Hypoxia-inducible factor–2 (HIF-2) regulates hepatic erythropoietin in vivo

Rankin, Erinn B.; Biju, Mangatt P.; Liu, Qingdu; Unger, Travis L.; Rha, Jennifer; Johnson, Randall S.; Simon, M. Celeste; Keith, Brian; Haase, Volker H.

doi:10.1172/jci30117

Cited by 514 publications

(481 citation statements)

References 72 publications

Supporting

Mentioning

436

Contrasting

Unclassified

Order By: Relevance

“…Conditional knockout of HIF-2α after birth demonstrated that HIF-2α plays a critical role in adult erythropoiesis [13]. In addition, studies using mice with conditional knockout of HIF-1α and/or HIF-2α in hepatocytes revealed that the hypoxic induction of liver EPO in anemic mice was also HIF-2α dependent [14].…”

Section: Mechanisms Of Renal Erythropoietin Productionmentioning

confidence: 99%

Hypoxia and the HIF system in kidney disease

2007

View full text Add to dashboard Cite

The kidney is sensitive to changes in oxygen delivery. This sensitivity has the merit of facilitating the kidneys in their adjustment of erythropoietin (EPO) production to changes in oxygen supply. The main determinant of EPO synthesis is the transcriptional activity of its gene in kidneys, which is related to local oxygen tensions. Regulation of EPO production is mediated by hypoxia-inducible factor (HIF). When local oxygen tension decreases, accumulated HIF binds to the key sequence of the EPO gene, the hypoxia-responsive element (HRE), and activates transcription of EPO. HIF consists of a constitutive β-subunit and one of alternative oxygen-regulated HIF α-subunits (HIF-1α, HIF-2α, and HIF-3α), and HIF-2α is responsible for erythropoietin production. However, the high sensitivity to changes in oxygen tension also makes the kidney prone to hypoxic injury. Severe energy depletion and subsequent activation of a number of critical alterations in metabolism occurs under hypoxic conditions. Hypoxia is also a profibrogenic stimulus. In addition to ischemic acute renal failure, hypoxia can also play a crucial role in the development of nephrotoxic acute kidney injury, radiocontrast nephropathy, and acute glomerulonephritis. Furthermore, accumulating evidence suggests that chronic hypoxia is a final common pathway to end-stage kidney failure in chronic kidney disease. Given that renal hypoxia has pivotal roles on the development and progression of both acute and chronic kidney disease, hypoxia can be a valid therapeutic target for chronic kidney disease. Activation of HIF leads to expression of a variety of adaptive genes in a coordinated manner. Studies utilizing HIF-stimulating agents proved efficacy in various kidney disease models, suggesting that HIF activation is an ideal target of future therapeutic approaches.

show abstract

Section: Mechanisms Of Renal Erythropoietin Productionmentioning

confidence: 99%

Hypoxia and the HIF system in kidney disease

2007

View full text Add to dashboard Cite

show abstract

“…In addition, Hif2a -/-mice display defects in hematopoietic development due to greatly reduced EPO levels in the kidney (Scortegagna et al 2003;Scortegagna et al 2005;Rankin et al 2007). Administration of exogenous EPO reverts this phenotype as well as some of the other defects associated with Hif2a elimination (Scortegagna et al 2005).…”

Section: Phenotypic Effects Of Hif-2α Eliminationmentioning

confidence: 99%

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

Pietras

Johnsson

Påhlman

2010

Current Topics in Microbiology and Immunology

View full text Add to dashboard Cite

“…Renal cysts at low frequency; inactivation of ARNT, but not HIF-1a suppressed the development of renal cysts Liver Haase et al 76 Rankin et al 31 Rankin et al 32 …”

Section: Proximal Renal Tubulementioning

confidence: 99%

“…For example, genes encoding glycolytic enzymes appear to be predominantly controlled by HIF-1, 29 whereas HIF-2 appears to be the main regulator of VEGF and EPO in tissues that express both HIF-1 and HIF-2. [30][31][32][33] Target gene preference may be the result of tissue-specific interactions with other nuclear factors, differential interactions with transcriptional cofactors or a reflection of tissue-and celltype-dependent differences in the ratios of HIF-a protein levels (for a review on this topic see Wenger et al 28 ).…”

mentioning

confidence: 99%

The VHL tumor suppressor and HIF: insights from genetic studies in mice

2008

View full text Add to dashboard Cite

The von Hippel-Lindau tumor suppressor gene product, pVHL, functions as the substrate recognition component of an E3-ubiquitin ligase, which targets the oxygen-sensitive a-subunit of hypoxia-inducible factor (HIF) for rapid proteasomal degradation under normoxic conditions and as such plays a central role in molecular oxygen sensing. Mutations in pVHL can be found in familial and sporadic clear cell carcinomas of the kidney, hemangioblastomas of the retina and central nervous system, and pheochromocytomas, underscoring its gatekeeper function in the pathogenesis of these tumors. Tissue-specific gene targeting of VHL in mice has demonstrated that efficient execution of pVHL-mediated HIF proteolysis under normoxia is fundamentally important for survival, proliferation, differentiation and normal physiology of many cell types, and has provided novel insights into the biological function of individual HIF transcription factors. In this review, we discuss the role of HIF in the development of the VHL phenotype. Germ-line mutations in the von Hippel-Lindau tumor (VHL) suppressor can be found in patients with VHL disease, a rare familial tumor syndrome characterized by the development of highly vascularized tumors in multiple organs. Major clinical manifestations of VHL disease include hemangioblastomas of the retina and central nervous system (CNS), renal cysts and renal cell carcinoma of the clear cell type (CC-RCC), pancreatic cysts and tumors, as well as pheochromocytomas. 1 The VHL tumor suppressor is also mutated in the majority of sporadic CC-RCCs, 2 highlighting its critical and central role in the regulation of cell growth and differentiation of epithelial kidney cells. Although the molecular function of the VHL gene product, pVHL, was initially not known when it was first identified by positional cloning in 1993, 3 observations that oxygen-dependent regulation of hypoxia-inducible genes was lost in VHL-deficient cell lines suggested a role for pVHL in oxygen sensing. [4][5][6] In a seminal paper, Maxwell et al. 7 showed that pVHL was critical for targeting the a-subunit of hypoxia-inducible factor (HIF) for oxygen-dependent proteolysis, thus providing a direct molecular link between VHLassociated tumorigenesis and oxygen sensing via HIF. HIFs belong to the PAS (Per-arylhydrocarbon receptor nuclear translocator (ARNT)-Sim) family of basic helix-loop-helix (bHLH) transcription factors and bind DNA as heterodimers. They consist of an oxygen-sensitive a-subunit and a constitutively expressed b-subunit, also known as ARNT or HIF-b. pVHL associates with the elongins B and C, cullin2 and Rbx [8][9][10][11][12] and functions as the substrate recognition component of an E3-ubiquitin ligase that ubiquitylates HIF-a. [13][14][15][16][17][18][19] All three HIF a-subunits, HIF-1a, HIF-2a and HIF-3a interact with pVHL. 7,20 This pVHL-HIF-a interaction is highly conserved between species, requires iron-and oxygen-dependent hydroxylation of specific proline residues (Pro402 and Pro564 in human HIF-1a; Pro405 and Pro531 in ...

show abstract

Hypoxia-inducible factor–2 (HIF-2) regulates hepatic erythropoietin in vivo

Cited by 514 publications

References 72 publications

Hypoxia and the HIF system in kidney disease

Hypoxia and the HIF system in kidney disease

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

The VHL tumor suppressor and HIF: insights from genetic studies in mice

Contact Info

Product

Resources

About