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Abstract: SA-OR106

The Direct Inhibitory Effect of Ferric Citrate on Phosphate-Induced Calcification and Osteoblastic Trans-Differentiation via Suppression of HIF1a Expression in Human Vascular Smooth Muscle Cells

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Tokumoto, Masanori, Fukuoka Dental College, Fukuoka, Japan
  • Yamada, Shunsuke, Kyushu University, Fukuoka, Japan
  • Nakano, Toshiaki, Kyushu University, Fukuoka, Japan
  • Tsuruya, Kazuhiko, Nara Medical School, Kashihara, Japan
  • Kitazono, Takanari, Kyushu University, Fukuoka, Japan
  • Ooboshi, Hiroaki, Fukuoka Dental College, Fukuoka, Japan
Background

Vascular calcification is a life-threatening pathophysiological abnormality in chronic kidney disease (CKD). Phosphate (P) is known as its main inducer, and it was recently reported that P enhances HIF1a expression, leading to osteoblastic trans-differentiation and calcification of cultured vascular smooth muscle cells (VSMCs). Because iron degrades HIF1a via activation of proryl hydroxylase (PHD), we examined direct effects of ferric citrate (FC), an iron-containing P binder, on P-induced calcification, osteoblastic trans-differentiation, and HIF1a expression in VSMCs.

Methods

Human VSMCs were cultured in DMEM plus 10%FCS and 2.0mM P with 0, 1, 5, 10, 50, 100, or 500mM FC for one or two weeks. The precipitated calcium (Ca) contents and expression of calcification inducers or inhibitors were evaluated.

Results

At 1 week, moderate to high concentrations (>=5mM) of FC equally decreased P-induced calcification by about 80% (p<0.01), while, at 2 weeks, FC inhibited calcification in a concentration-dependent manner and high concentrations (>=50mM) of FC reduced calcification by almost 90% (p<0.01). Moderate to high concentrations (>=5mM) of FC not only suppressed expression of osteoblastic trans-differentiation inducers (BMP2, RUNX2, SOX9, MSX2, PiT1, and MMP2), but also increased expression of calcification inhibitors, OPG and MGP (p<0.01). Moreover, moderate to high concentrations of FC inhibited expression of HIF1a and VEGF, a downstream gene of HIF1 (p<0.01). Expression of HIF1a and VEGF positively correlated with precipitated Ca content and expression of BMP2, RUNX2, SOX9, MSX2, PiT1, and MMP2, respectively (p<0.01), and negatively correlated with OPG and MGP expression (p<0.01).

Conclusion

FC, an iron-containing P binder, can directly inhibit P-induced calcification and osteoblastic trans-differentiation via suppression of HIF1a expression in cultured human VSMCs.

Funding

  • Government Support - Non-U.S.