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ABSTRACT. Oxygen tensions in the kidney are heterogeneous, and their changes presumably play an important role in renal physiologic and pathophysiologic processes. A family of hypoxia-inducible transcription factors (HIF) have been identified as mediators of transcriptional responses to hypoxia, which include the regulation of erythropoietin, metabolic adaptation, vascular tone, and neoangiogenesis.In vitro, the oxygen-regulated subunits HIF-1α and -2α are expressed in inverse relationship to oxygen tensions in every cell line investigated to date. The characteristics and functional significance of the HIF responsein vivoare largely unknown. High-amplification immunohistochemical analyses were used to study the expression of HIF-1α and -2α in kidneys of rats exposed to systemic hypoxia bleeding anemia, functional anemia (0.1% carbon monoxide), renal ischemia, or cobaltous chloride (which is known to mimic hypoxia). These treatments led to marked nuclear accumulation of HIF-1α and -2α in different renal cell populations. HIF-1α was mainly induced in tubular cells, including proximal segments with exposure to anemia/carbon monoxide, in distal segments with cobaltous chloride treatment, and in connecting tubules and collecting ducts with all stimuli. Staining for HIF-1α colocalized with inducible expression of the target genes heme oxygenase-1 and glucose transporter-1. HIF-2α was not expressed in tubular cells but was expressed in endothelial cells of a small subset of glomeruli and in peritubular endothelial cells and fibroblasts. The kidney demonstrates a marked potential for upregulation of HIF, but accumulation of HIF-1α and HIF-2α is selective with respect to cell type, kidney zone, and experimental conditions, with the expression patterns partly matching known oxygen profiles. The expression of HIF-2α in peritubular fibroblasts suggests a role in erythropoietin regulation.

Original publication

DOI

10.1097/01.asn.0000017223.49823.2a

Type

Journal article

Journal

Journal of the American Society of Nephrology

Publisher

American Society of Nephrology (ASN)

Publication Date

07/2002

Volume

13

Pages

1721 - 1732