Inorganic Phosphate Stimulates Fibronectin Expression in Renal Fibroblasts
Zhonghai Chen1, Dong Chen1, Thomas L. McCarthy2, Michael Centrella2, Yuning Zhang1 and Gilbert W. Moeckel1
1Department of Pathology and 2Department of Surgery, Yale School of Medicine, New Haven, CT, USA
ABSTRACT
Elevated plasma phosphate levels are signifcantly associated with progression of chronic kidney disease (CKD). Interstitial fibrosis is an important factor in the progression of CKD. In this study we investigate the role of inorganic phosphate in stimulating fibronectin (FN) synthesis in a kidney fibroblast cell line (NRK-49F). We find that phosphate increases FN abundance and message in a dose–dependent fashion and that both ERK1/2 and AKT are important signaling pathways that mediate phosphate-dependent FN expression in NRK-49F cells. Moreover phosphate srimulates the expression of the transcription factors osterix and NFATc1, which form complexes and mediate FN synthesis. Another transcription factor involved in phosphate-dependent FN synthesis is the AP1 family member c-Fos. In summary we show that even mildly elevated serum phosphate levels can induce synthesis of the interstitial matrix protein fibronectin through activation of ERK1/2 and AKT signaling pathways in kidney fibroblasts and that the synthesis of fibronectin is mediated by a transcriptional complex consisting of NFATc1, osterix and c-Fos.
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