Regulated oxygen sensing by protein hydroxylation in renal erythropoietin-producing cells

Wenger, Roland H.; Hoogewijs, David

doi:10.1152/ajprenal.00736.2009

Cited by 94 publications

(92 citation statements)

References 145 publications

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“…25 In this context, EPO may play tissue-specific physiologic roles possibly unrelated to erythropoiesis such as modulation of angiogenesis and cell survival. 26,27 The molecular pathways involved in the control of oxygen sensing and leading to EPO synthesis have been fully elucidated in recent years. 27 In vivo studies in rats as well as in vitro studies on EPO-producing cell lines clearly showed that EPO production depends on HIF-2a activation, 7,21,22 which, in turn, is modulated by the hydroxylation of its proline residues by PHD2.…”

Section: Discussionmentioning

confidence: 99%

Renal CD133+/CD73+ Progenitors Produce Erythropoietin under Hypoxia and Prolyl Hydroxylase Inhibition

Bussolati

Lauritano

Moggio

et al. 2013

Journal of the American Society of Nephrology

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The identity of the peritubular population of cells with mesenchymal phenotype thought responsible for producing erythropoietin in humans remains unclear. Here, renal CD133 + /CD73 + progenitor cells, isolated from the human renal inner medulla and described as a population of mesenchymal progenitors, released erythropoietin under hypoxic conditions. CD133 2 cells did not synthesize erythropoietin, and CD133 + progenitor cells stopped producing erythropoietin when they differentiated and acquired an epithelial phenotype. Inhibition of prolyl hydroxylases, using either dimethyloxalylglycine or a small hairpin RNA against prolyl hydroxylase-2, increased both hypoxia-inducible factor-2a (HIF-2a) expression and erythropoietin transcription. Moreover, under hypoxic conditions, inhibition of prolyl hydroxylase significantly increased erythropoietin release by CD133 + progenitors. Finally, blockade of HIF-2a impaired erythropoietin synthesis by CD133 + progenitors. Taken together, these results suggest that it is the renal CD133 + progenitor cells that synthesize and release erythropoietin under hypoxia, via the prolyl hydroxylase-HIF2a axis, in the human kidney. In addition, this study provides rationale for the therapeutic use of prolyl hydroxylase inhibitors in the setting of acute or chronic renal injury.

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Section: Discussionmentioning

confidence: 99%

Renal CD133+/CD73+ Progenitors Produce Erythropoietin under Hypoxia and Prolyl Hydroxylase Inhibition

Bussolati

Lauritano

Moggio

et al. 2013

Journal of the American Society of Nephrology

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“…Indeed, during the past decade a large number of PHD2-interacting proteins have been discovered, including both upstream regulators and downstream targets of PHD2, substantially increasing the complexity of the PHD/HIF oxygen-sensing regulation pathway. 7 Moreover, PHD2 has been reported to have hydroxylation-independent gene regulatory functions. [35][36][37] Another category, including the PHD2-R398X mutation and three other PHD2 truncated mutations described previously, 12 can be compared to the VHL truncation mutations (VHL disease type 1) which are not associated with the development of pheochromocytomas.…”

Section: Discussionmentioning

confidence: 99%

“…For example, renal and hepatic erythropoietin is regulated by the HIF-2α subunit in vivo. [4][5][6][7] Germline mutations in genes involved in the HIF pathway have been reported in association with syndromes that predispose patients to both neoplasms and/or congenital secondary erythrocytosis. 8 The most frequent mutations involve the VHL tumor suppressor gene.…”

Section: Introductionmentioning

confidence: 99%

Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia

Ladroue

Hoogewijs²,

Gad³

et al. 2011

Haematologica

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BackgroundCongenital secondary erythrocytoses are due to deregulation of hypoxia inducible factor resulting in overproduction of erythropoietin. The most common germline mutation identified in the hypoxia signaling pathway is the Arginine 200-Tryptophan mutant of the von Hippel-Lindau tumor suppressor gene, resulting in Chuvash polycythemia. This mutant displays a weak deficiency in hypoxia inducible factor α regulation and does not promote tumorigenesis. Other von Hippel-Lindau mutants with more deleterious effects are responsible for von Hippel-Lindau disease, which is characterized by the development of multiple tumors. Recently, a few mutations in gene for the prolyl hydroxylase domain 2 protein (PHD2) have been reported in cases of congenital erythrocytosis not associated with tumor formation with the exception of one patient with a recurrent extra-adrenal paraganglioma. Design and MethodsFive PHD2 variants, four of which were novel, were identified in patients with erythrocytosis. These PHD2 variants were functionally analyzed and compared with the PHD2 mutant previously identified in a patient with polycythemia and paraganglioma. The capacity of PHD2 to regulate the activity, stability and hydroxylation of hypoxia inducible factor α was assessed using hypoxia-inducible reporter gene, one-hybrid and in vitro hydroxylation assays, respectively. ResultsThis functional comparative study showed that two categories of PHD2 mutants could be distinguished: one category with a weak deficiency in hypoxia inducible factor α regulation and a second one with a deleterious effect; the mutant implicated in tumor occurrence belongs to the second category. ConclusionsAs observed with germline von Hippel-Lindau mutations, there are functional differences between the PHD2 mutants with regards to hypoxia inducible factor regulation. PHD2 mutation carriers do, therefore, need careful medical follow-up, since some mutations must be considered as potential candidates for tumor predisposition.Key words: hypoxia inducible factor, hypoxia-inducible transcription factor, PHD2, erythrocytosis.Citation: Ladroue C, Hoogewijs D, Gad S, Carcenac R, Storti F, Barrois M, Gimenez-Roqueplo A-P, Leporrier M, Casadevall N, Hermine O, Kiladjian J-J, Baruchel A, Fakhoury F, Bressac-de Paillerets B, Feunteun J, Mazure N, Pouysségur J, Wenger RH, Richard S, and Gardie B. Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia. Haematologica 2012;97(1):9-14.

