scholarly journals Oxidants are dispensable for HIF1α stability in hypoxia

2020 ◽  
Author(s):  
Amit Kumar ◽  
Manisha Vaish ◽  
Saravanan S. Karuppagounder ◽  
Irina Gazaryan ◽  
John W. Cave ◽  
...  
Keyword(s):  
Antioxidant Enzymes ◽  
Protein Stability ◽  
Oxygen Sensor ◽  
Lipid Peroxides ◽  
Prolyl Hydroxylase ◽  
Disease States ◽  
Hif Pathway ◽  
Hif Prolyl Hydroxylase ◽  
Kinetics Of

AbstractHypoxic adaptation mediated by HIF transcription factors has been shown to require mitochondria. Current models suggest that mitochondria regulate oxygen sensor (HIF prolyl hydroxylase) activity and HIF1α stability during hypoxia by either increasing mitochondrial peroxide as a second messenger or by serving as oxygen consumers that enhance the kinetics of cytoplasmic oxygen reduction. Here, we address the role of mitochondrial peroxide specifically in regulating HIF1α stability. We use state-of-the-art tools to evaluate the role of peroxide and other reactive oxygen species (ROS) in regulating HIF1α stability. We show that antioxidant enzymes are not homeostatically induced nor are peroxide levels increased in hypoxia. Forced expression of diverse antioxidant enzymes, all of which diminish peroxide, had disparate effects on HIF1α protein stability. Reduction of lipid peroxides by glutathione peroxidase-4 or superoxide by mitochondrial SOD failed to influence HIF1α protein stability. These data showed that mitochondrial, cytosolic and lipid ROS are dispensable for HIF1α stability and should affirm therapeutic efforts to activate the HIF pathway in disease states by HIF prolyl hydroxylase inhibition.

scholarly journals HIF1α stabilization in hypoxia is not oxidant-initiated

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Amit Kumar ◽  
Manisha Vaish ◽  
Saravanan S Karuppagounder ◽  
Irina Gazaryan ◽  
John W Cave ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Antioxidant Enzymes ◽  
Glutathione Peroxidase ◽  
Protein Stability ◽  
Lipid Peroxides ◽  
Second Messenger ◽  
Hypoxic Adaptation

Hypoxic adaptation mediated by HIF transcription factors requires mitochondria, which have been implicated in regulating HIF1α stability in hypoxia by distinct models that involve consuming oxygen or alternatively converting oxygen into the second messenger peroxide. Here, we use a ratiometric, peroxide reporter, HyPer to evaluate the role of peroxide in regulating HIF1α stability. We show that antioxidant enzymes are neither homeostatically induced nor are peroxide levels increased in hypoxia. Additionally, forced expression of diverse antioxidant enzymes, all of which diminish peroxide, had disparate effects on HIF1α protein stability. Moreover, decrease in lipid peroxides by glutathione peroxidase-4 or superoxide by mitochondrial SOD, failed to influence HIF1α protein stability. These data show that mitochondrial, cytosolic or lipid ROS were not necessary for HIF1α stability, and favor a model where mitochondria contribute to hypoxic adaptation as oxygen consumers.

scholarly journals Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients

2017 ◽  
Vol 45 (3) ◽  
pp. 187-199 ◽  
Author(s):  
Francesco Locatelli ◽  
Steven Fishbane ◽  
Geoffrey A. Block ◽  
Iain C. Macdougall
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Iron Metabolism ◽  
Treatment Options ◽  
Prolyl Hydroxylase ◽  
Hypoxia Inducible Factors ◽  
Anemia Management ◽  
Safety Considerations ◽  
Hif Pathway ◽  
Hif Prolyl Hydroxylase

Background: Anemia, a common complication of chronic kidney disease (CKD), has previously been attributed primarily to decreased production of erythropoietin. More recently, it has become apparent that the etiology of anemia involves several other factors, most notably dysfunctional iron metabolism, mediated via increased hepcidin activity and reduced clearance. Current management of anemia in patients with advanced CKD is based on erythropoiesis-stimulating agents and iron supplementation, along with red blood cell transfusions when necessary; however, safety considerations associated with these therapies highlight the need to pursue alternative treatment options targeting other mechanisms such as hypoxia-inducible factors (HIFs) that act as central regulators of erythropoiesis by coordinating a series of graded hypoxic responses. Summary: This review discusses the discovery of the HIF pathway and its regulation via HIF prolyl hydroxylase enzymes in the context of erythropoiesis and iron metabolism. The rationale for targeting this pathway and the clinical development of HIF prolyl hydroxylase inhibitors are reviewed, with a commentary on the potential implications of this class of agents in CKD anemia management. Key Messages: Pharmacologic activation of the HIF pathway results in a transient pseudo-hypoxic state that stimulates erythropoiesis in CKD patients with anemia. Results from clinical studies of a number of HIF prolyl hydroxylase inhibitors are increasingly available and provide support for the continued evaluation of the risk-benefit ratio of this novel therapeutic approach to the treatment of anemia in CKD.

