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erythropoiesis hypoxia

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https://www.readbyqxmd.com/read/28018974/hypoxia-sensing-through-%C3%AE-adrenergic-receptors
#1
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
#2
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
#3
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...
December 16, 2016: American Journal of Nephrology
https://www.readbyqxmd.com/read/27951566/new-strategies-for-anaemia-management-in-chronic-kidney-disease
#4
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
#5
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
#6
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
https://www.readbyqxmd.com/read/27821476/notch-downregulation-and-extramedullary-erythrocytosis-in-hif-prolyl-4-hydroxylase-2-deficient-mice
#7
Mikko N M Myllymäki, Jenni Määttä, Elitsa Y Dimova, Valerio Izzi, Timo Väisänen, Johanna Myllyharju, Peppi Koivunen, Raisa Serpi
Erythrocytosis is mainly driven by erythropoietin, which is regulated by hypoxia-inducible factor (HIF). Mutations in HIF prolyl 4-hydroxylase 2 (HIF-P4H-2/PHD2/EGLN1), the major downregulator of HIFα subunits, are found in familiar erythrocytosis, and large-spectrum conditional inactivation of HIF-P4H-2 in mice leads to severe erythrocytosis. Although bone marrow is the primary site for erythropoiesis, spleen remains capable for extramedullary erythropoiesis. We studied HIF-P4H-2 deficient mice (Hif-p4h-2(gt/gt)) which show slightly induced erythropoiesis upon aging despite non-increased erythropoietin levels, and identified spleen as the site of extramedullary erythropoiesis...
November 7, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27800508/phd2-from-hypoxia-regulation-to-disease-progression
#8
REVIEW
Ana M Meneses, Ben Wielockx
Oxygen represents one of the major molecules required for the development and maintenance of life. An adequate response to hypoxia is therefore required for the functioning of the majority of living organisms and relies on the activation of the hypoxia-inducible factor (HIF) pathway. HIF prolyl hydroxylase domain-2 (PHD2) has long been recognized as the major regulator of this response, controlling a myriad of outcomes that range from cell death to proliferation. However, this enzyme has been associated with more pathways, making the role of this protein remarkably complex under distinct pathologies...
2016: Hypoxia
https://www.readbyqxmd.com/read/27742192/hif-stabilization-by-prolyl-hydroxylase-inhibitors-for-the-treatment-of-anemia-in-chronic-kidney-disease
#9
Christina M Wyatt, Tilman B Drüeke
The treatment of anemia with erythropoiesis-stimulating agents and iron supplementation has become the standard of care in patients with chronic kidney disease. Because of the risks associated with this approach, hypoxia inducible factor stabilizing prolyl hydroxylase inhibitors were developed as a potential treatment alternative. In recent phase 2 trials, these agents raised hemoglobin in a predictable and controlled manner and improved markers of iron metabolism. More experience is needed to establish long-term efficacy, tolerability, and safety, and to determine whether their use is associated with lower iron requirements...
November 2016: Kidney International
https://www.readbyqxmd.com/read/27711215/heparanase-overexpression-reduces-hepcidin-expression-affects-iron-homeostasis-and-alters-the-response-to-inflammation
#10
Michela Asperti, Tanja Stuemler, Maura Poli, Magdalena Gryzik, Lena Lifshitz, Esther G Meyron-Holtz, Israel Vlodavsky, Paolo Arosio
Hepcidin is the key regulator of systemic iron availability that acts by controlling the degradation of the iron exporter ferroportin. It is expressed mainly in the liver and regulated by iron, inflammation, erythropoiesis and hypoxia. The various agents that control its expression act mainly via the BMP6/SMAD signaling pathway. Among them are exogenous heparins, which are strong hepcidin repressors with a mechanism of action not fully understood but that may involve the competition with the structurally similar endogenous Heparan Sulfates (HS)...
2016: PloS One
https://www.readbyqxmd.com/read/27690727/cord-blood-erythropoietin-and-cord-blood-nucleated-red-blood-cells-for-prediction-of-adverse-neonatal-outcome-associated-with-maternal-obesity-in-term-pregnancy-prospective-cohort-study
#11
Mahmoud H Ibrahim, Asmaa N Moustafa, Ahmed A Fadil Saedii, Ebtesam E Hassan
OBJECTIVE: To determine the adverse pregnancy outcomes associated with maternal prepregnancy overweight and obesity and we measure cord blood erythropoietin and NRBC count as indices of hypoxia and predictors of neonatal outcome. STUDY DESIGN: This prospective cohort study was done in Minia University Hospital, carried out from May 2015 to April 2016.270 full term neonates born to mothers of various body mass indices were included .Excluded were neonates with major factors known to be associated with a potential increase in fetal erythropoiesis...
