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Divergent Expression Patterns for Hypoxia-Inducible Factor-1 and Aryl Hydrocarbon Receptor Nuclear Transporter-2 in Developing Kidney

Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas

Correspondence to Dr. Dale R. Abrahamson, Department of Anatomy and Cell Biology, University of Kansas Medical Center, MS 3038, 3901 Rainbow Boulevard, Kansas City, KS 66160. Phone: 913-588-7000; Fax: 913-588-2710; E-mail: dabrahamson{at}kumc.edu

The hypoxia-inducible factors (HIF) are / 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 subunit. When oxygen tension falls, HIF- subunits translocate to the nucleus and, upon dimerization with HIF-, 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- subunits are stable regardless of oxygen concentration and constitutively translocate to the nucleus. It was shown previously that HIF-1 protein expression is nearly ubiquitous in newborn kidney and that HIF-1 dimerizes with either HIF-1 or -2. Here it is shown that aryl hydrocarbon receptor nuclear transporter-2 (ARNT2/HIF-2) also heterodimerized with HIF-1 and -2. ARNT2/HIF-2 protein was highly expressed in newborn kidney but decreased significantly with age, whereas HIF-1 levels remained relatively constant. By immunohistochemical analysis, widespread expression of HIF-1 was observed in developing and mature kidneys. ARNT2/HIF-2 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-2 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-2 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-1 and -2 suggest divergent roles during kidney development for these highly related bHLH-PAS proteins.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673