The role of kinetics of water and amide bonding in protein stability

Soft Matter ◽  
2008 ◽  
Vol 4 (2) ◽  
pp. 328-336 ◽  
Author(s):  
D. Porter ◽  
F. Vollrath
Keyword(s):  
Protein Stability ◽  
Kinetics Of

scholarly journals The oxygen sensor Prolyl hydroxylase domain 2 regulates the in vivo suppressive capacity of regulatory T cells

2021 ◽  
Author(s):  
Yousra Ajouaou ◽  
Abdulkader Azouz ◽  
Anaelle Taquin ◽  
Hind Hussein ◽  
Fabienne Andris ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cell ◽  
Oxygen Sensor ◽  
Prolyl Hydroxylase ◽  
Treg Function ◽  
Ifn Γ ◽  
Prolyl Hydroxylase Domain

The oxygen sensor PHD2 (prolyl hydroxylase domain 2) plays an important role in cell hypoxia adaptation by regulating the stability of HIF proteins (HIF1α and HIF2α) in numerous cell types including T lymphocytes. The role of oxygen sensor on immune cells, in particular on regulatory T cell (Treg) function, has not been fully elucidated. The purpose of our study was to evaluate the role of PHD2 in the regulation of Treg phenotype and function. We demonstrate herein that selective ablation of PHD2 expression in Treg (PHD2ΔTreg mice) leads to a spontaneous systemic inflammatory syndrome, as evidenced by weight loss, development of a rectal prolapse, splenomegaly, shortening of the colon and elevated expression of IFN-γ in the mesenteric lymph nodes, intestine and spleen. PHD2 deficiency in Tregs led to an increased number of activated CD4 conventional T cells expressing an effector/Th1-like phenotype. Concomitantly, the expression of innate-type cytokines such as IL1-β, IL-12p40, IL-12p35 and TNF-α was found to be elevated in peripheral (gut) tissues and spleen. PHD2ΔTreg mice also displayed an enhanced sensitivity to DSS-induced colitis and to toxoplasmosis, suggesting that PHD2-deficient Tregs do not efficiently control inflammatory response in vivo, in particular immune responses characterized by IFN-γ production. Further analysis revealed that Treg dysregulation is largely prevented in PHD2-HIF2α (PHD2-HIF2αΔTreg mice), but not in PHD2-HIF1α (PHD2-HIF1αΔTreg mice) double KOs, suggesting an important and possibly selective role of the PHD2-HIF2α axis in the control of Treg function. Finally, the transcriptomic analysis of PHD2-deficient Tregs revealed an altered expression of several chemokine receptors including CXCR3, a finding corroborated by the altered in vivo localization of PHD2-deficient Tregs in splenic tissues. Collectively, these findings uncover an important role of the PHD2-HIF2α axis in regulatory T cell positioning and trafficking.

scholarly journals The oxygen sensor Prolyl hydroxylase domain 2 regulates the in vivo suppressive capacity of regulatory T cells

2021 ◽  
Author(s):  
Yousra Ajouaou ◽  
Abdulkader Azouz ◽  
Anaelle Taquin ◽  
Hind Hussein ◽  
Fabienne Andris ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cell ◽  
Oxygen Sensor ◽  
Prolyl Hydroxylase ◽  
Treg Function ◽  
Ifn Γ ◽  
Prolyl Hydroxylase Domain

