期刊
BLOOD
卷 121, 期 8, 页码 1436-1445出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-08-449181
关键词
-
类别
资金
- MeDDrive-Programm (TU Dresden, Germany)
- DFG [WI 3291/1-1, WI 3291/1-2, FA225/22]
- Swiss National Science Foundation
- National Institutes of Health [5R01EY019721]
- COST Action [TD0901]
- Deutsche Forschungsgemeinschaft [DFG] Germany
- British Heart Foundation [RG/10/15/28578] Funding Source: researchfish
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)
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据