title: Erythropoietin production by PDGFR-β(+) cells.
abstract: PDGFR-β-expressing cells of the kidneys are considered as a relevant site of erythropoietin (EPO) production. The origin of these cells, their contribution to renal EPO production, and if PDGFR-β-positive cells in other organs are also capable to express EPO are less clear. We addressed these questions in mice, in which hypoxia-inducible transcription factors were stabilized in PDGFR-β(+) cells by inducible deletion of the von Hippel-Lindau (Vhl) protein. Vhl deletion led to a 600-fold increase of plasma EPO concentration, 170-fold increase of renal EPO messenger RNA (mRNA) levels, and an increase of hematocrit values up to 70 %. Intrarenal localization of EPO-expressing cells coincided with the zonal heterogeneity and distribution of cells expressing PDGFR-β. Amongst a variety of extrarenal organs only adrenal glands showed significant EPO mRNA expression after Vhl deletion in PDGFR-β(+) cells. EPO mRNA, plasma EPO, and hematocrit fell to subnormal values if HIF-2α, but not HIF-1α, was deleted either alone or in combination with Vhl in PDGFR-β(+) cells. Treatment of mice with a prolyl-hydroxylase inhibitor caused an increase of EPO mRNA abundance and plasma EPO concentrations in wild-type mice and in mice lacking HIF-1α in PDGFR-β(+) cells but exerted no effect in mice lacking HIF-2α in PDGFR-β(+) cells. These findings suggest that PDGFR-β(+) cells are the only relevant site of EPO expression in the kidney and that HIF-2 is the essential transcription factor triggering EPO expression therein. Moreover, our findings suggest that PDGFR-β(+) cells elaborating EPO might arise from the metanephric mesenchyme, rather than from the neural crest.
authors.affiliation: Institute of Physiology, University of Regensburg, 93053, Regensburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Gerl
authors.affiliation: Institute of Physiology and Zürich Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Nolan
authors.affiliation: Institute of Physiology, University of Regensburg, 93053, Regensburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Karger
authors.affiliation: Institute of Physiology, University of Regensburg, 93053, Regensburg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Fuchs
authors.affiliation: Institute of Physiology and Zürich Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland.
authors.forename: Roland H
authors.initials: RH
authors.lastname: Wenger
authors.affiliation: Institute of Biochemistry, Emil-Fischer-Center, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Claus C
authors.initials: CC
authors.lastname: Stolt
authors.affiliation: Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Willam
authors.affiliation: Institute of Physiology, University of Regensburg, 93053, Regensburg, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Kurtz
authors.affiliation: Institute of Physiology, University of Regensburg, 93053, Regensburg, Germany. birguel.kurt@ur.de.
authors.forename: Birgül
authors.initials: B
authors.lastname: Kurt
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D004921:Erythropoietin / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007668:Kidney / Q000000981:diagnostic imaging / Q000378:metabolism; D051379:Mice; D064800:Prolyl-Hydroxylase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064800:Prolyl-Hydroxylase Inhibitors; D012333:RNA, Messenger; D020797:Receptor, Platelet-Derived Growth Factor beta; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1
keywords: Adrenal gland; Erythropoietin; HIF-2; Inducible deletion of Vhl; Kidney; PDGFR-β-expressing cells