High inorganic phosphate causes DNMT1 phosphorylation and subsequent fibrotic fibroblast activation

2016 | journal article; research paper. A publication with affiliation to the University of Göttingen.

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​High inorganic phosphate causes DNMT1 phosphorylation and subsequent fibrotic fibroblast activation​
Tan, X.; Xu, X.; Zeisberg, E. M.   & Zeisberg, M. ​ (2016) 
Biochemical and Biophysical Research Communications472(3) pp. 459​-464​.​ DOI: https://doi.org/10.1016/j.bbrc.2016.01.077 

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Authors
Tan, Xiaoying; Xu, X.; Zeisberg, Elisabeth M. ; Zeisberg, Michael 
Abstract
Phosphate is an essential constituent of critical cellular functions including energy metabolism, nucleic acid synthesis and phosphorylation-dependent cell signaling. Increased plasma phosphate levels are an independent risk factor for lowered life-expectancy as well as for heart and kidney failure. Nevertheless, direct cellular effects of elevated phosphate concentrations within the microenvironment are poorly understood and have been largely neglected in favor of phosphor-regulatory hormones. Because interstitial fibrosis is the common determinant of chronic progressive kidney disease, and because fibroblasts are major mediators of fibrogenesis, we here explored the effect of high extracellular phosphate levels on renal fibroblasts. We demonstrate that high inorganic phosphate directly induces fibrotic fibroblast activation associated with increased proliferative activity, increased expression of alpha-smooth muscle actin and increased synthesis of type I collagen. We further demonstrate that such fibroblast activation is dependent on phosphate influx, aberrant phosphorylation of DNA methyltransferase DNMT1 and aberrant CpG island promoter methylation. In summary, our studies demonstrate that elevated phosphate concentrations induce pro-fibrotic fibroblast activation independent of phospho-regulatory hormones. (C) 2016 Published by Elsevier Inc.
Issue Date
2016
Journal
Biochemical and Biophysical Research Communications 
Project
SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz 
SFB 1002 | C01: Epigenetische Kontrolle der Herzfibrose 
Working Group
RG E. Zeisberg (Kardiales Stroma) 
RG M. Zeisberg (Renale Fibrogenese) 
External URL
https://sfb1002.med.uni-goettingen.de/production/literature/publications/138
ISSN
1090-2104; 0006-291X

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