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“…Physiologically, increased systemic erythropoiesis is a major adaptation to hypoxia. The reduced tissue oxygen level is sensed mainly by the kidney, resulting in increased production of EPO, a key regulator of erythropoiesis (78). EPO binds to EPO receptors on the surface of erythroid progenitors (79), where it prevents their apoptosis and induces the proliferation and differentiation into rbcs (80,81).…”

Section: Erythropoietic Activity Suppresses Hepcidin Expressionmentioning

confidence: 99%

Iron regulation by hepcidin

Zhao

Zhang²,

Enns³

2013

J. Clin. Invest.

195

158

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Discovery and function of hepcidin in iron homeostasisHepcidin is a key peptide hormone that regulates iron homeostasis in chordates. Hepcidin was initially characterized as an antimicrobial peptide in a mass spectrometry-based search for cysteine-rich defensin-like peptides in blood (1) and in urine (2). However, both groups showed that hepcidin displays only a weak antimicrobial activity. Further, unlike defensins, which vary in sequence among species, hepcidin is highly conserved from zebrafish to humans. Shortly after hepcidin was described, subtractive hybridization studies comparing the livers of normal and iron overloaded mice established a connection between iron loading and increased hepcidin mRNA (3, 4). The fundamental insight into hepcidin's role in iron homeostasis came in 2004 with the discovery that hepcidin acts to lower iron in the blood by binding to and downregulating the iron transporter, ferroportin (FPN1) (5). FPN1 is the only known transporter that is responsible for the efflux of iron from cells. Downregulation of FPN1 by hepcidin in splenic and hepatic macrophages decreases the ability of macrophages to export recycled iron from senescent rbcs, which constitute the primary source of iron in the plasma. In addition, a high concentration of hepcidin in the blood decreases the transport of iron out of intestinal epithelial cells, further limiting iron in the blood. Control of hepcidin expressionHepcidin is synthesized, processed to an active form, and secreted predominantly by hepatocytes (6, 7). The expression of hepcidin is mediated through the bone morphogenetic protein (BMP) and JAK2/STAT3 signaling pathways (Figure 1). Under nonpathological conditions, iron levels in the body upregulate hepcidin expression. Although the underlying mechanisms are poorly understood, recent studies have documented the essential roles of hemojuvelin (HJV), hereditary hemochromatosis protein (HFE), transferrin receptor 2 (TfR2), and matriptase-2 (MT2, encoded by the gene TMPRSS6) in the process of hepcidin regulation in humans and animal models as well as of BMP6, neogenin, and BMP receptors (ActRIIA/ALK2/ALK3) in animal models (8)(9)(10)(11)(12)(13)(14)(15)(16)(17).Intact BMP signaling is essential for hepcidin expression. The canonical BMP-signaling pathway is initiated upon BMP binding to a BMP receptor complex on the cell surface, which activates the receptor kinase to phosphorylate the cytoplasmic proteins SMAD1, SMAD5, and SMAD8. These phosphorylated, receptor-regulated SMADs then form transcription factor complexes with SMAD4, consisting of receptor-regulated SMADs and SMAD4, that translocate into the nucleus to induce the transcription of target genes such as hepcidin (18). In mice, liver-specific disruption of SMAD4 or the BMP receptors ALK2 or ALK3 markedly decreased hepcidin expression, resulting in iron overload (15,19).BMP6. At least 20 BMPs are expressed in mammals. In vitro studies reveal that BMP2, -4, -5, -6, -7, and -9 can robustly induce BMP signaling and markedly increase hepcidin expres...

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Regulated oxygen sensing by protein hydroxylation in renal erythropoietin-producing cells

Cited by 94 publications

References 145 publications

Renal CD133+/CD73+ Progenitors Produce Erythropoietin under Hypoxia and Prolyl Hydroxylase Inhibition

Renal CD133+/CD73+ Progenitors Produce Erythropoietin under Hypoxia and Prolyl Hydroxylase Inhibition

Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia

Iron regulation by hepcidin

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