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erythropoiesis hypoxia

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https://www.readbyqxmd.com/read/28412770/anemia-in-chronic-kidney-disease
#1
Meredith A Atkinson, Bradley A Warady
Anemia is common and associated with adverse outcomes in children with chronic kidney disease (CKD). Many factors contribute to declining hemoglobin as CKD progresses, but impaired production of erythropoietin by failing kidneys is a central cause. Hepcidin-mediated iron restriction also contributes to anemia by downregulating both intestinal iron absorption and release of stored iron for erythropoiesis. The core components of anemia management remain erythropoiesis-stimulating agents (ESA) and iron supplementation, but despite these therapies, a substantial number of children remain anemic...
April 15, 2017: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
https://www.readbyqxmd.com/read/28410559/the-irony-of-iron-overload-and-iron-deficiency-in-chronic-obstructive-pulmonary-disease
#2
Suzanne M Cloonan, Sharon Mumby, Ian M Adcock, Augustine M K Choi, Kian Fan Chung, Gregory J Quinlan
Chronic obstructive pulmonary disease (COPD) is a debilitating inflammatory lung disease associated with cigarette smoking and is third leading cause of death worldwide. With the recent emergence of genome wide association studies (GWAS), the identification of multiple COPD susceptibility genes has enhanced and expanded our understanding of the pathogenic mechanisms associated with this debilitating lung disease. An example of such a pathogenic mechanism is the role of iron metabolism in the onset and progression of COPD...
April 14, 2017: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/28376077/maternal-nutrient-restriction-in-guinea-pigs-leads-to-fetal-growth-restriction-with-evidence-for-chronic-hypoxia
#3
Alexander A Elias, Yohei Maki, Brad Matushewski, Karen Nygard, Timothy R H Regnault, Bryan S Richardson
BACKGROUND: We determined if maternal nutrient restriction (MNR) in guinea pigs leading to fetal growth restriction (FGR), impacts markers for tissue hypoxia implicating a mechanistic role for chronic hypoxia. METHODS: Guinea pigs were fed ad libitum (Control) or 70% of the control diet pre-pregnant switching to 90% at mid-pregnancy (MNR). Near term, Hypoxyprobe-1 (HP-1), a marker of tissue hypoxia, was injected into pregnant sows. Fetuses were then necropsied and liver, kidney and placental tissues were processed for erythropoietin (EPO), EPO-receptor (EPOR), and VEGF protein levels, and for HP-1 immunoreactivity (IR)...
April 4, 2017: Pediatric Research
https://www.readbyqxmd.com/read/28371815/phase-2-studies-of-oral-hypoxia-inducible-factor-prolyl-hydroxylase-inhibitor-fg-4592-for-treatment-of-anemia-in-china
#4
Nan Chen, Jiaqi Qian, Jianghua Chen, Xueqing Yu, Changlin Mei, Chuanming Hao, Gengru Jiang, Hongli Lin, Xinzhou Zhang, Li Zuo, Qiang He, Ping Fu, Xuemei Li, Dalvin Ni, Stefan Hemmerich, Cameron Liu, Lynda Szczech, Anatole Besarab, Thomas B Neff, Kin-Hung Peony Yu, Frank H Valone
Background.: FG-4592 (roxadustat) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (HIF-PHI) promoting coordinated erythropoiesis through the transcription factor HIF. Two Phase 2 studies were conducted in China to explore the safety and efficacy of FG-4592 (USAN name: roxadustat, CDAN name: ), a HIF-PHI, in patients with anemia of chronic kidney disease (CKD), both patients who were dialysis-dependent (DD) and patients who were not dialysis-dependent (NDD). Methods...
March 27, 2017: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/28335733/effects-of-short-term-hyperoxia-on-erythropoietin-levels-and-microcirculation-in-critically-ill-patients-a-prospective-observational-pilot-study
#5
Abele Donati, Elisa Damiani, Samuele Zuccari, Roberta Domizi, Claudia Scorcella, Massimo Girardis, Alessia Giulietti, Arianna Vignini, Erica Adrario, Rocco Romano, Laura Mazzanti, Paolo Pelaia, Mervyn Singer
BACKGROUND: The normobaric oxygen paradox states that a short exposure to normobaric hyperoxia followed by rapid return to normoxia creates a condition of 'relative hypoxia' which stimulates erythropoietin (EPO) production. Alterations in glutathione and reactive oxygen species (ROS) may be involved in this process. We tested the effects of short-term hyperoxia on EPO levels and the microcirculation in critically ill patients. METHODS: In this prospective, observational study, 20 hemodynamically stable, mechanically ventilated patients with inspired oxygen concentration (FiO2) ≤0...
