PHF14: an innate inhibitor against the progression of renal fibrosis following folic acid-induced kidney injury.
PHF14: an innate inhibitor against the progression of renal fibrosis following folic acid-induced kidney injury.
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PHF14：一种先天抑制剂，可抑制叶酸诱导的肾损伤后肾纤维化的进展。
DOI：
10.1038/srep39888
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发表时间：
2017-01-03
影响因子：
4.6
通讯作者：
Mao Z
中科院分区：
文献类型：
--
作者：
Yang B;Chen S;Wu M;Zhang L;Ruan M;Chen X;Chen Z;Mei C;Mao Z
PHF 14是一个新发现的胚胎组织间充质生长调节因子。先前的研究表明，phf 14缺失突变体在出生后就由于主要器官（包括肾脏）的间质组织增生而死亡。本研究的目的是探讨PHF 14在肾纤维化中的作用。通过研究慢性肾损伤小鼠模型，我们发现在叶酸给药诱导的肾损伤后，PHF 14在纤维化肾脏中上调。与野生型小鼠相比，PHF 14-null小鼠在促纤维化刺激后表现出更严重的肾纤维化。此外，大鼠肾成纤维细胞中的PHF 14通过转化生长因子-β（TGF-β）刺激而上调;而当smad 3磷酸化被阻断时，这种上调被抑制。染色质免疫沉淀（ChIP）分析进一步表明磷酸化Smad 3（p-Smad 3）作为转录因子增强PHF 14表达。PHF 14表达的缺乏增强了TGF-β诱导的I型胶原和α-平滑肌肌动蛋白（α-SMA）的体外合成。PHF 14通过选择性抑制血小板源性生长因子受体-α（PDGFR-α）的转录，参与抑制血小板源性生长因子（PDGF）信号的过度激活。总之，在体内和体外纤维化模型中，PHF 14表达上调，TGF-β/smad 3/PHF 14通路通过抑制PDGFR-α表达在TGF-β主导的肾促纤维化过程中充当自限性机制。
PHF14 is a newly identified regulator of mesenchyme growth in embryonic tissues. Previous studies have shown that phf14-null mutants die just after birth due to interstitial tissue hyperplasia in major organs, including the kidneys. The aim of this study was to investigate PHF14 function in renal fibrosis. By studying the chronic kidney injury mouse model, we found that PHF14 was upregulated in fibrotic kidneys after renal insults induced by folic acid administration. Compared with wild-type mice, PHF14-null mice showed more severe renal fibrosis after pro-fibrotic stimuli. Moreover, PHF14 in rat renal fibroblasts was upregulated by transforming growth factor-β (TGF-β) stimulation; while this upregulation was inhibited when smad3 phosphorylation was blocked. A chromatin immunoprecipitation (ChIP) assay further indicated that phospho-smad3 (p-smad3) acted as a transcription factor to enhance PHF14 expression. A lack of PHF14 expression enhanced collagen I and α-smooth muscle actin (α-SMA) synthesis induced by TGF-β in vitro. PHF14 was involved in inhibition of platelet-derived growth factor (PDGF) signaling overactivation by selectively repressing PDGF receptor-α (PDGFR-α) transcription. In summary, PHF14 expression was upregulated in fibrotic models in vivo and in vitro, and the TGF-β/smad3/PHF14 pathway acted as a self-limiting mechanism in the TGF-β-dominated renal pro-fibrotic process by suppressing PDGFR-α expression.
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