Krüppel-like factor 4 contributes to high phosphate-induced phenotypic switching of vascular smooth muscle cells into osteogenic cells

Tadashi Yoshida, Maho Yamashita, Matsuhiko Hayashi

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Hyperphosphatemia in chronic kidney disease is highly associated with vascular calcification. Previous studies have shown that high phosphate-induced phenotypic switching of vascular smooth muscle cells (SMCs) into osteogenic cells plays an important role in the calcification process. In the present study, we determined whether Krüppel-like factor 4 (Klf4) and phosphorylated Elk-1, transcriptional repressors of SMC differentiation marker genes activated by intimal atherogenic stimuli, contributed to this process. Rat aortic SMCs were cultured in the medium with normal (0.9 mmol/liter) or high (4.5 mmol/ liter) phosphate concentration. Results showed that high phosphate concentration induced SMC calcification. Moreover, high phosphate decreased expression of SMC differentiation marker genes including smooth muscle α-actin and SM22α, whereas it increased expression of osteogenic genes, such as Runx2 and osteopontin. High phosphate also induced Klf4 expression, although it did not phosphorylate Elk-1. In response to high phosphate, Klf4 selectively bound to the promoter regions of SMC differentiation marker genes. Of importance, siRNA-mediated knockdown of Klf4 blunted high phosphate-induced suppression of SMC differentiation marker genes, as well as increases in expression of osteogenic genes and calcium deposition. Klf4 was also induced markedly in the calcified aorta of adenine-induced uremic rats. Results provide novel evidence that Klf4 mediates high phosphate-induced conversion of SMCs into osteogenic cells.

Original languageEnglish
Pages (from-to)25706-25714
Number of pages9
JournalJournal of Biological Chemistry
Volume287
Issue number31
DOIs
Publication statusPublished - 2012 Jul 27

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Vascular Smooth Muscle
Smooth Muscle Myocytes
Muscle
Phosphates
Cells
Differentiation Antigens
Genes
Cell Differentiation
Rats
Tunica Intima
Hyperphosphatemia
Vascular Calcification
Gene Expression
Osteopontin
Adenine
Chronic Renal Insufficiency
Genetic Promoter Regions
Small Interfering RNA
Smooth Muscle
Aorta

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Krüppel-like factor 4 contributes to high phosphate-induced phenotypic switching of vascular smooth muscle cells into osteogenic cells. / Yoshida, Tadashi; Yamashita, Maho; Hayashi, Matsuhiko.

In: Journal of Biological Chemistry, Vol. 287, No. 31, 27.07.2012, p. 25706-25714.

Research output: Contribution to journalArticle

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