Expression of a homologously recombined erythopoietin-SV40 T antigen fusion gene in mouse liver: evidence for erythropoietin production by Ito cells

Maxwell, PH; Dj, Ferguson; Osmond, MK; Pugh, Christopher W.; Heryet, A; Doe, BG; Johnson, Martin H.; Ratcliffe, P J

doi:10.1182/blood.v84.6.1823.bloodjournal8461823

Cited by 18 publications

(15 citation statements)

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“…The liver is a second main source of erythropoietin, where the hormone is produced by stellate cells and hepatocytes 72,73 . The liver is the predominant production site during fetal and early postnatal life, and might also contribute to erythropoietin production in adulthood, although the extent of this contribution is unclear.…”

Section: Production In the Liver And Other Organsmentioning

confidence: 99%

HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond

Maxwell¹,

2015

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Small-molecule stabilizers of hypoxia inducible factor (HIF) are being developed for the treatment of renal anaemia. These molecules inhibit prolyl hydroxylase domain-containing (PHD) enzymes, resulting in HIF activation and increased production of erythropoietin. Currently, renal anaemia is treated with recombinant human erythropoietin or related analogues, referred to as conventional erythropoiesis stimulating agents (ESAs). Advantages of PHD enzyme inhibitors over conventional ESAs include their oral administration and their simpler - and potentially cheaper - production. Importantly, inhibition of PHD enzymes is likely to have a range of consequences other than increasing levels of erythropoietin, and these effects could be beneficial - for instance by reducing the need for parenteral iron - but might in some instances be harmful. Several companies are currently testing PHD enzyme inhibitors in patients with renal anaemia and have reported clear evidence of efficacy without serious safety concerns. A central question that current studies are beginning to address is whether using PHD enzyme inhibitors will influence hard end points, including mortality and the rate of cardiovascular events. In terms of approaches to therapy, the exquisite specificity of conventional ESAs is a striking contrast to the pleiotropic effects of activating HIF. Excitingly, PHD inhibitors could also be useful for conditions besides renal anaemia, such as protection from ischaemic injury.

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Section: Production In the Liver And Other Organsmentioning

confidence: 99%

HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond

Maxwell¹,

2015

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“…The latter express four groups of polypeptide growth factors: (a) polypeptides that enhance proliferation in an autocrine or paracrine way (HGF, vascular endothelial growth factor [VEGF], ET-1, IGF-II, and possibly TGF-␣, EGF, and acidic fibroblast growth factor, (b) TGF-␤ superfamily members (TGF-␤ 1,2,3 and BMP-6), (c) neurotrophins (NGF, BDGF, NT-3, NT-4/5), and (d) hematopoietic growth factors such as erythropoietin (EPO). 252 Hepatocyte growth factor mRNA can be readily demonstrated in quiescent cells in vivo. 90,91 HGF stimulates parenchymal cell proliferation and is 50 times more potent than TGF-␣.…”

Section: Secretion Of Paracrine Juxtacrine Autocrine and Chemoattrmentioning

confidence: 99%

History, Heterogeneity, Developmental Biology, and Functions of Quiescent Hepatic Stellate Cells

