Endothelin-converting enzyme is a plausible target gene for hypoxia-inducible factor.
Endothelin-converting enzyme is a plausible target gene for hypoxia-inducible factor.
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DOI：
10.1038/ki.2014.362
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发表时间：
2015-04
影响因子：
19.6
通讯作者：
M. Khamaisi;Hala Toukan;J. Axelrod;C. Rosenberger;G. Skarzinski;A. Shina;R. Meidan;R. Koesters;S. Rosen;G. Walkinshaw;I. Mimura;M. Nangaku;S. Heyman
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文献类型：
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作者：
M. Khamaisi;Hala Toukan;J. Axelrod;C. Rosenberger;G. Skarzinski;A. Shina;R. Meidan;R. Koesters;S. Rosen;G. Walkinshaw;I. Mimura;M. Nangaku;S. Heyman
肾内皮素转换酶（ECE）-1在实验性糖尿病和放射造影剂给药后被诱导，其特征在于肾缺氧、缺氧诱导因子（HIF）稳定和内皮素合成增强。我们在体外和体内检测ECE-1是否可能是HIF的靶基因。ECE-1的转录和表达增加培养的血管内皮细胞和近端肾小管细胞系，缺氧，含羞草碱或氯化钴。已知这些干预通过抑制HIF-脯氨酰羟化酶来稳定HIF信号传导。在大鼠中，含羞草碱或FG-4497抑制HIF-脯氨酰羟化酶可增加肾小管中HIF-1 α的免疫染色，主要是在远端肾单位段。这与显著增强的ECE-1蛋白表达相关，主要在肾髓质。在条件性von Hippel-Lindau基因敲除小鼠中，ECE-1免疫染色随着时间的推移逐渐显著增加，同时HIF表达增强。由于HIF和STAT3是交叉刺激的，我们在小鼠中通过STAT3激活触发HIF表达，转染或注射嵌合IL-6/IL-6受体蛋白，并发现了类似的ECE-1表达增强模式。缺氧内皮细胞中的染色质免疫沉淀序列（ChIP-seq）和PCR分析鉴定了ECE-1启动子和内含子区域的HIF结合。因此，我们的研究结果表明，ECE-1可能是一个新的HIF靶基因。
Renal endothelin-converting enzyme (ECE)-1 is induced in experimental diabetes and following radiocontrast administration, conditions characterized by renal hypoxia, hypoxia-inducible factor (HIF) stabilization, and enhanced endothelin synthesis. Here we tested whether ECE-1 might be a HIF-target genein vitroandin vivo. ECE-1 transcription and expression increased in cultured vascular endothelial and proximal tubular cell lines, subject to hypoxia, to mimosine or cobalt chloride. These interventions are known to stabilize HIF signaling by inhibition of HIF-prolyl hydroxylases. In rats, HIF-prolyl-hydroxylase inhibition by mimosine or FG-4497 increased HIF-1α immunostaining in renal tubules, principally in distal nephron segments. This was associated with markedly enhanced ECE-1 protein expression, predominantly in the renal medulla. A progressive and dramatic increase in ECE-1 immunostaining over time, in parallel with enhanced HIF expression, was also noted in conditional von Hippel-Lindau knockout mice. Since HIF and STAT3 are cross-stimulated, we triggered HIF expression by STAT3 activation in mice, transfected by or injected with a chimeric IL-6/IL-6-receptor protein, and found a similar pattern of enhanced ECE-1 expression. Chromatin immunoprecipitation sequence (ChIP-seq) and PCR analysis in hypoxic endothelial cells identified HIF binding at the ECE-1 promoter and intron regions. Thus, our findings suggest that ECE-1 may be a novel HIF-target gene.