title: Hypoxia-inducible factor-2alpha-expressing interstitial fibroblasts are the only renal cells that express erythropoietin under hypoxia-inducible factor stabilization.
abstract: The adaptation of erythropoietin production to oxygen supply is determined by the abundance of hypoxia-inducible factor (HIF), a regulation that is induced by a prolyl hydroxylase. To identify cells that express HIF subunits (HIF-1alpha and HIF-2alpha) and erythropoietin, we treated Sprague-Dawley rats with the prolyl hydroxylase inhibitor FG-4497 for 6 h to induce HIF-dependent erythropoietin transcription. The kidneys were analyzed for colocalization of erythropoietin mRNA with HIF-1alpha and/or HIF-2alpha protein along with cell-specific identification markers. FG-4497 treatment strongly induced erythropoietin mRNA exclusively in cortical interstitial fibroblasts. Accumulation of HIF-2alpha was observed in these fibroblasts and in endothelial and glomerular cells, whereas HIF-1alpha was induced only in tubular epithelia. A large proportion (over 90% in the juxtamedullary cortex) of erythropoietin-expressing cells coexpressed HIF-2alpha. No colocalization of erythropoietin and HIF-1alpha was found. Hence, we conclude that in the adult kidney, HIF-2alpha and erythropoietin mRNA colocalize only in cortical interstitial fibroblasts, which makes them the key cell type for renal erythropoietin synthesis as regulated by HIF-2alpha.
authors.affiliation: Department of Anatomy, Charité, Berlin, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Paliege
authors.forename: Christian
authors.initials: C
authors.lastname: Rosenberger
authors.forename: Anja
authors.initials: A
authors.lastname: Bondke
authors.forename: Lina
authors.initials: L
authors.lastname: Sciesielski
authors.forename: Ahuva
authors.initials: A
authors.lastname: Shina
authors.forename: Samuel N
authors.initials: SN
authors.lastname: Heyman
authors.forename: Lee A
authors.initials: LA
authors.lastname: Flippin
authors.forename: Michael
authors.initials: M
authors.lastname: Arend
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Klaus
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bachmann
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis*; D004921:Erythropoietin / Q000096:biosynthesis*; D005347:Fibroblasts / Q000378:metabolism*; D007668:Kidney / Q000166:cytology* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D000099162:Endothelial PAS Domain-Containing Protein 1