October 3, 2016: Journal of Maternal-fetal & Neonatal Medicine
https://www.readbyqxmd.com/read/27683416/prolyl-4-hydroxylase-2-and-3-coregulate-murine-erythropoietin-in-brain-pericytes
#12
Andres A Urrutia, Aqeela Afzal, Jacob Nelson, Olena Davidoff, Kenneth W Gross, Volker H Haase
A classic response to systemic hypoxia is the increased production of red blood cells due to hypoxia-inducible factor (HIF)-mediated induction of erythropoietin (EPO). EPO is a glycoprotein hormone that is essential for normal erythropoiesis and is predominantly synthesized by peritubular renal interstitial fibroblast-like cells, which express cellular markers characteristic of neuronal cells and pericytes. To investigate whether the ability to synthesize EPO is a general functional feature of pericytes, we used conditional gene targeting to examine the von Hippel-Lindau/prolyl-4-hydroxylase domain (PHD)/HIF axis in cell-expressing neural glial antigen 2, a known molecular marker of pericytes in multiple organs...
November 24, 2016: Blood
https://www.readbyqxmd.com/read/27650732/vadadustat-a-novel-oral-hif-stabilizer-provides-effective-anemia-treatment-in-nondialysis-dependent-chronic-kidney-disease
#13
Pablo E Pergola, Bruce S Spinowitz, Charlotte S Hartman, Bradley J Maroni, Volker H Haase
Current treatment of anemia in chronic kidney disease (CKD) with erythropoiesis-stimulating agents can lead to substantial hemoglobin oscillations above target range and high levels of circulating erythropoietin. Vadadustat (AKB-6548), a novel, titratable, oral hypoxia-inducible factor prolyl hydroxylase inhibitor induces endogenous erythropoietin synthesis and enhances iron mobilization. In this 20-week, double-blind, randomized, placebo-controlled, phase 2b study, we evaluated the efficacy and safety of once-daily vadadustat in patients with stages 3a to 5 non-dialysis-dependent CKD...
November 2016: Kidney International
https://www.readbyqxmd.com/read/27541284/neuroprotection-and-cd131-gdnf-akt-pathway-of-carbamylated-erythropoietin-in-hypoxic-neurons
#14
Jing Ding, Jing Wang, Qin-Ying Li, Jie-Zhong Yu, Cun-Gen Ma, Xin Wang, Chuan-Zhen Lu, Bao-Guo Xiao
Carbamylated erythropoietin (CEPO), an EPO derivative, is attracting widespread interest due to neuroprotective effects without erythropoiesis. However, little is known about molecular mechanisms behind CEPO-mediated neuroprotection. In primary neurons with oxygen-glucose deprivation (OGD) and mice with hypoxia-reoxygenation, the neuroprotection and possible molecular mechanism of CEPO were performed by immunohistochemistry and immunocytochemistry, Western blot, RT-PCR, and ELISA. The comparisons were analyzed by ANOVA followed by unpaired two-tailed Student's t test...
August 19, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27537859/emerging-drugs-for-the-treatment-of-kidney-disease-induced-anemia
#15
Jolanta Malyszko, Jacek S Malyszko
INTRODUCTION: Anemia has been remained one of the most characteristic and visible manifestations of chronic renal failure. Correction of anemia requires two main treatment strategies: increased stimulation of erythropoiesis, and maintenance of an adequate iron supply to the bone marrow. AREAS COVERED: Erythropoiesis activating agents became a mainstay in the treatment of renal anemia for more than 25 years. Recently, there have been several attempts to introduce new drugs to stimulate erythropoiesis or affect the hepcidin-ferroportin pathway...
