Sodium-dependent phosphate cotransporters and vascular calcification.
OBJECTIVE
Vascular calcification is associated with cardiovascular events in patients with end-stage renal disease and diabetes. Hyperphosphatemia is a risk factor for vascular calcification in these patients. Sodium-dependent phosphate cotransporters are required for cellular phosphate uptake. This review focuses on the potential role of phosphate transport and type III sodium-dependent phosphate cotransporters in the process of vascular calcification.


RESULTS
Consistent with clinical and animal studies, elevated phosphate induces mineralization of cultured smooth muscle cells in vitro. Calcification is concomitant with osteochondrogenic phenotype change in smooth muscle cells characterized by induction of osteochondrogenic differentiation marker, Runx2, and inhibition of smooth muscle cell lineage marker, SM22. Inhibition of the type III sodium-dependent phosphate cotransporter, Pit-1, blocks phosphate-induced smooth muscle cell calcification. Moreover, the phosphate-induced osteochondrogenic phenotype modulation is also abrogated by Pit-1 inhibition. Pit-1 is upregulated by several calcification-promoting factors, including tumor necrosis factor-alpha, bone morphogenetic protein 2, platelet-derived growth factor and elevated calcium.


CONCLUSIONS
Phosphate uptake via Pit-1 is required for osteochondrogenic phenotypic change and calcification of vascular smooth muscle cells in vitro. Modulation of Pit-1 expression or its transport activity may provide a novel therapeutic target for intervention of vascular calcification.
Li
Xianwu
X
Department of Bioengineering, University of Washington, Seattle, Washington 98195-5061, USA.
Giachelli
Cecilia M
CM
D000818:Animals; D002114:Calcinosis / Q000209:etiology*; D002318:Cardiovascular Diseases / Q000209:etiology*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000503:physiopathology; D051379:Mice; D010710:Phosphates / Q000378:metabolism; D051381:Rats; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000502:physiology*; D050817:Transcription Factor Pit-1 / Q000502:physiology*
C494187:POU1F1 protein, human; D010710:Phosphates; C493588:Slc20a1 protein, rat; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D050817:Transcription Factor Pit-1