@article{1b407f3f1523493ba94a7db46ba66543,
title = "DNA methyltransferase inhibition restores erythropoietin production in fibrotic murine kidneys",
abstract = "Renal erythropoietin-producing cells (REPCs) remain in the kidneys of patients with chronic kidney disease, but these cells do not produce sufficient erythropoietin in response to hypoxic stimuli. Treatment with HIF stabilizers rescues erythropoietin production in these cells, but the mechanisms underlying the decreased response of REPCs in fibrotic kidneys to anemic stimulation remain elusive. Here, we show that fibroblast-like FOXD1+ progenitor-derived kidney pericytes, which are characterized by the expression of α1 type I collagen and PDGFRβ, produce erythropoietin through HIF2α regulation but that production is repressed when these cells differentiate into myofibroblasts. DNA methyltransferases and erythropoietin hypermethylation are upregulated in myofibroblasts. Exposure of myofibroblasts to nanomolar concentrations of the demethylating agent 5-azacytidine increased basal expression and hypoxic induction of erythropoietin. Mechanistically, the profibrotic factor TGF-β1 induced hypermethylation and repression of erythropoietin in pericytes; these effects were prevented by 5-azacytidine treatment. These findings shed light on the molecular mechanisms underlying erythropoietin repression in kidney myofibroblasts and demonstrate that clinically relevant, nontoxic doses of 5-azacytidine can restore erythropoietin production and ameliorate anemia in the setting of kidney fibrosis in mice.",
author = "Chang, {Yu Ting} and Yang, {Ching Chin} and Pan, {Szu Yu} and Chou, {Yu Hsiang} and Chang, {Fan Chi} and Lai, {Chun Fu} and Tsai, {Ming Hsuan} and Hsu, {Huan Lun} and Lin, {Ching Hung} and Chiang, {Wen Chih} and Wu, {Ming Shiou} and Chu, {Tzong Shinn} and Chen, {Yung Ming} and Lin, {Shuei Liong}",
note = "Funding Information: We thank David Brenner (UCSD, La Jolla, California, USA) and Jeremy Duffield (University of Washington, Seattle, Washington, USA) for Col1a1-GFPTg mice; William Stallcup (Burnham Institute, La Jolla, California, USA) for anti-PDGFRβ antibody; the Core Laboratories of the Department of Medical Research of National Taiwan University Hospital; the Cell Sorting Core Facility and Imaging Core Facility of the First Core Laboratory of National Taiwan University College of Medicine for equipment support and technical assistance; the Transgenic Mouse Model Core Facility of the National Core Facility Program for Biotechnology, the Ministry of Science and Technology (MOST), Taiwan; the Gene Knockout Mouse Core Laboratory of National Taiwan University Center of Genomic Medicine; and Mars T.Y. Lin for editing the manuscript. Y.M. Chen is supported by MOST (101- 2314-B-002-084, 104-2314-B-002-156). S.L. Lin is supported by MOST (102-2628-B-002-015, 102-2321-B002-045, 103-2321- B-002-014), National Taiwan University Hospital (102-S2042, 103-S2405, 104-UN015, 104-EDN02), National Taiwan University (NTU-ICRP-104R7559-2), and the Mrs. Hsiu-Chin Lee Kidney Research Foundation.",
year = "2016",
month = feb,
day = "1",
doi = "10.1172/JCI82819",
language = "English",
volume = "126",
pages = "721--731",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "American Society for Clinical Investigation",
number = "2",
}