September 2016: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/27491085/loss-of-vhl-in-the-zebrafish-pronephros-recapitulates-early-stages-of-human-clear-cell-renal-cell-carcinoma
#16
Haley R Noonan, Ana M Metelo, Caramai N Kamei, Randall T Peterson, Iain A Drummond, Othon Iliopoulos
Patients with von Hippel-Lindau (VHL) disease harbor a germline mutation in the VHL gene leading to the development of several tumor types including clear cell renal cell carcinoma (ccRCC). In addition, the VHL gene is inactivated in over 90% of sporadic ccRCC cases. 'Clear cell' tumors contain large, proliferating cells with 'clear cytoplasm', and a reduced number of cilia. VHL inactivation leads to the stabilization of hypoxia inducible factors 1a and 2a [HIF1a and HIF2a (HIF2a is also known as EPAS1)] with consequent up-regulation of specific target genes involved in cell proliferation, angiogenesis and erythropoiesis...
August 1, 2016: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/27406619/enhanced-erythropoietin-response-to-acute-hypoxemia-in-mice-with-pharmacological-depression-of-erythropoiesis
#17
M P Martínez, M I Conti, C E Lezón, R M Alippi, C E Bozzini
The recent report of a depression of stimulated production of erythropoietin (EPO) in mice with enhanced erythropoiesis suggests that unknown mechanism (s) other than hypoxia may be involved in the regulation of EPO formation. The present study was thus designed to investigate EPO production during acute hypoxemia in a mouse model in which the oxygen-carrying capacity of blood, the plasma EPO level, and the plasma EPO half-life were within normal values in spite of a marked depression of the red cell production rate (RCPR) induced by cyclophosphamide (CP) administration...
1996: Hematology (Amsterdam, Netherlands)
https://www.readbyqxmd.com/read/27398985/characterization-of-erythropoietin-and-hepcidin-in-the-regulation-of-persistent-injury-associated-anemia
#18
Ines G Alamo, Kolenkode B Kannan, Michael A Smith, Philip A Efron, Alicia M Mohr
BACKGROUND: The cause of persistent injury-associated anemia is multifactorial and includes acute blood loss, an altered erythropoietin (EPO) response, dysregulation of iron homeostasis, and impaired erythropoiesis in the setting of chronic inflammation/stress. Hepcidin plays a key role in iron homeostasis and is regulated by anemia and inflammation. Erythropoietin is a main regulator of erythropoiesis induced by hypoxia. A unique rodent model of combined lung injury (LC)/hemorrhagic shock (HS) (LCHS)/chronic restraint stress (CS) was used to produce persistent injury-associated anemia to further investigate the roles of EPO, hepcidin, iron, ferritin, and the expression of EPO receptors (EPOr)...
October 2016: Journal of Trauma and Acute Care Surgery
https://www.readbyqxmd.com/read/27348128/erythropoietin
#19
Wolfgang Jelkmann
Total hemoglobin (Hb) mass is an important determinant of aerobic power. The glycoprotein erythropoietin (Epo) promotes the production of red blood cells (RBCs). The present article reviews the regulation of erythropoiesis and ways of its manipulation. The various Epos, e.g. recombinant human (rh)Epo and (epoetin), and their long-acting analogues can be misused by cheating athletes, but the drugs are detectable by chemical tests, because their glycan isoform structures differ from those of endogenous Epo. Still, anti-doping control has become more difficult, since additional erythropoiesis-stimulating agents have become available (Epo mimetics, activin inhibitors, and small-molecule chemical drugs activating EPO expression)...
2016: Frontiers of Hormone Research
https://www.readbyqxmd.com/read/27346747/mass-spectrometric-characterization-of-the-hypoxia-inducible-factor-hif-stabilizer-drug-candidate-bay-85-3934-molidustat-and-its-glucuronidated-metabolite-bay-348-and-their-implementation-into-routine-doping-controls
#20
Josef Dib, Cynthia Mongongu, Corinne Buisson, Adeline Molina, Wilhelm Schänzer, Uwe Thuss, Mario Thevis
The development of new therapeutics potentially exhibiting performance-enhancing properties implicates the risk of their misuse by athletes in amateur and elite sports. Such drugs necessitate preventive anti-doping research for consideration in sports drug testing programmes. Hypoxia-inducible factor (HIF) stabilizers represent an emerging class of therapeutics that allows for increasing erythropoiesis in patients. BAY 85-3934 is a novel HIF stabilizer, which is currently undergoing phase-2 clinical trials...
June 27, 2016: Drug Testing and Analysis
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