Angiogenic growth factors augment K-Cl cotransporter expression in erythroid cells via hypoxia-inducible factor-1α.
Angiogenic growth factors augment K-Cl cotransporter expression in erythroid cells via hypoxia-inducible factor-1α.
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DOI：
10.1002/ajh.23631
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发表时间：
2014-03
影响因子：
12.8
通讯作者：
Joiner, Clinton H.
中科院分区：
文献类型：
--
作者：
Gonsalves, Caryn S.;Crable, Scott;Chandra, Sharat;Li, Wei;Kalra, Vijay K.;Joiner, Clinton H.
氯化钾共转运体(KCC)家族蛋白广泛表达，参与钾离子和氯离子的跨上皮运动和细胞体积的调节。KCC活性在网织红细胞中很高，有助于镰刀状红细胞的脱水。由于镰状细胞患者血浆中血管内皮生长因子(VEGF)和胎盘生长因子(PlGF)水平均升高，且已有研究表明血管内皮生长因子可增加KCC在其他细胞中的表达，因此我们推测VEGF和PlGF影响红系细胞中KCC的表达。人红系K562细胞经血管内皮生长因子和平台生长因子处理后，KCC1、KCC3b和KCC4的mRNA和蛋白水平均升高。血管内皮生长因子和血小板生长因子介导的细胞信号涉及血管内皮生长因子R1及其下游效应分子，特别是PI-3激酶、p38 MAP激酶、mTOR、NADPH氧化酶、JNK激酶和HIF-1α。启动子分析、EMSA和CHIP分析表明，VEGF和PlGF介导的KCC3b和KCC4转录在其启动子中含有缺氧反应元件(HRE)基序。在正常小鼠体内，腺病毒介导的PlGF过表达，导致红系前体细胞mKCC3和mKCC4表达增加，证实了这些结果。我们的研究表明，血管内皮生长因子和血小板生长因子通过激活HIF-1α来调节红系细胞中KCC3b和KCC4的转录，而不依赖于低氧。这些研究为调节红细胞前体细胞体积提供了新的治疗靶点，从而改善镰状细胞病中红细胞脱水的情况。上午好。J.血醇。2014年，89：273-281。©2013 Wiley期刊，Inc.
The potassium chloride cotransporters (KCC) family of proteins are widely expressed and are involved in the transepithelial movement of potassium and chloride ions and the regulation of cell volume. KCC activity is high in reticulocytes, and contributes to the dehydration of sickle red blood cells. Because plasma levels of both vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are elevated in sickle cell individuals, and VEGF has been shown to increase KCC expression in other cells, we hypothesized that VEGF and PlGF influence KCC expression in erythroid cells. Both VEGF and PlGF treatment of human erythroid K562 cells increased both mRNA and protein levels of KCC1, KCC3b, and KCC4. VEGF- and PlGF-mediated cellular signaling involved VEGF-R1 and downstream effectors, specifically, PI-3 kinase, p38 MAP kinase, mTOR, NADPH-oxidase, JNK kinase, and HIF-1α. VEGF and PlGF-mediated transcription of KCC3b and KCC4 involved hypoxia response element (HRE) motifs in their promoters, as demonstrated by promoter analysis, EMSA and ChiP. These results were corroborated in vivo by adenoviral-mediated overexpression of PlGF in normal mice, which led to increased expression of mKCC3 and mKCC4 in erythroid precursors. Our studies show that VEGF and PlGF regulate transcription of KCC3b and KCC4 in erythroid cells via activation of HIF-1α, independent of hypoxia. These studies provide novel therapeutic targets for regulation of cell volume in RBC precursors, and thus, amelioration of dehydration in RBCs in sickle cell disease. Am. J. Hematol. 89:273–281, 2014. © 2013 Wiley Periodicals, Inc.
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影响因子：
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