Expression of Hypoxia-Inducible Factor-1α and -2α in... : Journal of the American Society of Nephrology (original) (raw)

Hormones, Growth Factors, Cell Signaling, Cell Biology and Structure

Expression of Hypoxia-Inducible Factor-1α and -2α in Hypoxic and Ischemic Rat Kidneys

Rosenberger, Christian*,†; Mandriota, Stefano‡; Ju[Combining Diaeresis]rgensen, Jan Steffen*; Wiesener, Michael S.*; Ho[Combining Diaeresis]rstrup, Jan H.*; Frei, Ulrich*; Ratcliffe, Peter J.‡; Maxwell, Patrick H.‡; Bachmann, Sebastian†; Eckardt, Kai-Uwe*

Departments of *Nephrology and Medical Intensive Care and †Anatomy, Charite[Combining Acute Accent], Humboldt University, Berlin, Germany, and ‡Welcome Trust Centre for Human Genetics, Oxford, United Kingdom.

Correspondence to Dr. Kai-Uwe Eckardt, Department of Nephrology and Medical Intensive Care, Charite[Combining Acute Accent], Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. Phone: ++49-30-4505-53433; Fax: ++49-30-4505-53909; E-mail: [email protected]

Accepted March 07, 2002

Received January 29, 2002

Journal of the American Society of Nephrology 13(7):p 1721-1732, July 2002. | DOI: 10.1097/01.ASN.0000017223.49823.2A

Abstract

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 response in vivo are 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.