Elevated plasma phosphate levels are signifcantly associated with progression of chronic kidneydisease (CKD). Interstitial fibrosis is an important factor in the progression of CKD. In this studywe investigate the role of inorganic phosphate in stimulating fibronectin (FN) synthesis in akidney fibroblast cell line (NRK-49F). We find that phosphate increases FN abundance andmessage in a dose–dependent fashion and that both ERK1/2 and AKT are important signalingpathways that mediate phosphate-dependent FN expression in NRK-49F cells. Moreoverphosphate srimulates the expression of the transcription factors osterix and NFATc1, whichform complexes and mediate FN synthesis. Another transcription factor involved in phosphatedependentFN synthesis is the AP1 family member c-Fos. In summary we show that evenmildly elevated serum phosphate levels can induce synthesis of the interstitial matrix proteinfibronectin through activation of ERK1/2 and AKT signaling pathways in kidney fibroblasts andthat the synthesis of fibronectin is mediated by a transcriptional complex consisting of NFATc1,osterix and c-Fos.

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