March 23, 2017: BMC Anesthesiology
https://www.readbyqxmd.com/read/28331872/induction-of-erythropoiesis-by-hypoxia-inducible-factor-prolyl-hydroxylase-inhibitors-without-promotion-of-tumor-initiation-progression-or-metastasis-in-a-vegf-sensitive-model-of-spontaneous-breast-cancer
#6
Todd W Seeley, Mark D Sternlicht, Stephen J Klaus, Thomas B Neff, David Y Liu
The effects of pharmacological hypoxia-inducible factor (HIF) stabilization were investigated in the MMTV-Neu(ndl)-YD5 (NeuYD) mouse model of breast cancer. This study first confirmed the sensitivity of this model to increased vascular endothelial growth factor (VEGF), using bigenic NeuYD;MMTV-VEGF-25 mice. Tumor initiation was dramatically accelerated in bigenic animals. Bigenic tumors were also more aggressive, with shortened doubling times and increased lung metastasis as compared to NeuYD controls. In separate studies, NeuYD mice were treated three times weekly from 7 weeks of age until study end with two different HIF prolyl hydroxylase inhibitors (HIF-PHIs), FG-4497 or roxadustat (FG-4592)...
2017: Hypoxia
https://www.readbyqxmd.com/read/28302014/role-of-hepcidin-25-in-chronic-kidney-disease-anemia-and-beyond
#7
Norishi Ueda, Kazuya Takasawa
Iron is an essential element for all living organisms, but produces toxic oxidants. Thus, iron homeostasis is tightly regulated in mammals. Hepcidin-25 (hepcidin) has emerged as a molecule that regulates iron metabolism. Binding of hepcidin to its receptor, ferroportin, inhibits intestinal iron absorption and iron efflux from hepatocytes and macrophages. Decreased hepcidin enhances iron absorption and efflux. Hepcidin could be predictive of iron status and the response to iron supplementation or erythropoietin-stimulating agents...
March 16, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28299673/roles-of-runx-in-hypoxia-induced-responses-and-angiogenesis
#8
Sun Hee Lee, Sarala Manandhar, You Mie Lee
During the past two decades, Runt domain transcription factors (RUNX1, 2, and 3) have been investigated in regard to their function, structural elements, genetic variants, and roles in normal development and pathological conditions. The Runt family proteins are evolutionarily conserved from Drosophila to mammals, emphasizing their physiological importance. A hypoxic microenvironment caused by insufficient blood supply is frequently observed in developing organs, growing tumors, and tissues that become ischemic due to impairment or blockage of blood vessels...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28263291/iron-suppresses-erythropoietin-expression-via-oxidative-stress-dependent-hypoxia-inducible-factor-2-alpha-inactivation
#9
Keisuke Oshima, Yasumasa Ikeda, Yuya Horinouchi, Hiroaki Watanabe, Hirofumi Hamano, Yoshitaka Kihira, Seiji Kishi, Yuki Izawa-Ishizawa, Licht Miyamoto, Tasuku Hirayama, Hideko Nagasawa, Keisuke Ishizawa, Koichiro Tsuchiya, Toshiaki Tamaki
Renal anemia is a major complication in chronic kidney disease (CKD). Iron supplementation, as well as erythropoiesis-stimulating agents, are widely used for treatment of renal anemia. However, excess iron causes oxidative stress via the Fenton reaction, and iron supplementation might damage remnant renal function including erythropoietin (EPO) production in CKD. EPO gene expression was suppressed in mice following direct iron treatment. Hypoxia-inducible factor-2 alpha (HIF-2α), a positive regulator of the EPO gene, was also diminished in the kidney of mice following iron treatment...
March 6, 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28242135/hypoxia-inducible-factor-prolyl-hydroxylase-inhibitors-a%C3%A2-potential-new-treatment-for-anemia-in-patients-with-ckd
#10
REVIEW
Nupur Gupta, Jay B Wish
Erythropoiesis-stimulating agents (ESAs) increase hemoglobin levels, reduce transfusion requirements, and have been the standard of treatment for anemia in patients with chronic kidney disease (CKD) since 1989. Many safety concerns have emerged regarding the use of ESAs, including an increased occurrence of cardiovascular events and vascular access thrombosis. Hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) enzyme inhibitors are a new class of agents for the treatment of anemia in CKD. These agents work by stabilizing the HIF complex and stimulating endogenous erythropoietin production even in patients with end-stage kidney disease...
