scholarly journals Hypoxic regulation of erythropoiesis and iron metabolism

2010 ◽  
Vol 299 (1) ◽  
pp. F1-F13 ◽  
Author(s):  
Volker H. Haase
Keyword(s):  
Transcription Factor ◽  
Blood Cell ◽  
Molecular Basis ◽  
Molecular Mechanisms ◽  
Oxygen Sensor ◽  
Hypoxia Inducible Factor ◽  
Adaptation To Hypoxia ◽  
Cellular Adaptation ◽  
Hypoxic Induction ◽  
Highly Sensitive

The kidney is a highly sensitive oxygen sensor and plays a central role in mediating the hypoxic induction of red blood cell production. Efforts to understand the molecular basis of oxygen-regulated erythropoiesis have led to the identification of erythropoietin (EPO), which is essential for normal erythropoiesis and to the purification of hypoxia-inducible factor (HIF), the transcription factor that regulates EPO synthesis and mediates cellular adaptation to hypoxia. Recent insights into the molecular mechanisms that control and integrate cellular and systemic erythropoiesis-promoting hypoxia responses and their potential as a therapeutic target for the treatment of renal anemia are discussed in this review.

scholarly journals The HIF target ATG9A is essential for epithelial barrier function and tight junction biogenesis

2020 ◽  
Vol 31 (20) ◽  
pp. 2249-2258
Author(s):  
Alexander S. Dowdell ◽  
Ian M. Cartwright ◽  
Matthew S. Goldberg ◽  
Rachael Kostelecky ◽  
Tyler Ross ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Tight Junction ◽  
Barrier Function ◽  
Intestinal Epithelial Cells ◽  
Hypoxia Inducible Factor ◽  
Epithelial Barrier ◽  
Adaptation To Hypoxia ◽  
Intestinal Epithelial ◽  
Hypoxia Response ◽  
Epithelial Barrier Function

The transcription factor hypoxia-inducible factor (HIF) mediates adaptation to hypoxia. We found that HIF regulates the autophagy protein ATG9A in intestinal epithelial cells. Subsequent knockdown of ATG9A resulted in tight junction mislocalization and cytoskeletal defects. These results suggest a link among the hypoxia response, autophagy, and junctional biogenesis.

scholarly journals The Transcription Factor ZNF395 Is Required for the Maximal Hypoxic Induction of Proinflammatory Cytokines in U87-MG Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Christine Herwartz ◽  
Paola Castillo-Juárez ◽  
Linda Schröder ◽  
Blanca L. Barron ◽  
Gertrud Steger
Keyword(s):  
Transcription Factor ◽  
Proinflammatory Cytokines ◽  
Transcriptional Activation ◽  
Hypoxia Inducible Factor ◽  
Tumor Hypoxia ◽  
Hypoxic Induction ◽  
Hypoxic Conditions ◽  
Astrocytoma Cell ◽  
Ambient Oxygen

Hypoxia activates the expression of proangiogenic and survival promoting factors as well as proinflammatory cytokines that support tissue inflammation. Hypoxia and inflammation are associated with tumor progression. The identification of the factors participating in the hypoxia associated inflammation is essential to develop strategies to control tumor hypoxia. The transcription factor ZNF395 was found to be overexpressed in various tumors including glioblastomas particularly in the network of a hypoxic response pointing to a functional role of ZNF395. On the other hand, ZNF395 was suggested to have tumor suppressor activities which may rely on its repression of proinflammatory factors. To address these conflictive observations, we investigated the role of ZNF395 in the expression of proinflammatory cytokines in the astrocytoma cell line U87-MG under hypoxia. We show that ZNF395 is a target gene of the hypoxia inducible factor HIF-1α. By gene expression analysis, RT-PCR and ELISA, we demonstrated that the siRNA-mediated suppression of ZNF395 impairs the hypoxic induction of IL-1β, IL-6, IL-8, and LIF in U87-MG cells. At ambient oxygen concentrations, ZNF395 had no enhancing effect, indicating that this transcriptional activation by ZNF395 is restricted to hypoxic conditions. Our results suggest that ZNF395 contributes to hypoxia associated inflammation by superactivating proinflammatory cytokines.

scholarly journals Clinical significance of expression of the marker of adaptation to hypoxia HIF-1α in pregnant women with initial forms of venous disease

2020 ◽  
Author(s):  
E. Iu. Iupatov ◽  
L. I. Maltseva ◽  
T. P. Zefirova ◽  
R. S. Zamaleeva ◽  
I. M. Ignatiev ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Pregnant Women ◽  
Hypoxia Inducible Factor ◽  
Perinatal Outcomes ◽  
Main Group ◽  
Control Group ◽  
Adaptation To Hypoxia ◽  
Venous Disease ◽  
Healthy Children ◽  
Venous Valves

