vascular smooth muscle cell differentiation and skeletal anabolism. This leads to susceptibility to vascular calcification due to osteoblastic transition of neointimal cells in atherosclerotic plaques and a form of renal osteodystrophy, the adynamic bone disorder (ABD) through inhibition of osteoblast differentiation and survival. The ABD contributes to vascular calcification through disturbed phosphate balance. We have demonstrated that the serum phosphorus is a direct stimulus to heterotopic mineralization in the vasculature. Phosphorus stimulates osteogenic differentiation in the neointima and vascular media in chronic kidney disease. We are interested in the role of the serum phosphorus as a newly discovered cardiovascular risk factor that contributes to the excess mortality of kidney failure. In the vasculature, we have defined key roles for bone morphogenetic proteins in the proliferation of differentiation of vascular smooth muscle cells. The basis for pathologic vascular calcification that complicates end stage kidney disease involves loss of repression of an osteoblastic transcriptonal/differentiation program stimulated by vascular injury such as hyperphosphatemia, oxidized LDL and reactive oxygen species. In vascular smooth muscle cells and osteoclasts, our research has focused on osteopontin, a ligand of the avb3 integrin which induces cell signals emanating from a signaling complex organized around the actin caping protein, gelsolin. Gelsolin is critical for podosome assembly/disassembly in motile cells such as osteoclasts and vascular smooth muscle cells, and we have focused on mechanisms of actin ring assembly/disassembly. The signal molecules generated in the gelsolin-associated complex include phosphatidylinositol 3,4,5-tris-phosphate (PIP3), activation of c-src, and the rho GTPase. Recent studies have focused on PIP3 dependent proteins, specifically a PIP3 dependent kinase, Akt, that we demonstrate to be critical in RANKL signaling and osteoclast differentiation and a PIP3 phosphatase, PTEN. Recently, we have made important discorveries related to the role of miRNA in the differentiation of osteoclasts.
Selected Publications:
Kokubo T, Ishikawa N, Uchida H, Chasnoff SE, Xie X, Matthew S, Hruska KA, Choi ET. CKD accelerates development of neointimal hyperplasia in arteriovenous fistulas. J Amer Soc Nephrol 2009 20:1236-1245. PMCID:PMC2689906
Sugatani T, Hruska KA. Impaired microRNA pathways diminish osteoclast differentiation and function. J Biol Chem 2009 284:4667-4678. PMCID:PMC2640963
Mathew S, Tustison K, Sugatani T, Chaudhary LR, Rifas L, Hruska KA. The Mechanism of Phosphorus as a Cardiovascular Risk Factor in CKD. J Am Soc Nephrol. 2008 19: 1092-1105.
Mathew S, Lund R, Chaudhary L, Geurs T, Hruska KA. Vitamin D Receptor Activators Can Protect against Vascular Calcification. J Am Soc Nephrol 2008 19: 1509-1519.
Hruska KA, Mathew S, Lund R, Qiu P and Pratt R. Hyperphosphatemia of chronic kidney disease. Kidney Int. 2008 74(2): 148-57.
Last Updated: 08/11/2009 |