DNA methyltransferase inhibition restores erythropoietin production in fibrotic murine kidneys

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 und...

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Published in:The Journal of clinical investigation 2016-02, Vol.126 (2), p.721-731
Main Authors: Chang, Yu-Ting, Yang, Ching-Chin, Pan, Szu-Yu, Chou, Yu-Hsiang, Chang, Fan-Chi, Lai, Chun-Fu, Tsai, Ming-Hsuan, Hsu, Huan-Lun, Lin, Ching-Hung, Chiang, Wen-Chih, Wu, Ming-Shiou, Chu, Tzong-Shinn, Chen, Yung-Ming, Lin, Shuei-Liong
Format: Article
Language:English
Subjects:
Anemia
Animals
Azacitidine - pharmacology
Basic Helix-Loop-Helix Transcription Factors - genetics
Basic Helix-Loop-Helix Transcription Factors - metabolism
Biomedical research
Collagen Type I - biosynthesis
Collagen Type I - genetics
Deoxyribonucleic acid
Development and progression
DNA
DNA methylation
DNA Modification Methylases - antagonists & inhibitors
DNA Modification Methylases - genetics
DNA Modification Methylases - metabolism
Enzymes
Erythropoietin
Erythropoietin - biosynthesis
Erythropoietin - genetics
Fibroblasts
Fibrosis
Genetic aspects
Health aspects
Hospitals
Hypoxia
Kidney diseases
Kidneys
Laboratories
Medical research
Mice
Mice, Transgenic
Myofibroblasts - metabolism
Myofibroblasts - pathology
Pericytes - metabolism
Pericytes - pathology
Plasma
Proteins
Receptor, Platelet-Derived Growth Factor beta - genetics
Receptor, Platelet-Derived Growth Factor beta - metabolism
Regulation
Renal Insufficiency, Chronic - drug therapy
Renal Insufficiency, Chronic - genetics
Renal Insufficiency, Chronic - metabolism
Renal Insufficiency, Chronic - pathology
Rodents
Studies
University colleges
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/jci82819