Aim: to study the activity of the hypoxia marker HIF-1α (hypoxia-inducible factor-1α) in pregnant women with phlebopathy.Materials and Methods. We examined 70 women with phlebopathy in the dynamics of pregnancy. The main group consisted of 30 patients whose newborns had signs of hypoxia; the control group consisted of 40 women with healthy children. All women underwent ultrasound examinations of the veins of the lower extremities and pelvis with an assessment of vascular patency, the condition of the venous valves, and the phenomenon of platelet sludge. The expression of the HIF-1α transcription factor at 18–20 and 36 weeks was performed by real-time PCR.Results. Disorder of veins functional state was found in all pregnant women of the main group, which was accompanied by the formation of platelet sludge of varying degrees in the area of the venous valves in the majority, signs of endothelial dysfunction and venous hypoxia – an increase in the expression of the hypoxia gene HIF1-α by 2.18 times. In the women of the control group the indicators were not violated.Conclusion. The transcription factor HIF1-α can be considered a marker of unfavorable perinatal outcomes in pregnant women with signs of phlebopathy.

scholarly journals HIF-stabilization prevents delayed fracture healing

2020 ◽  
Author(s):  
Annemarie Lang ◽  
Sarah Helfmeier ◽  
Jonathan Stefanowski ◽  
Aditi Kuppe ◽  
Vikram Sunkara ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Hypoxia Inducible Factor ◽  
Cost Effective ◽  
Supporting Cell ◽  
Adaptation To Hypoxia ◽  
Preventive Strategy ◽  
Low Oxygen ◽  
Cellular Adaptation

AbstractThe initial phase of fracture healing decides on success of bone regeneration and is characterized by an inflammatory milieu and low oxygen tension (hypoxia). Negative interference with or prolongation of this fine-tuned initiation phase will ultimately lead to a delayed or incomplete healing such as non-unions which then requires an effective and gentle therapeutic intervention. Common reasons include a dysregulated immune response, immunosuppression or a failure in cellular adaptation to the inflammatory hypoxic milieu of the fracture gap and a reduction in vascularizing capacity by environmental noxious agents (e.g. rheumatoid arthritis, smoking). The hypoxia-inducible factor (HIF)-1α is responsible for the cellular adaptation to hypoxia, activating angiogenesis and supporting cell attraction and migration to the fracture gap. Here, we hypothesized that stabilizing HIF-1α could be a cost-effective and low-risk prevention strategy of fracture healing disorders. Therefore, we combined a well-known HIF-stabilizer – deferoxamine (DFO) – and a less known HIF-enhancer – macrophage migration inhibitory factor (MIF) – to synergistically induce improved fracture healing. Stabilization of HIF-1α enhanced calcification and osteogenic differentiation of MSCs in vitro. In vivo, the application of DFO with or without MIF during the initial healing phase accelerated callus mineralization and vessel formation in a clinically relevant mouse-osteotomy-model in a compromised healing setting. Our findings provide support for a promising preventive strategy towards bone healing disorders in patients with a higher risk due to e.g. delayed neovascularization by accelerating fracture healing using DFO and MIF to stabilize HIF-1α.

Oxygen sensing and hypoxia-induced responses

2007 ◽  
Vol 43 ◽  
pp. 1-16 ◽  
Author(s):  
Mathew L. Coleman ◽  
Peter J. Ratcliffe
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Oxygen Sensing ◽  
Hypoxia Inducible Factor ◽  
Signalling Pathway ◽  
Adaptation To Hypoxia ◽  
Induced Responses ◽  
Intracellular Proteins ◽  
Multicellular Organisms ◽  
Direct Incorporation

Low cellular oxygenation (hypoxia) represents a significant threat to the viability of affected tissues. Multicellular organisms have evolved a highly conserved signalling pathway that directs many of the changes in gene expression that underpin physiological oxygen homoeostasis. Oxygen-sensing enzymes in this pathway control the activity of the HIF (hypoxia-inducible factor) transcription factor by the direct incorporation of molecular oxygen into the post-translational hydroxylation of specific residues. This represents the canonical hypoxia signalling pathway which regulates a plethora of genes involved in adaptation to hypoxia. The HIF hydroxylases have been identified in other biological contexts, consistent with the possibility that they have other substrates. Furthermore, several intracellular proteins have been demonstrated, directly or indirectly, to be hydroxylated, although the protein hydroxylases responsible have yet to be identified. This chapter will summarize what is currently known about the canonical HIF hydroxylase signalling pathway and will speculate on the existence of other oxygen-sensing enzymes and the role they may play in signalling hypoxia through other pathways.

