DNA methyltransferase inhibition restores erythropoietin production in fibrotic murine kidneys
DNA methyltransferase inhibition restores erythropoietin production in fibrotic murine kidneys
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DOI：
10.1172/jci82819
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发表时间：
2016-02-01
影响因子：
15.9
通讯作者：
Lin, Shuei-Long
中科院分区：
文献类型：
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作者：
Chang, Yu-Ting;Yang, Ching-Chin;Lin, Shuei-Long
肾脏促红细胞生成素生成细胞(REPC)仍然存在于慢性肾脏疾病患者的肾脏中，但这些细胞在低氧刺激下不能产生足够的促红细胞生成素。使用HIF稳定剂治疗可以挽救这些细胞中促红细胞生成素的产生，但纤维化肾脏中促红细胞生成素对贫血刺激的反应降低的机制仍不清楚。在这里，我们展示了成纤维样FOXD1(+)前体细胞来源的肾脏周细胞，其特征是表达α1型胶原和PDGFRβ，通过HIF2α调节产生促红细胞生成素，但当这些细胞分化为肌成纤维细胞时，这种产生被抑制。DNA甲基转移酶和促红细胞生成素高甲基化在肌成纤维细胞中上调。肌肉成纤维细胞暴露于纳摩尔浓度的脱甲基剂5-氮杂胞苷增加了基础表达和低氧诱导的促红细胞生成素。在机制上，促纤维化因子转化生长因子-β1诱导周细胞中促红细胞生成素的高甲基化和抑制；这些作用可被5-氮胞苷治疗所阻止。这些发现阐明了肾脏肌成纤维细胞中促红细胞生成素抑制的分子机制，并证明了临床上无毒剂量的5-氮胞苷可以恢复促红细胞生成素的产生，并改善小鼠肾脏纤维化时的贫血。
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 alpha 1 type I collagen and PDGFR beta, produce erythropoietin through HIF2 alpha 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-beta 1 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.