February 24, 2017: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
https://www.readbyqxmd.com/read/28142212/neuroprotection-and-endocytosis-erythropoietin-receptors-in-insect-nervous-systems
#11
Natasa Miljus, Bita Massih, Marissa A Weis, Jan Vincent Rison, Christel B Bonnas, Inge Sillaber, Hannelore Ehrenreich, Bart R H Geurten, Ralf Heinrich
Erythropoietin (Epo) plays a dual role as an erythropoiesis-stimulating hormone and a locally produced cytoprotectant in various vertebrate tissues. Splice variants and engineered derivatives of Epo that mediate neuroprotection but do not stimulate erythropoiesis suggest that alternative receptors, different from the 'classical' homodimeric receptor involved in haematopoiesis, mediate neuroprotective Epo functions. Previous studies on grasshoppers demonstrated neuroprotective and neuroregenerative effects of Epo that involved similar transduction pathways as in mammals...
January 31, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28132948/added-value-of-hepcidin-quantification-for-the-diagnosis-and-follow-up-of-anemia-related-diseases
#12
REVIEW
Thibaud Lefebvre, Sigismond Lasocki, Martine Fénéant-Thibault, Pierre-Jean Lamy, Séverine Cunat, Madeleine Ropert-Bouchet, Patricia Aguilar-Martinez, Sylvain Lehmann, Constance Delaby
Iron homeostasis is based on a strict control of both intestinal iron absorption and iron recycling through reticulo-endothelial system. Hepcidin controls the iron fluxes in order to maintain sufficient iron levels for erythropoietic activities, hemoproteins synthesis or enzymes function, but also to limit its toxic accumulation throughout the body. Hepcidin expression is regulated by various stimuli: inflammation and iron stimulate the production of the peptide, while anemia, erythropoiesis and hypoxia repress its production...
February 1, 2017: Annales de Biologie Clinique
https://www.readbyqxmd.com/read/28119134/erythropoietin-as-a-performance-enhancing-drug-its-mechanistic-basis-detection-and-potential-adverse-effects
#13
Olivier Salamin, Tiia Kuuranne, Martial Saugy, Nicolas Leuenberger
Erythropoietin (EPO) is the main hormone regulating red blood cell (RBC) production. The large-scale production of a recombinant human erythropoietin (rHuEPO) by biotechnological methods has made possible its widespread therapeutic use as well as its misuse in sports. Since the marketing of the first epoetin in 1989, the development has progressed to the third-generation analogs. However, the production of rHuEPO is costly, and the frequent administration of an injectable formula is not optimal for compliance of therapeutic patients...
January 21, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28118622/targeting-hypoxia-inducible-factors-for-the-treatment-of-anemia-in-chronic-kidney-disease-patients
#14
Francesco Locatelli, Steven Fishbane, Geoffrey A Block, Iain C Macdougall
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...
2017: American Journal of Nephrology
https://www.readbyqxmd.com/read/28018974/hypoxia-sensing-through-%C3%AE-adrenergic-receptors
#15
Hoi I Cheong, Kewal Asosingh, Olivia R Stephens, Kimberly A Queisser, Weiling Xu, Belinda Willard, Bo Hu, Josephine Kam Tai Dermawan, George R Stark, Sathyamangla V Naga Prasad, Serpil C Erzurum
Life-sustaining responses to low oxygen, or hypoxia, depend on signal transduction by HIFs, but the underlying mechanisms by which cells sense hypoxia are not completely understood. Based on prior studies suggesting a link between the β-adrenergic receptor (β-AR) and hypoxia responses, we hypothesized that the β-AR mediates hypoxia sensing and is necessary for HIF-1α accumulation. Beta blocker treatment of mice suppressed hypoxia induction of renal HIF-1α accumulation, erythropoietin production, and erythropoiesis in vivo...