Hypoxic induction ofCtgfis directly mediated by Hif-1

2004 ◽  
Vol 287 (6) ◽  
pp. F1223-F1232 ◽  
Author(s):  
Debra F. Higgins ◽  
Mangatt P. Biju ◽  
Yasuhiro Akai ◽  
Anton Wutz ◽  
Randall S. Johnson ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Hypoxia Inducible Factor ◽  
Direct Interaction ◽  
Tubular Epithelial Cell ◽  
Hypoxic Induction ◽  
Helix Loop Helix ◽  
Expression Of Genes ◽  
Fibrotic Disorders

CTGF plays a significant role in the development of renal fibrosis by mediating the fibrotic effects of transforming growth factor (TGF)-β1and has been shown to be hypoxia inducible in human breast cancer cells. It has been suggested that hypoxia is an important underlying cause for the development of renal fibrosis through the modulation of profibrotic genes. One of the key mediators of the cell's response to lowered oxygen environments is hypoxia-inducible-factor-1 (HIF-1), a basic helix-loop-helix transcription factor, which enables cells to adapt to hypoxia by regulating the expression of genes involved in increasing oxygen availability ( VEGF, erythropoietin) and enhancing glucose uptake and metabolism ( Glut-1, PGK). In this paper, we have used primary tubular epithelial cell cultures from a tetracycline-inducible- Hif- 1α knockout murine model to further elucidate the role of Hif-1 in the hypoxic-induction of Ctgf expression. We show that hypoxia response elements present upstream of Ctgf enable direct interaction of Hif-1 transcription factor with the Ctgf promoter, resulting in increased transcription of Ctgf mRNA. Cells deficient in Hif- 1α were incapable of inducing Ctgf mRNA in response to hypoxia, suggesting an absolute requirement of Hif-1. Furthermore, the observed Hif-1-mediated hypoxic stimulation of Ctgf expression was found to occur independently of TGF-β1signaling. Our findings have important implications for a number of fibrotic disorders in which hypoxia, CTGF, and TGF-β1are involved, including renal, dermal, hepatic, and pulmonary fibrosis.

Mechanisms and triggers of adaptation to hypoxia

2021 ◽  
Vol 19 (3) ◽  
pp. 269-280
Author(s):  
Andrey V. Lyubimov ◽  
Dmitriy V. Cherkashin ◽  
Semen V. Efimov ◽  
Andrey E. Alanichev ◽  
Valeriy S. Ivanov ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Side Effects ◽  
Partial Pressure ◽  
Molecular Mechanisms ◽  
Oxygen Metabolism ◽  
External Factors ◽  
Iron Chelators ◽  
Adaptation To Hypoxia ◽  
Partial Pressure Of Oxygen ◽  
Prophylactic Use

It is believed that hypoxia-induced factor (HIF1) is the key mediator of oxygen metabolism. It was first identified as a transcription factor activated in cells and tissues by lowering the partial pressure of oxygen (O2). The HIF1 activator spectrum includes both external factors hypoxia, psycho-emotional stress and in ternal factors and varies from hormones to iron chelators. This review is dedicated to the molecular mechanisms of HIF1 activation, some of its natural activators HIF1, the potential for which is due to the low level of toxicity and the reduced likelihood of undesirable side effects. In turn, this opens up new options to treat diseases associated with local and general ischemia and hypoxia, the possibilities of their prophylactic use for researchers and clinicians in order to reduce the degree of damage in the event of an unforeseen condition of acute injurious to organs and tissues by hypoxia and reperfusion after it.

scholarly journals Inhibition of Endothelial PHD2 Suppresses Post-Ischemic Kidney Inflammation through Hypoxia-Inducible Factor-1

2020 ◽  
Vol 31 (3) ◽  
pp. 501-516 ◽  
Author(s):  
Ganeshkumar Rajendran ◽  
Michael P. Schonfeld ◽  
Ratnakar Tiwari ◽  
Shengping Huang ◽  
Rafael Torosyan ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Molecular Mechanisms ◽  
Oxygen Sensor ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hypoxia Inducible Factor ◽  
Inflammatory Cells ◽  
Renal Ischemia ◽  
Renal Ischemia Reperfusion Injury

