HIF-1α is a protective factor in conditional PHD2-βdeficient mice suffering from severe HIF-2-induced excessive erythropoiesis

Autor: Kathrin Geiger, Ben Wielockx, Guo-Hua Fong, Georg Breier, Vasuprada Iyengar, David M. Poitz, Max Gassmann, Gustavo B. Baretton, Joanna Kalucka, David R. Greaves, Teresa Otto, Alex M. Sykes, Alexander Weidemann, S. Bergmann, Steffen Jahn, Antje Muschter, Kristin Franke, Joachim Fandrey, Stefan R. Bornstein, Michael H. Muders, Rashim Pal Singh, Soulafa Mamlouk, Triantafyllos Chavakis, Kathrin Wieczorek, Tatsiana Ripich
Přispěvatelé: University of Zurich, Wielockx, Ben
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Keratinocytes
Male
1303 Biochemistry
2720 Hematology
Medizin
nerve degeneration
Kidney
Severity of Illness Index
Biochemistry
1307 Cell Biology
Nerve Degeneration/genetics
Mice
0302 clinical medicine
Basic Helix-Loop-Helix Transcription Factors
Cells
Cultured
Mice
Knockout
0303 health sciences
heart sound p2
Polycythemia/genetics
Neurodegeneration
Hematopoiesis
Extramedullary/physiology
Brain
Hematology
Kidney/cytology
10081 Institute of Veterinary Physiology
purl.org/pe-repo/ocde/ford#3.02.06 [https]
Haematopoiesis
medicine.anatomical_structure
Hypoxia-inducible factors
10076 Center for Integrative Human Physiology
Hematopoiesis
Extramedullary
030220 oncology & carcinogenesis
Thrombocytopenia/genetics
Erythropoiesis
Female
Procollagen-proline dioxygenase
medicine.drug
Hypoxia-Inducible Factor 1
alpha Subunit/genetics
medicine.medical_specialty
kidney
mice
Immunology
Procollagen-Proline Dioxygenase
610 Medicine & health
Polycythemia
Brain/physiology
Biology
Hypoxia-Inducible Factor-Proline Dioxygenases
03 medical and health sciences
Red Cells
Iron
and Erythropoiesis
Procollagen-Proline Dioxygenase/genetics
Internal medicine
medicine
protective factors
Animals
Humans
Erythropoietin
Transcription factor
030304 developmental biology
2403 Immunology
Basic Helix-Loop-Helix Transcription Factors/genetics
Keratinocytes/cytology
Erythropoietin/genetics
Cell Biology
Fibroblasts
Hypoxia-Inducible Factor 1
alpha Subunit
medicine.disease
Thrombocytopenia
Erythrocytosis
Mice
Inbred C57BL
Endocrinology
Fibroblasts/cytology
Nerve Degeneration
Cancer research
570 Life sciences
biology
erythropoiesis
Zdroj: BLOOD
Franke, K, Kalucka, J, Mamlouk, S, Singh, R P, Muschter, A, Weidemann, A, Iyengar, V, Jahn, S, Wieczorek, K, Geiger, K, Muders, M, Sykes, A M, Poitz, D M, Ripich, T, Otto, T, Bergmann, S, Breier, G, Baretton, G, Fong, G-H, Greaves, D R, Bornstein, S, Chavakis, T, Fandrey, J, Gassmann, M & Wielockx, B 2013, ' HIF-1α is a protective factor in conditional PHD2-deficient mice suffering from severe HIF-2α-induced excessive erythropoiesis ', Blood, vol. 121, no. 8, pp. 1436-45 . https://doi.org/10.1182/blood-2012-08-449181
DOI: 10.1182/blood-2012-08-449181
Popis: 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.
Databáze: OpenAIRE
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