The mechanism of phosphorus as a cardiovascular risk factor in CKD.
Hyperphosphatemia and vascular calcification have emerged as cardiovascular risk factors among those with chronic kidney disease. This study examined the mechanism by which phosphorous stimulates vascular calcification, as well as how controlling hyperphosphatemia affects established calcification. In primary cultures of vascular smooth muscle cells derived from atherosclerotic human aortas, activation of osteoblastic events, including increased expression of bone morphogenetic protein 2 (BMP-2) and the transcription factor RUNX2, which normally play roles in skeletal morphogenesis, was observed. These changes, however, did not lead to matrix mineralization until the phosphorus concentration of the media was increased; phosphorus stimulated expression of osterix, a second critical osteoblast transcription factor. Knockdown of osterix with small interference RNA (siRNA) or antagonism of BMP-2 with noggin prevented matrix mineralization in vitro. Similarly, vascular BMP-2 and RUNX2 were upregulated in atherosclerotic mice, but significant mineralization occurred only after the induction of renal dysfunction, which led to hyperphosphatemia and increased aortic expression of osterix. Administration of oral phosphate binders or intraperitoneal BMP-7 decreased expression of osterix and aortic mineralization. It is concluded that, in chronic kidney disease, hyperphosphatemia stimulates an osteoblastic transcriptional program in the vasculature, which is mediated by osterix activation in cells of the vascular tunica media and neointima.
Mathew
Suresh
S
Department of Pediatrics, Washington University, St. Louis, Missouri 63110, USA.
Tustison
Kimberly S
KS
Sugatani
Toshifumi
T
Chaudhary
Lala R
LR
Rifas
Leonard
L
Hruska
Keith A
KA
D000818:Animals; D002114:Calcinosis / Q000150:complications / Q000209:etiology; D002318:Cardiovascular Diseases / Q000209:etiology*; D002478:Cells, Cultured; D002908:Chronic Disease; D006801:Humans; D007674:Kidney Diseases / Q000150:complications*; D051379:Mice; D010758:Phosphorus / Q000502:physiology*; D012307:Risk Factors; D014652:Vascular Diseases / Q000150:complications / Q000209:etiology
D010758:Phosphorus