BackgroundProlyl-4-hydroxylase domain-containing proteins 1–3 (PHD1 to PHD3) regulate the activity of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2, transcription factors that are key regulators of hypoxic vascular responses. We previously reported that deficiency of endothelial HIF-2 exacerbated renal ischemia-reperfusion injury, whereas inactivation of endothelial PHD2, the main oxygen sensor, provided renoprotection. Nevertheless, the molecular mechanisms by which endothelial PHD2 dictates AKI outcomes remain undefined.MethodsTo investigate the function of the endothelial PHD2/HIF axis in ischemic AKI, we examined the effects of endothelial-specific ablation of PHD2 in a mouse model of renal ischemia-reperfusion injury. We also interrogated the contribution of each HIF isoform by concurrent endothelial deletion of both PHD2 and HIF-1 or both PHD2 and HIF-2.ResultsEndothelial deletion of Phd2 preserved kidney function and limited transition to CKD. Mechanistically, we found that endothelial Phd2 ablation protected against renal ischemia-reperfusion injury by suppressing the expression of proinflammatory genes and recruitment of inflammatory cells in a manner that was dependent on HIF-1 but not HIF-2. Persistence of renoprotective responses after acute inducible endothelial-specific loss of Phd2 in adult mice ruled out a requirement for PHD2 signaling in hematopoietic cells. Although Phd2 inhibition was not sufficient to induce detectable HIF activity in the kidney endothelium, in vitro experiments implicated a humoral factor in the anti-inflammatory effects generated by endothelial PHD2/HIF-1 signaling.ConclusionsOur findings suggest that activation of endothelial HIF-1 signaling through PHD2 inhibition may offer a novel therapeutic approach against ischemic AKI.

scholarly journals Hypoxia Inducible Factor Pathway and Physiological Adaptation: A Cell Survival Pathway?

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Hemant Kumar ◽  
Dong-Kug Choi
Keyword(s):  
Cell Survival ◽  
Hypoxia Inducible Factor ◽  
Tumor Formation ◽  
Physiological Adaptation ◽  
Metabolic Adaptation ◽  
Excess Oxygen ◽  
Adaptation To Hypoxia ◽  
Cellular Adaptation ◽  
Cellular Environment ◽  
Hif Pathway

Oxygen homeostasis reflects the constant body requirement to generate energy. Hypoxia (0.1–1% O2), physioxia or physoxia (∼1–13%), and normoxia (∼20%) are terms used to define oxygen concentration in the cellular environment. A decrease in oxygen (hypoxia) or excess oxygen (hyperoxia) could be deleterious for cellular adaptation and survival. Hypoxia can occur under both physiological (e.g., exercise, embryonic development, underwater diving, or high altitude) and pathological conditions (e.g., inflammation, solid tumor formation, lung disease, or myocardial infarction). Hypoxia plays a key role in the pathophysiology of heart disease, cancers, stroke, and other causes of mortality. Hypoxia inducible factor(s) (HIFs) are key oxygen sensors that mediate the ability of the cell to cope with decreased oxygen tension. These transcription factors regulate cellular adaptation to hypoxia and protect cells by responding acutely and inducing production of endogenous metabolites and proteins to promptly regulate metabolic pathways. Here, we review the role of the HIF pathway as a metabolic adaptation pathway and how this pathway plays a role in cell survival. We emphasize the roles of the HIF pathway in physiological adaptation, cell death, pH regulation, and adaptation during exercise.

scholarly journals Glucocorticoid-Dependent Mechanisms of Brain Tolerance to Hypoxia

2021 ◽  
Vol 22 (15) ◽  
pp. 7982
Author(s):  
Elena Rybnikova ◽  
Natalia Nalivaeva
Keyword(s):  
Cross Talk ◽  
Glucocorticoid Receptors ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Later Life ◽  
Adaptation To Hypoxia ◽  
Hypoxic Injury ◽  
Hypoxic Tolerance ◽  
Resistance To Stress ◽  
The Brain

Adaptation of organisms to stressors is coordinated by the hypothalamic-pituitary-adrenal axis (HPA), which involves glucocorticoids (GCs) and glucocorticoid receptors (GRs). Although the effects of GCs are well characterized, their impact on brain adaptation to hypoxia/ischemia is still understudied. The brain is not only the most susceptible to hypoxic injury, but also vulnerable to GC-induced damage, which makes studying the mechanisms of brain hypoxic tolerance and resistance to stress-related elevation of GCs of great importance. Cross-talk between the molecular mechanisms activated in neuronal cells by hypoxia and GCs provides a platform for developing the most effective and safe means for prevention and treatment of hypoxia-induced brain damage, including hypoxic pre- and post-conditioning. Taking into account that hypoxia- and GC-induced reprogramming significantly affects the development of organisms during embryogenesis, studies of the effects of prenatal and neonatal hypoxia on health in later life are of particular interest. This mini review discusses the accumulated data on the dynamics of the HPA activation in injurious and non-injurious hypoxia, the role of the brain GRs in these processes, interaction of GCs and hypoxia-inducible factor HIF-1, as well as cross-talk between GC and hypoxic signaling. It also identifies underdeveloped areas and suggests directions for further prospective studies.

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