title: High inorganic phosphate causes DNMT1 phosphorylation and subsequent fibrotic fibroblast activation.
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 induce pro-fibrotic fibroblast activation independent of phospho-regulatory hormones.
authors.affiliation: Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen, Germany; Department of Cardiology and Pneumology, Göttingen University Medical Center, Georg August University, Göttingen, Germany.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Tan
authors.affiliation: Department of Cardiology and Pneumology, Göttingen University Medical Center, Georg August University, Göttingen, Germany.
authors.forename: Xingbo
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Cardiology and Pneumology, Göttingen University Medical Center, Georg August University, Göttingen, Germany; German Center for Cardiovascular Research (DZHK), Göttingen, Germany.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Zeisberg
authors.affiliation: Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen, Germany; German Center for Cardiovascular Research (DZHK), Göttingen, Germany. Electronic address: mzeisberg@med.uni-goettingen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Zeisberg
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005355:Fibrosis; D006801:Humans; D010710:Phosphates / Q000008:administration & dosage / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects
chemical_list: D010710:Phosphates; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human
keywords: Epigenetics; Fibrosis; Phosphate; Ras