High inorganic phosphate causes DNMT1 phosphorylation and subsequent fibrotic fibroblast activation

Biochemical and Biophysical Research Communications
Xiaoying TanMichael Zeisberg

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 α-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 ind...Continue Reading

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Citations

Sep 27, 2018·American Journal of Physiology. Cell Physiology·Zhaoyu LiXuming Dai
Sep 18, 2020·Nature Communications·Yinghui HuangJinghong Zhao
Sep 7, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Ping HeMohammed S Razzaque

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