Freeburg Paul B, Abrahamson Dale R
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City 66160, USA.
J Am Soc Nephrol. 2004 Oct;15(10):2569-78. doi: 10.1097/01.ASN.0000141464.02967.29.
The hypoxia-inducible factors (HIF) are alpha/beta heterodimeric transcription factors of the basic helix-loop-helix-Per-Arnt-Sim (bHLH-PAS) superfamily and are chiefly responsible for cellular adaptation to oxygen deprivation. HIF function relies on the stabilization of the alpha subunit. When oxygen tension falls, HIF-alpha subunits translocate to the nucleus and, upon dimerization with HIF-beta, activate transcription of target genes, including vascular endothelial growth factor, vascular endothelial growth factor receptor-1 and -2, and WT-1, which are vital for kidney development. HIF-beta subunits are stable regardless of oxygen concentration and constitutively translocate to the nucleus. It was shown previously that HIF-1beta protein expression is nearly ubiquitous in newborn kidney and that HIF-1beta dimerizes with either HIF-1alpha or -2alpha. Here it is shown that aryl hydrocarbon receptor nuclear transporter-2 (ARNT2/HIF-2beta) also heterodimerized with HIF-1alpha and -2alpha. ARNT2/HIF-2beta protein was highly expressed in newborn kidney but decreased significantly with age, whereas HIF-1beta levels remained relatively constant. By immunohistochemical analysis, widespread expression of HIF-1beta was observed in developing and mature kidneys. ARNT2/HIF-2beta protein distribution was restricted to distal segments of developing nephrons and in mature kidney was confined specifically to thick ascending limb of Henle's loop. The data presented here suggest that ARNT2/HIF-2beta is required at high levels during nephrogenesis in distal tubules and later exclusively in thick ascending limb. Furthermore, Hypoxyprobe-1 and lotus lectin co-localization studies showed that developing proximal convoluted tubules were the most severely hypoxic nephron segment in immature kidney. Because HIF-2beta protein was not abundantly expressed in this segment, it may not be engaged in mediating responses to severe hypoxia. The differential distribution patterns for HIF-1beta and -2beta suggest divergent roles during kidney development for these highly related bHLH-PAS proteins.
缺氧诱导因子（HIF）是碱性螺旋-环-螺旋-珀-阿恩特-西姆（bHLH-PAS）超家族的α/β异二聚体转录因子，主要负责细胞对缺氧的适应。HIF的功能依赖于α亚基的稳定性。当氧张力下降时，HIF-α亚基转位至细胞核，并与HIF-β二聚化后，激活包括血管内皮生长因子、血管内皮生长因子受体-1和-2以及WT-1等靶基因的转录，这些基因对肾脏发育至关重要。HIF-β亚基无论氧浓度如何都很稳定，并持续转位至细胞核。先前研究表明，HIF-1β蛋白表达在新生肾脏中几乎普遍存在，且HIF-1β与HIF-1α或-2α二聚化。本文研究表明，芳烃受体核转运蛋白-2（ARNT2/HIF-2β）也与HIF-1α和-2α异二聚化。ARNT2/HIF-2β蛋白在新生肾脏中高表达，但随年龄增长显著下降，而HIF-1β水平相对保持恒定。通过免疫组化分析，在发育中和成熟的肾脏中均观察到HIF-1β的广泛表达。ARNT2/HIF-2β蛋白分布局限于发育中的肾单位远端节段，在成熟肾脏中则特异性地局限于髓袢升支粗段。本文数据表明，ARNT2/HIF-2β在远端肾小管肾发生过程中高水平表达是必需的，随后仅在髓袢升支粗段表达。此外，Hypoxyprobe-1和莲花凝集素共定位研究表明，发育中的近端曲管是未成熟肾脏中缺氧最严重的肾单位节段。由于HIF-2β蛋白在该节段中表达不丰富，它可能不参与介导对严重缺氧的反应。HIF-1β和-2β的不同分布模式表明，这些高度相关的bHLH-PAS蛋白在肾脏发育过程中具有不同的作用。