Geerts¹

2001

Semin Liver Dis

685

572

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In 1876, von Kupffer described liver Sternzellen (star-shaped cells). The functions of these cells remained enigmatic for 75 years until Ito observed lipid-containing perisinusoidal cells in human liver. In 1971, Wake demonstrated that the Sternzellen of von Kupffer and the fat-storing cells described by Ito were identical. Wake also established that these cells were important sites of vitamin A storage. Soon thereafter, Kent and Popper demonstrated that the stellate cells were intimately linked to the pathogenesis of hepatic fibrosis. Since then, these cells have been studied in detail. Quiescent stellate cells represent 5-8% of the total number of liver cells. They play a cardinal role in storage and controlled release of retinoids. They control extracellular matrix (ECM) turnover in the space of Disse by secreting the correct amounts of a limited number of ECM molecules, and by releasing matrix metalloproteinases and their inhibitors. By virtue of their long cytoplasmic processes, quiescent stellate cells presumably contribute to the control of blood flow through the sinusoidal capillaries. They are important sources of paracrine, autocrine, juxtacrine, and chemoattractant factors that maintain homeostasis in the microenvironment of the hepatic sinusoid.Objectives: Upon completion of this article, the reader should be able to (1) describe the morphology and intrahepatic localization of stellate cells, (2) discuss the pros and cons of the markers that are currently used to stain stellate cells in liver tissue, (3) compare stellate cells to other hepatic fibrogenic cells, (4) understand the concept of extrahepatic stellate cells, and (5) list the major physiological functions of hepatic stellate cells. Accreditation: Tufts University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. TUSM takes full responsibility for the content, quality, and scientific integrity of this continuing education activity. Credit: Tufts University School of Medicine designates this education activity for a maximum of 1.0 hour credit toward the AMA Physicians Recognition Award in category one. Each physician should claim only those hours that he/she actually spent in the educational activity.

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“…However, before birth, the fetal liver is the main site of EPO production, although the mechanism of the switch from the liver to kidney remains unclear 118 . Both hepatocytes and Ito cells express EPO 119 and show an expression pattern that is strictly regulated by the P o 2 gradient, with high expression around central veins and extended expression to the periportal field when hypoxia or anaemia occurs 120,121 . Therefore, it has been proposed that changes in the P o 2 gradient around birth may contribute to the switch, although reduction of either hepatic or renal oxygenation does not affect the switch (for a review, see Moritz et al 122 ).…”

Section: Extrarenal Epo Expressionmentioning

confidence: 99%

Hypoxia‐induced Erythropoietin Production: A Paradigm for Oxygen‐regulated Gene Expression

Stockmann¹,

Fandrey²

2006

Clin Exp Pharma Physio

139

113

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The mechanisms controlling the expression of the gene encoding for the hormone erythropoietin (EPO) are exemplary for oxygen-regulated gene expression. In humans and other mammals, hypoxia modulates EPO levels by increasing expression of the EPO gene. An association between polycythaemia and people living at high altitudes was first reported more than 100 years ago. Since the identification of EPO as the humoral regulator of red blood cell production and the cloning of the EPO gene, considerable progress has been made in understanding the regulation of EPO gene expression. This has finally led to the identification of a widespread cellular oxygen-sensing mechanism. Central to this mechanism is the transcription factor complex hypoxia-inducible factor (HIF)-1. The abundance and activity of HIF-1, a heterodimer of an alpha- and beta-subunit, is predominantly regulated by oxygen-dependent post-translational hydroxylation of the alpha-subunit. Non-heme ferrous iron containing hydroxylases use dioxygen and 2-oxoglutarate to specifically target proline and an asparagine residue in HIF-1alpha. As such, the three prolyl hydroxylases (prolyl hydroxylase domain-containing protein (PHD) 1, PHD2 and PHD3) and the asparagyl hydroxylase (factor inhibiting HIF (FIH)-1) act as cellular oxygen sensors. In addition to erythropoiesis, HIF-1 regulates a broad range of physiologically relevant genes involved in angiogenesis, apoptosis, vasomotor control and energy metabolism. Therefore, the HIF system is implicated in the pathophysiology of many human diseases. In addition to the tight regulation by oxygen tension, temporal and tissue-specific signals limit expression of the EPO gene primarily to the fetal liver and the adult kidney.

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Expression of a homologously recombined erythopoietin-SV40 T antigen fusion gene in mouse liver: evidence for erythropoietin production by Ito cells

Cited by 18 publications

References 0 publications

HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond

HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond

History, Heterogeneity, Developmental Biology, and Functions of Quiescent Hepatic Stellate Cells

Hypoxia‐induced Erythropoietin Production: A Paradigm for Oxygen‐regulated Gene Expression

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