Abstract The oxygen sensor PHD2 (prolyl hydroxylase domain 2) plays an important role in cell hypoxia adaptation by regulating the stability of HIF proteins (HIF1α and HIF2α) in numerous cell types including T lymphocytes. The role of oxygen sensor on immune cells, in particular on regulatory T cell (Treg) function, has not been fully elucidated. The purpose of our study was to evaluate the role of PHD2 in the regulation of Treg phenotype and function. We demonstrate herein that selective ablation of PHD2 expression in Treg (PHD2ΔTreg mice) leads to a spontaneous systemic inflammatory syndrome, as evidenced by weight loss, development of a rectal prolapse, splenomegaly, shortening of the colon and elevated expression of IFN-γ in the mesenteric lymph nodes, intestine and spleen. PHD2 deficiency in Tregs led to an increased number of activated CD4 conventional T cells expressing an effector/Th1-like phenotype. Concomitantly, the expression of innate-type cytokines such as IL1-β, IL-12p40, IL-12p35 and TNF-α was found to be elevated in peripheral (gut) tissues and spleen. PHD2ΔTreg mice also displayed an enhanced sensitivity to DSS-induced colitis and to toxoplasmosis, suggesting that PHD2-deficient Tregs do not efficiently control inflammatory response in vivo, in particular immune responses characterized by IFN-γ production. Further analysis revealed that Treg dysregulation is largely prevented in PHD2-HIF2α (PHD2-HIF2αΔTreg mice), but not in PHD2-HIF1α (PHD2-HIF1αΔTreg mice) double KOs, suggesting an important and possibly selective role of the PHD2-HIF2α axis in the control of Treg function. Finally, the transcriptomic analysis of PHD2-deficient Tregs revealed an altered expression of several chemokine receptors including CXCR3, a finding corroborated by the altered in vivo localization of PHD2-deficient Tregs in splenic tissues. Collectively, these findings uncover an important role of the PHD2-HIF2α axis in regulatory T cell positioning and trafficking.

scholarly journals Lipid Peroxides and Antioxidant Enzymes in Cisplatin-Induced Chronic Nephrotoxicity in Rats

2005 ◽  
Vol 2005 (3) ◽  
pp. 139-143 ◽  
Author(s):  
Ricardo González ◽  
Cheyla Romay ◽  
Aluet Borrego ◽  
Frank Hernández ◽  
Nelson Merino ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Antioxidant Enzymes ◽  
Glutathione Peroxidase ◽  
Antioxidant System ◽  
Renal Damage ◽  
Lipid Peroxides ◽  
Thiobarbituric Acid ◽  
Thiobarbituric Acid Reactive Substances ◽  
Repeated Doses

Cisplatin (CDDP), an anticancer drug, induces remarkable toxicity in the kidneys of animals and humans and it has been well documented that reactive oxygen species and the renal antioxidant system are strongly involved in acute renal damage induced by CDDP. The aim of the present study was to investigate whether or not the renal antioxidant system plays also an important role in chronic renal damage induced by repeated doses of CDDP (1 mg/kg intraperitoneally twice weekly during 10 weeks in rats). In order to elucidate it, serum creatinine and urea levels, renal glutathione and thiobarbituric acid-reactive substances (TBARS) content, as well as renal superoxide dismutase and glutathione peroxidase activities were measured in the kidney homogenates of chronically CDDP-treated rats and additionally histological studies were performed in the rat kidneys. The chronic treatment with CDDP induced a significant increase in creatinine and urea levels in serum, but the other parameters mentioned above were not significantly modified as compared to the values in nontreated rats. Taking into account these results, we conclude that chronic CDDP administration induces also severe nephrotoxicity, in contrast to CDDP acute application, without any significant modification in the activity of relevant antioxidant enzymes such as superoxide dismutase and glutathione peroxidase, renal glutathione and lipid peroxides, by which the role of the antioxidant system in chronic nephrotoxicity induced by CDDP in rats is uncertain.

scholarly journals Catalytic Antioxidants in the Kidney

Antioxidants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 130
Author(s):  
Yu Ah Hong ◽  
Cheol Whee Park
Keyword(s):  
Antioxidant Enzymes ◽  
Reactive Nitrogen Species ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Lipid Peroxides ◽  
Hypertensive Nephropathy ◽  
Antioxidant Agents

Reactive oxygen species and reactive nitrogen species are highly implicated in kidney injuries that include acute kidney injury, chronic kidney disease, hypertensive nephropathy, and diabetic nephropathy. Therefore, antioxidant agents are promising therapeutic strategies for kidney diseases. Catalytic antioxidants are defined as small molecular mimics of antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase, and some of them function as potent detoxifiers of lipid peroxides and peroxynitrite. Several catalytic antioxidants have been demonstrated to be effective in a variety of in vitro and in vivo disease models that are associated with oxidative stress, including kidney diseases. This review summarizes the evidence for the role of antioxidant enzymes in kidney diseases, the classifications of catalytic antioxidants, and their current applications to kidney diseases.

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