title: HIF-1α is a protective factor in conditional PHD2-deficient mice suffering from severe HIF-2α-induced excessive erythropoiesis.
abstract: Erythropoiesis must be tightly balanced to guarantee adequate oxygen delivery to all tissues in the body. This process relies predominantly on the hormone erythropoietin (EPO) and its transcription factor hypoxia inducible factor (HIF). Accumulating evidence suggests that oxygen-sensitive prolyl hydroxylases (PHDs) are important regulators of this entire system. Here, we describe a novel mouse line with conditional PHD2 inactivation (cKO P2) in renal EPO producing cells, neurons, and astrocytes that displayed excessive erythrocytosis because of severe overproduction of EPO, exclusively driven by HIF-2α. In contrast, HIF-1α served as a protective factor, ensuring survival of cKO P2 mice with HCT values up to 86%. Using different genetic approaches, we show that simultaneous inactivation of PHD2 and HIF-1α resulted in a drastic PHD3 reduction with consequent overexpression of HIF-2α-related genes, neurodegeneration, and lethality. Taken together, our results demonstrate for the first time that conditional loss of PHD2 in mice leads to HIF-2α-dependent erythrocytosis, whereas HIF-1α protects these mice, providing a platform for developing new treatments of EPO-related disorders, such as anemia.
authors.affiliation: Emmy Noether Research Group, University of Technology, Dresden, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Franke
authors.forename: Joanna
authors.initials: J
authors.lastname: Kalucka
authors.forename: Soulafa
authors.initials: S
authors.lastname: Mamlouk
authors.forename: Rashim Pal
authors.initials: RP
authors.lastname: Singh
authors.forename: Antje
authors.initials: A
authors.lastname: Muschter
authors.forename: Alexander
authors.initials: A
authors.lastname: Weidemann
authors.forename: Vasuprada
authors.initials: V
authors.lastname: Iyengar
authors.forename: Steffen
authors.initials: S
authors.lastname: Jahn
authors.forename: Kathrin
authors.initials: K
authors.lastname: Wieczorek
authors.forename: Kathrin
authors.initials: K
authors.lastname: Geiger
authors.forename: Michael
authors.initials: M
authors.lastname: Muders
authors.forename: Alex M
authors.initials: AM
authors.lastname: Sykes
authors.forename: David M
authors.initials: DM
authors.lastname: Poitz
authors.forename: Tatsiana
authors.initials: T
authors.lastname: Ripich
authors.forename: Teresa
authors.initials: T
authors.lastname: Otto
authors.forename: Sybille
authors.initials: S
authors.lastname: Bergmann
authors.forename: Georg
authors.initials: G
authors.lastname: Breier
authors.forename: Gustavo
authors.initials: G
authors.lastname: Baretton
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Fong
authors.forename: David R
authors.initials: DR
authors.lastname: Greaves
authors.forename: Stefan
authors.initials: S
authors.lastname: Bornstein
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
authors.forename: Joachim
authors.initials: J
authors.lastname: Fandrey
authors.forename: Max
authors.initials: M
authors.lastname: Gassmann
authors.forename: Ben
authors.initials: B
authors.lastname: Wielockx
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000502:physiology; D002478:Cells, Cultured; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D006411:Hematopoiesis, Extramedullary / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D015603:Keratinocytes / Q000166:cytology; D007668:Kidney / Q000166:cytology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism; D011086:Polycythemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index; D013921:Thrombocytopenia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D011393:Procollagen-Proline Dioxygenase; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C490189:Egln1 protein, mouse