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DNA methyltransferase inhibition restores erythropoietin production in fibrotic murine kidneys
Yu-Ting Chang, … , Yung-Ming Chen, Shuei-Liong Lin
Yu-Ting Chang, … , Yung-Ming Chen, Shuei-Liong Lin
Published February 1, 2016
Citation Information: J Clin Invest. 2016;126(2):721-731. https://doi.org/10.1172/JCI82819.
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Categories: Research Article Nephrology

DNA methyltransferase inhibition restores erythropoietin production in fibrotic murine kidneys

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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.

Authors

Yu-Ting Chang, Ching-Chin Yang, Szu-Yu Pan, Yu-Hsiang Chou, Fan-Chi Chang, Chun-Fu Lai, Ming-Hsuan Tsai, Huan-Lun Hsu, Ching-Hung Lin, Wen-Chih Chiang, Ming-Shiou Wu, Tzong-Shinn Chu, Yung-Ming Chen, Shuei-Liong Lin

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Figure 1

Col1a1-GFP+ pericytes are REPCs.

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Col1a1-GFP+ pericytes are REPCs.
(A) Hematocrit (Hct) and plasma EPO co...
(A) Hematocrit (Hct) and plasma EPO concentrations and renal expression of Epo, Phd2, Phd3, and Vegfa normalized by Ubc in mice with and without phlebotomy (Con). Phlebotomy was performed 1 day before analysis. n = 5 per group. (B) Confocal images of kidney sections of EpoIRES-RFP/+ Col1a1-GFPTg mice. Arrowheads indicate EPO-RFP+Col1a1-GFP+ pericytes. T, renal tubules. Original magnification, ×400. Scale bar: 20 μm. (C) Expression of Epo, Phd2, Phd3, and Vegfa in Col1a1-GFP+PDGFRβ+ kidney pericytes isolated from Col1a1-GFPTg mice. n = 5 per group. (D) Fluorescent (left) and bright-field (right) images of primary cultures of live Col1a1-GFP+ kidney pericytes. Original magnification, ×400. Scale bar: 25 μm. (E) Epo expression and supernatant EPO concentration of Col1a1-GFP+ kidney pericytes cultured in chambers with normoxia (21% O2) or hypoxia (0.5% O2) for 24 hours. n = 4 per group. (F and G) Epo expression of Col1a1-GFP+ kidney pericytes cultured in the presence of CoCl2. n = 4 per group. (H) Epo expression of Col1a1-GFP+ kidney pericytes cultured in the presence of IOX2 for 24 hours. n = 4 per group. Student’s t test and 1-way ANOVA were used for analyses of data in A, C, and E and F–H, respectively. *P < 0.05, †P < 0.01, ‡P < 0.001.
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