December 22, 2016: JCI Insight
https://www.readbyqxmd.com/read/28002958/discovery-of-n-bis-4-methoxyphenyl-methyl-4-hydroxy-2-pyridazin-3-yl-pyrimidine-5-carboxamide-mk-8617-an-orally-active-pan-inhibitor-of-hypoxia-inducible-factor-prolyl-hydroxylase-1-3-hif-phd1-3-for-the-treatment-of-anemia
#16
John S Debenham, Christina Madsen-Duggan, Matthew J Clements, Thomas F Walsh, Jeffrey T Kuethe, Mikhail Reibarkh, Scott P Salowe, Lisa M Sonatore, Richard Hajdu, James A Milligan, Denise M Visco, Dan Zhou, Russell B Lingham, Dominique Stickens, Julie A DeMartino, Xinchun Tong, Michael Wolff, Jianmei Pang, Randy R Miller, Edward C Sherer, Jeffrey J Hale
The discovery of novel 4-hydroxy-2-(heterocyclic)pyrimidine-5-carboxamide inhibitors of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD) is described. These are potent, selective, orally bioavailable across several species, and active in stimulating erythropoiesis. Mouse and rat studies showed hematological changes with elevations of plasma EPO and circulating reticulocytes following single oral dose administration, while 4-week q.d. po administration in rat elevated hemoglobin levels. A major focus of the optimization process was to decrease the long half-life observed in higher species with early compounds...
December 22, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27978511/effects-of-daprodustat-a-novel-hypoxia-inducible-factor-prolyl-hydroxylase-inhibitor-on-anemia-management-in-japanese-hemodialysis-subjects
#17
Tadao Akizawa, Yoshiharu Tsubakihara, Masaomi Nangaku, Yukihiro Endo, Hiromu Nakajima, Tomoko Kohno, Yukiko Imai, Natsumi Kawase, Katsutoshi Hara, John Lepore, Alexander Cobitz
BACKGROUND: Daprodustat (GSK1278863) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor being developed for treatment of anemia associated with chronic kidney disease (CKD). The effect of daprodustat in Japanese CKD patients with anemia has not been previously investigated. METHODS: We evaluated the relationship between daprodustat dose and hemoglobin response in Japanese patients on hemodialysis (HD) with anemia in a 4-week, phase II, double-blind, placebo-controlled study...
2017: American Journal of Nephrology
https://www.readbyqxmd.com/read/27951566/new-strategies-for-anaemia-management-in-chronic-kidney-disease
#18
Francesco Locatelli, Lucia Del Vecchio
Erythropoiesis-stimulating agents (ESAs) and iron therapy are the standard of care for normocytic normochromic anaemia, which is a frequent comorbidity of patients with chronic kidney disease. In a large percentage of patients, ESAs and iron increase haemoglobin levels, thus reducing the risk of blood transfusions and improving patient quality of life. However, randomised trials have raised some concerns about higher haemoglobin targets and/or high ESA dose use. These concerns include higher cardiovascular and thrombosis risk, cancer progression, and increased mortality...
2017: Contributions to Nephrology
https://www.readbyqxmd.com/read/27833947/erythropoietin-and-co-intrinsic-structure-and-functional-disorder
#19
REVIEW
Vladimir N Uversky, Elrashdy M Redwan
Erythropoietin (Epo) is a heavily glycosylated protein, with its main function being related to erythropoiesis, where it controls red blood cell production via interaction with the Epo receptor (EpoR). It also plays a number of important roles in various hormonal, growth factor, and cytokine pathways. These roles are defined by Epo partners, such as the homodimeric (EpoR)2 receptor, the heterodimeric EpoR/βCR receptor and hypoxia inducing factor (HIF). Although the main structural features of both Epo and EpoR are conserved in vertebrates, the secretion sites of Epo in mammals are different from those in other vertebrates...
December 20, 2016: Molecular BioSystems
https://www.readbyqxmd.com/read/27829948/increased-hematocrit-during-sodium-glucose-cotransporter-2-inhibitor-therapy-indicates-recovery-of-tubulointerstitial-function-in-diabetic-kidneys
#20
REVIEW
Motoaki Sano, Makoto Takei, Yasuyuki Shiraishi, Yoshihiko Suzuki
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been attracting attention for cardiovascular as well as antidiabetic effects since the results of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME Trial) were reported. The hematocrit increases during treatment with SGLT2 inhibitors, which have a diuretic effect but do not cause sufficient hemoconcentration to increase the risk of cerebral infarction. Elevation of the hematocrit during SGLT2 inhibitor therapy is presumed to involve enhancement of erythropoiesis in addition to hemoconcentration...
December 2016: Journal of Clinical Medicine Research
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