Defects in embryonic development of EGLN1/PHD2 knockdown transgenic mice are associated with induction of Igfbp in the placenta

Ozolins̆, Terence R.S.; Fisher, Timothy S.; Nadeau, D. M.; Stock, Jeffrey L.; Klein, Anita S.; Milici, Anthony J.; Morton, Daniel G.; Wilhelms, Margaret B.; Brissette, William H.; Li, Baiyong

doi:10.1016/j.bbrc.2009.08.057

Cited by 17 publications

(13 citation statements)

References 27 publications

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“…Recent RNAi-based studies confirmed the major role of PHD2 in Epo regulation in vitro as well as in vivo and showed that FIH and the other PHD family members can play a modulatory role in Epo gene expression (32,98). However, to directly investigate the function of these proteins in the kidney, a transgenic mouse model would be required which targets specifically the REPOS cells.…”

Section: Hereditary Erythrocytosis Reveals Phd2 Vhl and Hif-2␣ As Kmentioning

confidence: 88%

Regulated oxygen sensing by protein hydroxylation in renal erythropoietin-producing cells

Wenger

Hoogewijs

2010

American Journal of Physiology-Renal Physiology

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The kidney is a major site of systemic oxygen sensing, regulating blood erythrocyte and hence oxygen content by hypoxia-inducible erythropoietin (Epo) expression. A constant ratio between blood perfusion and oxygen consumption, a stable corticomedullary oxygen gradient, and a relatively low tissue Po(2) are the prerequisites for the function of renal Epo-producing and oxygen-sensing (REPOS) cells, which are located in the juxtamedullary cortex. In kidney disease, renal oxygen consumption is decreased, leading to an increase in Po(2), dysfunction of REPOS cells, and anemia. The molecular principles of cellular oxygen sensing have been elucidated in the last few years, and genetically altered mouse models as well as hereditary diseases causing erythrocytosis have clarified the oxygen-signaling cascade leading to increased Epo expression in REPOS cells. However, the consequences of a number of recently discovered factors for the regulation of oxygen signaling in REPOS cells are unclear, asking for novel cell culture models which might be hampered by the putative neuron-like nature of this enigmatic cell type.

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Section: Hereditary Erythrocytosis Reveals Phd2 Vhl and Hif-2␣ As Kmentioning

confidence: 88%

Regulated oxygen sensing by protein hydroxylation in renal erythropoietin-producing cells

Wenger

Hoogewijs

2010

American Journal of Physiology-Renal Physiology

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“…For instance, PHD1−/− mice demonstrate a reprogrammed basal metabolic profile in normal tissue which decreases exercise performance but these animals are protected against acute liver and muscle ischemia 39,40 . PHD2 homozygous knockout is embryonic lethal due to developmental angiogenesis dysfunction 41,42 . PHD2 heterozygous knockout animals demonstrate enhanced tumor angiogenesis but decreased metastasis 41 .…”

Section: Prolyl-hydroxylases and Hif Expressionmentioning

confidence: 99%

Hypoxia: an alarm signal during intestinal inflammation

Colgan

Taylor

2010

Nat Rev Gastroenterol Hepatol

395

405

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Intestinal epithelial cells that line the mucosal surface of the gastrointestinal tract are positioned between an anaerobic lumen and a highly metabolic lamina propria. As a result of this unique anatomy, intestinal epithelial cells function within a steep physiologic oxygen gradient relative to other cell types. Furthermore, during active inflammatory disease such as IBD, metabolic shifts toward hypoxia are severe. Studies in vitro and in vivo have shown that the activation of hypoxia-inducible factor (HIF) serves as an alarm signal for the resolution of inflammation in various murine disease models. Amelioration of disease occurs, at least in part, through transcriptional up-regulation of non-classical epithelial barrier genes. There is much recent interest in harnessing hypoxia-inducible pathways, including targeting the hypoxia-inducible factor (HIF) and the proyl-hydroxylase enzyme (which stabilizes HIF), for therapy of IBD. Here, we review the signaling pathways involved and define how hypoxia may serve as an endogenous alarm signal for mucosal inflammatory disease. We also discuss the upside and potential downsides of targeting these pathways to treat patients with IBD.

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“…Studies in PHD1 −/− mice, for example, have revealed decreased exercise performance, abnormal basal metabolism (136, 137), and increased intestinal barrier function due to decreased epithelial apoptosis (138). By contrast, homozygous PHD2-knockout is embryonically lethal due to abnormal developmental angiogenesis (139, 140), and PHD2-heterozygous knockout animals show enhanced tumor angiogenesis (139). PHD3-homozygous knockout mice show reduced neuronal apoptosis, abnormal sympathoadrenal development, and reduced blood pressure (141).…”

Section: Therapeutic Implications Of Inflammatory Hypoxiamentioning

confidence: 99%

Hypoxia and Mucosal Inflammation

Colgan

Campbell

Kominsky

2016

Annu. Rev. Pathol. Mech. Dis.

106

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Sites of inflammation are defined by significant changes in metabolic activity. Recent studies have suggested that O2 metabolism and hypoxia play a prominent role in inflammation so-called “inflammatory hypoxia,” which results from a combination of recruited inflammatory cells (e.g., neutrophils and monocytes), the local proliferation of multiple cell types, and the activation of multiple O2-consuming enzymes during inflammation. These shifts in energy supply and demand result in localized regions of hypoxia and have revealed the important function off the transcription factor HIF (hypoxia-inducible factor) in the regulation of key target genes that promote inflammatory resolution. Analysis of these pathways has provided multiple opportunities for understanding basic mechanisms of inflammation and has defined new targets for intervention. Here, we review recent work addressing tissue hypoxia and metabolic control of inflammation and immunity.

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Defects in embryonic development of EGLN1/PHD2 knockdown transgenic mice are associated with induction of Igfbp in the placenta

Cited by 17 publications

References 27 publications

Regulated oxygen sensing by protein hydroxylation in renal erythropoietin-producing cells

Regulated oxygen sensing by protein hydroxylation in renal erythropoietin-producing cells

Hypoxia: an alarm signal during intestinal inflammation

Hypoxia and Mucosal Inflammation

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