title: Inducible glomerular erythropoietin production in the adult kidney.
abstract: Hypoxia-inducible factor (HIF)-2-triggered erythropoietin production in renal interstitial fibroblast-like cells is the physiologically relevant source of erythropoietin for regulating erythropoiesis. During renal fibrosis, these cells transform into myofibroblasts and lose their ability to produce sufficient erythropoietin leading to anemia. To find if other cells for erythropoietin production might exist in the kidney we tested for the capability of nonepithelial glomerular cells to elaborate erythropoietin. Therefore, HIF transcription factors were stabilized by cell-specific deletion of the von Hippel-Lindau (VHL) gene. Inducible deletion of VHL in glomerular connexin40-expressing cells (endothelial, renin-expressing, and mesangial cells) markedly increased glomerular erythropoietin mRNA expression levels, plasma erythropoietin concentrations, and hematocrit values. These changes were mimicked by inducible cell-specific VHL deletion in renin-expressing and in mesangial cells but not in endothelial cells. The increases of erythropoietin production were absent, when VHL was co-deleted with HIF-2. The induction of glomerular erythropoietin expression was associated with the downregulation of juxtaglomerular renin expression, again in a HIF-2-dependent manner. Thus, VHL deletion in renin-expressing and in mesangial cells induces the capability to produce relevant amounts of erythropoietin and to suppress renin expression in the adult kidney if HIF-2 is stabilized.
authors.affiliation: Institute of Physiology, University of Regensburg, Regensburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Gerl
authors.affiliation: Developmental Biology Institute, Aix-Marseille University, Marseille, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Miquerol
authors.affiliation: Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.
authors.forename: Vladimir T
authors.initials: VT
authors.lastname: Todorov
authors.affiliation: Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.
authors.forename: Christian P M
authors.initials: CP
authors.lastname: Hugo
authors.affiliation: Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, and University of Münster, Faculty of Medicine, Münster, Germany.
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
authors.affiliation: Institute of Physiology, University of Regensburg, Regensburg, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Kurtz
authors.affiliation: Institute of Physiology, University of Regensburg, Regensburg, Germany.
authors.forename: Birgül
authors.initials: B
authors.lastname: Kurt