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Elevated phosphorus modulates vitamin D receptor-mediated gene expression in human vascular smooth muscle cells

Abbott Laboratories, Abbott Park, Illinois

Submitted 13 December 2006 ; accepted in final form 21 August 2007

Clinical observations show that an increase in serum inorganic phosphorus (P_i) is linked to higher cardiovascular (CV) mortality, while vitamin D receptor (VDR) agonist therapy is associated with survival benefit in stage 5 chronic kidney disease. Smooth muscle cells (SMCs) play an important role in CV pathophysiology, but the interaction between P_i and the VDR signaling pathway in SMCs is not known. Real-time RT-PCR studies revealed that elevated P_i (2.06 mM) modulated VDR-mediated regulation of a panel of genes including thrombomodulin and osteopontin in SMCs. DNA microarray results demonstrated that increasing P_i from 0.9 to 2.06 mM exerted a widespread modulating effect on VDR-mediated gene expression. A total of 325 target genes were affected by paricalcitol at 0.9 mM P_i, with 195 up- and 130 downregulated. The number of target genes affected by paricalcitol at 2.06 mM P_i decreased to 86, with 55 up- and 31 downregulated. VDR-mediated gene expression in As4.1 cells (a juxtaglomerular cell-like cell line derived from kidney tumors in SV40 T-antigen transgenic mice) and peroxisome proliferator-activated receptor (PPAR)-mediated gene expression in SMCs were also altered by elevated P_i, suggesting that the observation is not unique to VDR in SMCs. Mechanism analysis showed that elevated P_i had no significant effect on VDR or PPAR protein level but altered the cytosolic vs. nuclear distribution of NF-B or nuclear receptor corepressor 1 (NCoR1). Our results demonstrate for the first time that elevated P_i affects VDR-mediated gene expression in human coronary artery SMCs and the effect is not limited to VDR in SMCs.

paricalcitol; hyperphosphatemia; microarray; gene expression