Oxygen-regulated Transferrin Expression Is Mediated by Hypoxia-inducible Factor-1

Rolfs, Andreas; Kvietikova, Ivica; Gassmann, Max; Wenger, Roland H.

doi:10.1074/jbc.272.32.20055

Cited by 377 publications

(267 citation statements)

References 40 publications

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“…Furthermore, HIF activation influences genes that play important roles in iron metabolism, including transferrin [15], ferroportin [16], and possibly hepcidin [16]. Thus, in addition to increased EPO expression, HIF regulates various pathways leading to efficient erythropoiesis [16].…”

Section: Mechanisms Of Renal Erythropoietin Productionmentioning

confidence: 99%

Hypoxia and the HIF system in kidney disease

2007

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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.

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Section: Mechanisms Of Renal Erythropoietin Productionmentioning

confidence: 99%

Hypoxia and the HIF system in kidney disease

2007

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“…Reporter gene and mammalian one-and two-hybrid assays Cloning of the HIF-dependent firefly luciferase reporter gene constructs pGLTfHBSww, pGLTfHBSmm and pH3SVL was described previously (Rolfs et al, 1997;Wanner et al, 2000). Cells were co-transfected with 500 ng pH3SVL and 20 ng pRLSV40 Renilla luciferase reporter vector (Promega, Madison, WI, USA) to control for differences in transfection efficiency.…”

Section: Immunoblottingmentioning

confidence: 99%

Onconeuronal cerebellar degeneration-related antigen, Cdr2, is strongly expressed in papillary renal cell carcinoma and leads to attenuated hypoxic response

Balamurugan

et al. 2009

Oncogene

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The onconeuronal cerebellar degeneration-related antigen Cdr2 is associated with paraneoplastic syndromes. Neoplastic expression of Cdr2 in ovary and breast tumors triggers an autoimmune response that suppresses tumor growth by developing tumor immunity, but culminates in cerebellar degeneration when Cdr2-specific immune cells recognize neuronal Cdr2. We identified Cdr2 as a novel interactor of the hypoxia-inducible factor (HIF) prolyl-4-hydroxylase PHD1 and provide evidence that Cdr2 might represent a novel important tumor antigen in renal cancer. Strong Cdr2 protein expression was observed in 54.2% of papillary renal cell carcinoma (pRCC) compared with 7.8% of clear-cell RCC and no staining was observed in chromophobe RCC or oncocytoma. High Cdr2 protein levels correlated with attenuated HIF target gene expression in these solid tumors, and Cdr2 overexpression in tumor cell lines reduced HIF-dependent transcriptional regulation. This effect was because of both attenuation of hypoxic protein accumulation and suppression of the transactivation activity of HIF-1a. pRCC is known for its tendency to avascularity, usually associated with a lower pathological stage and higher survival rates. We provide evidence that Cdr2 protein strongly accumulates in pRCC, attenuates the HIF response to tumor hypoxia and may become of diagnostic importance as novel renal tumor marker.

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“…Anemia results in tissue hypoxia, which is a known activator of the expression of many genes involved in iron metabolism, such as transferrin [17], TfR [18,19], ferritin [20], and ceruloplasmin [21]. To evaluate the effect of hypoxia on Lcn2 gene expression, mice were treated with CoCl 2 , a chemical inducer of hypoxia-like responses.…”

Section: Lcn2 Expression Is Stimulated By Hypoxiamentioning

confidence: 99%

Anemia upregulates lipocalin 2 in the liver and serum

Jiang

Constante

Santos

2008

Blood Cells, Molecules, and Diseases

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Lipocalin 2 (Lcn2), a mammalian protein that is expressed and secreted in various pathologic states, binds siderophores, which are high-affnity iron chelators. Besides its role in limiting iron availability to pathogens in the setting of bacterial infection, Lcn2:siderophore complexes can also deliver iron to cells. In this study, we examined Lcn2 regulation in the liver of mice in situations of increased iron utilization, namely, during anemia. Anemia induced by phlebotomy, iron deprivation, or phenylhydrazine treatment was associated with upregulation of Lcn2 gene expression in the liver and elevation of serum Lcn2 protein levels. We further explored the participation of several factors known to co-occur during anemia, including hypoxia, changes in iron levels, and erythropoietic drive, in the regulation of Lcn2 by anemia. We found that hypoxia, but not iron or erythropoietin, caused an induction of Lcn2 expression. The upregulation of Lcn2 levels by anemia and hypoxia, which is not directly mediated by iron or erythropoietin, suggests a possible physiological role for Lcn2 during increased iron utilization and mobilization from stores.

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Oxygen-regulated Transferrin Expression Is Mediated by Hypoxia-inducible Factor-1

Cited by 377 publications

References 40 publications

Hypoxia and the HIF system in kidney disease

Hypoxia and the HIF system in kidney disease

Onconeuronal cerebellar degeneration-related antigen, Cdr2, is strongly expressed in papillary renal cell carcinoma and leads to attenuated hypoxic response

Anemia upregulates lipocalin 2 in the liver and serum

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