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

被引：68

作者：

Franke, Kristin ^{[1
,2
]}

Kalucka, Joanna ^{[1
,2
]}

Mamlouk, Soulafa ^{[1
,2
]}

Singh, Rashim Pal ^{[1
,2
]}

Muschter, Antje ^{[1
,2
]}

Weidemann, Alexander ^{[3
]}

Iyengar, Vasuprada ^{[1
,2
]}

Jahn, Steffen ^{[2
]}

Wieczorek, Kathrin ^{[2
]}

Geiger, Kathrin ^{[2
]}

Muders, Michael ^{[2
]}

Sykes, Alex M. ^{[4
]}

Poitz, David M. ^{[5
]}

Ripich, Tatsiana ^{[6
]}

Otto, Teresa ^{[7
]}

Bergmann, Sybille ^{[8
]}

Breier, Georg ^{[2
,9
,10
]}

Baretton, Gustavo ^{[2
]}

Fong, Guo-Hua ^{[11
]}

Greaves, David R. ^{[12
]}

Bornstein, Stefan ^{[13
]}

Chavakis, Triantafyllos ^{[13
]}

Fandrey, Joachim ^{[7
]}

Gassmann, Max ^{[14
,15
,16
]}

Wielockx, Ben ^{[1
,2
,9
,10
]}

机构：

[1] Tech Univ Dresden, Emmy Noether Res Grp, D-01307 Dresden, Germany

[2] Tech Univ Dresden, Inst Pathol, D-01307 Dresden, Germany

[3] Univ Clin Erlangen, Dept Nephrol & Hypertens, Erlangen, Germany

[4] Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany

[5] Tech Univ Dresden, Dept Internal Med & Cardiol, D-01307 Dresden, Germany

[6] Tech Univ Dresden, Inst Physiol Chem, D-01307 Dresden, Germany

[7] Univ Duisburg Essen, Dept Physiol, Essen, Germany

[8] Tech Univ Dresden, Inst Clin Chem & Lab Med, D-01307 Dresden, Germany

[9] Tech Univ Dresden, DFG Res Ctr, D-01307 Dresden, Germany

[10] Tech Univ Dresden, Cluster Excellence Regenerat Therapies Dresden, D-01307 Dresden, Germany

[11] Univ Connecticut, Ctr Hlth, Dept Cell Biol, Ctr Vasc Biol, Farmington, CT USA

[12] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England

[13] Carl Gustav Carus Univ Hosp, Dept Med 3, Dresden, Germany

[14] Univ Zurich, Inst Vet Physiol, Vetsuisse Fac, Zurich, Switzerland

[15] Univ Zurich, Zurich Ctr Integrat Human Physiol ZIHP, Zurich, Switzerland

[16] Univ Peruana Cayetano Heredia, Lima, Peru

来源：

BLOOD | 2013年 / 121卷 / 08期

基金：

美国国家卫生研究院; 瑞士国家科学基金会;

关键词：

HYDROXYLASE DOMAIN PROTEIN-2; PHD2; MUTATION; HIF2A GENE; ERYTHROCYTOSIS; EXPRESSION; HYPOXIA; CYTOKINES; POLYCYTHEMIA; ASTROCYTES; PATHWAY;

D O I：

10.1182/blood-2012-08-449181

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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-2 alpha. In contrast, HIF-1 alpha 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-1 alpha resulted in a drastic PHD3 reduction with consequent overexpression of HIF-2 alpha-related genes, neurodegeneration, and lethality. Taken together, our results demonstrate for the first time that conditional loss of PHD2 in mice leads to HIF-2 alpha-dependent erythrocytosis, whereas HIF-1 alpha protects these mice, providing a platform for developing new treatments of EPO-related disorders, such as anemia. (Blood. 2013;121(8):1436-1445)

引用

页码：1436 / 1445

页数：10

共 51 条

[1] Disturbance in the HIF-1α pathway associated with erythrocytosis:: Further evidences brought by frameshift and nonsense mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene [J].