title: Chronic hypoxia-inducible transcription factor-2 activation stably transforms juxtaglomerular renin cells into fibroblast-like cells in vivo.
abstract: On the basis of previous observations that deletion of the von Hippel-Lindau protein (pVHL) in juxtaglomerular (JG) cells of the kidney suppresses renin and induces erythropoietin expression, this study aimed to characterize the events underlying this striking change of hormone expression. We found that renin cell-specific deletion of pVHL in mice leads to a phenotype switch in JG cells, from a cuboid and multiple vesicle-containing form into a flat and elongated form without vesicles. This shift of cell phenotype was accompanied by the disappearance of marker proteins for renin cells (e.g., aldo-keto reductase family 1, member 7 and connexin 40) and by the appearance of markers of fibroblast-like cells (e.g., collagen I, ecto-5'-nucleotidase, and PDGF receptor-β). Furthermore, hypoxia-inducible transcription factor-2α (HIF-2α) protein constitutively accumulated in these transformed cells. Codeletion of pVHL and HIF-2α in JG cells completely prevented the phenotypic changes. Similar to renin expression in normal JG cells, angiotensin II negatively regulated erythropoietin expression in the transformed cells. In summary, chronic activation of HIF-2 in renal JG cells leads to a reprogramming of the cells into fibroblast-like cells resembling native erythropoietin-producing cells located in the tubulointerstitium.
authors: Institute of Physiology, University of Regensburg, Regensburg, Germany birguel.kurt@vkl.uni-regensburg.de.
authors: Birguel
authors: B
authors: Kurt
authors: Institute of Physiology, University of Regensburg, Regensburg, Germany.
authors: Katharina
authors: K
authors: Gerl
authors: Institute of Physiology, University of Regensburg, Regensburg, Germany.
authors: Christian
authors: C
authors: Karger
authors: Institute of Physiology, University of Regensburg, Regensburg, Germany.
authors: Ilona
authors: I
authors: Schwarzensteiner
authors: Institute of Physiology, University of Regensburg, Regensburg, Germany.
authors: Armin
authors: A
authors: Kurtz
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D004921:Erythropoietin / Q000097:blood*; D005347:Fibroblasts / Q000378:metabolism; D007606:Juxtaglomerular Apparatus / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D012083:Renin / Q000097:blood* / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D006623:von Hippel-Lindau Disease / Q000097:blood / Q000473:pathology*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D015720:5'-Nucleotidase; D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D024042:Collagen Type I; D004921:Erythropoietin; D020797:Receptor, Platelet-Derived Growth Factor beta; D012083:Renin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1
keywords: erythropoietin; fibroblast; renin-angiotensin system