Erythropoietin production by interstitial cells of hypoxic monkey kidneys

Fisher, James W.; Koury, Stephen T.; Ducey, Thomas F.; Mendel, Sandra L.

doi:10.1046/j.1365-2141.1996.d01-1864.x

Cited by 81 publications

(49 citation statements)

References 21 publications

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“…Previous studies of renal EPO-producing cells have suggested other sites of EPO synthesis including peritubular interstitial cells and capillaries. 20,[27][28][29] The detection of EPO mRNA in proximal tubule cells after hypoxia agrees with others. [30][31][32][33] Lack of EPO signal in normoxia and its sharp localization in hypoxia support the specificity of our ISH technique.…”

Section: Discussionsupporting

confidence: 78%

Superoxide dismutase-3 promotes full expression of the EPO response to hypoxia

Suliman

Ali

Piantadosi

2004

Blood

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Section: Discussionsupporting

confidence: 78%

Superoxide dismutase-3 promotes full expression of the EPO response to hypoxia

Suliman

Ali

Piantadosi

2004

Blood

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“…More recently, several investigators demonstrated EPO mRNA localized only in peritubular capillary beds of hypoxic kidneys (9,13). Still others have demonstrated EPO synthesis in interstitial cells of peritubular capillaries (16). In our study, staining clearly demonstrated specific immunoreactivity only in proximal tubule cells of rat kidneys as confirmed by hematoxylin-eosin staining in parallel sections.…”

Section: Discussionsupporting

confidence: 58%

17β-Estradiol decreases hypoxic induction of erythropoietin gene expression

Mukundan

Resta

Kanagy

2002

American Journal of Physiology-Regulatory, Integrative and Comp

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Mukundan, Harshini, Thomas C. Resta, and Nancy L. Kanagy. 17␤-Estradiol decreases hypoxic induction of erythropoietin gene expression. Am J Physiol Regulatory Integrative Comp Physiol 283: R496-R504, 2002. First published April 4, 2002 10.1152/ajpregu.00573.2001.-Exposure to chronic hypoxia induces erythropoietin (EPO) production to facilitate oxygen delivery to hypoxic tissues. Previous studies from our laboratory found that ovariectomy (OVX) exacerbates the polycythemic response to hypoxia and treatment with 17␤-estradiol (E2-␤) inhibits this effect. We hypothesized that E2-␤ decreases EPO gene expression during hypoxia. Because E2-␤ can induce nitric oxide (NO) production and NO can attenuate EPO synthesis, we further hypothesized that E2-␤ inhibition of EPO gene expression is mediated by NO. These hypotheses were tested in OVX catheterized rats treated with E2-␤ (20 g/day) or vehicle for 14 days and exposed to 8 or 12 h of hypoxia (12% O 2) or normoxia. We found that E2-␤ treatment significantly decreased EPO synthesis and gene expression during hypoxia. E2-␤ treatment did not induce endothelial NO synthase (eNOS) expression in the kidney but potentiated hypoxiainduced increases in plasma nitrates. We conclude that E2-␤ decreases hypoxic induction of EPO. However, this effect does not appear to be related to changes in renal eNOS expression. nitric oxide; polycythemia; hypoxia CHRONIC EXPOSURE TO HYPOXIA can cause a number of pathophysiological conditions including pulmonary hypertension and chronic mountain sickness. Hypoxic induction of erythropoiesis leads to polycythemia, which may contribute to the development of these diseases. Erythropoiesis is mediated by the small glycoprotein hormone erythropoietin (EPO; Refs. 3, 12). In adults, EPO is primarily synthesized in the kidney and stimulates red blood cell synthesis in bone marrow. During hypoxia, elevated red blood cell numbers help to compensate for compromised oxygen delivery to tissues.The physiological and biochemical properties of EPO have been extensively studied, but there are few studies to investigate gender differences in regulation of the hormone. It has been demonstrated that 17␤-estradiol (E2-␤) can influence the expression of hypoxiainducible genes such as vascular endothelial growth factor and endothelin-1 (ET-1) (4, 11, 58). However, estrogen regulation of EPO gene expression is not well understood. In some tissues such as the uterus and ovaries, E2-␤ has been shown to induce EPO production (34, 67). However, this regulation seems to be independent of pathways involved in hypoxic stimulation of EPO synthesis. In contrast, several investigators have shown that women living at high altitude have a lower hematocrit compared with men at the same altitude. Peschle et al. (40) observed that administration of estrogen benzoate (10 g/day) to ovariectomized (OVX) rats attenuated increases in plasma iron following hypoxia. Studies from our laboratory (46) have also shown that OVX augments hypoxia-induced increases in hematocrit in rats (0.5 atm, ...

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“…1,2 As a secreted monomeric sialoglycoprotein, EPO then targets developing erythroblasts, and is essential for red cell formation during definitive bone marrow and fetal liver erythropoiesis. [3][4][5][6][7][8] Prospective roles for EPO in promoting primitive red cell formation in yolk sac also have recently been described.…”

Section: Introductionmentioning

confidence: 99%

EPO receptor circuits for primary erythroblast survival

Sathyanarayana

Dev

Fang

et al. 2008

Blood

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EPO functions primarily as an erythroblast survival factor, and its antiapoptotic actions have been proposed to involve predominantly PI3-kinase and BCL-X pathways. Presently, the nature of EPOregulated survival genes has been investigated through transcriptome analyses of highly responsive, primary bone marrow erythroblasts. Two proapoptotic factors, Bim and FoxO3a, were rapidly repressed not only via the wild-type EPOR, but also by PY-deficient knocked-in EPOR alleles. In parallel, Pim1 and Pim3 kinases and Irs2 were induced. For this survival gene set, induction failed via a PY-null EPOR-HM allele, but was restored upon reconstitution of a PY343 STAT5-binding site within a related EPOR-H allele. Notably, EPOR-HM supports erythropoiesis at steady state but not during anemia, while EPOR-H exhibits near wildtype EPOR activities. EPOR-H and the wild-type EPOR (but not EPOR-HM) also markedly stimulated the expression of Trb3 pseudokinase, and intracellular serpin, Serpina-3G. For SERPINA-3G and TRB3, ectopic expression in EPOdependent progenitors furthermore significantly inhibited apoptosis due to cytokine withdrawal. BCL-XL and BCL2 also were studied, but in highly responsive Kit pos CD71 high Ter119 neg erythroblasts, neither was EPO modulated. EPOR survival circuits therefore include the repression of Bim plus IntroductionIn response to anemia, erythropoietin (EPO) is expressed by interstitial kidney and fetal liver cells via hypoxia-inducible transcription factor pathways. 1,2 As a secreted monomeric sialoglycoprotein, EPO then targets developing erythroblasts, and is essential for red cell formation during definitive bone marrow and fetal liver erythropoiesis. [3][4][5][6][7][8] Prospective roles for EPO in promoting primitive red cell formation in yolk sac also have recently been described. 9 Beyond this, recombinant EPO has been demonstrated in ischemia and other cell damage models to provide cytoprotective effects for injured renal, cardiac, retinal, and neuronal tissues. 10,11 Taken together, these considerations have heightened interest in the specific nature of key EPO action mechanisms, especially those associated with progenitor cell survival.EPO's prime effects are mediated via interactions with its dimeric single-transmembrane receptor (EPOR). [3][4][5][6][7][8]12 These interactions appear to evoke EPOR conformational events, 13 which are relayed to an upstream Janus kinase, JAK2 14 (and JAK2 likewise may preassemble with EPOR dimers at a juxtamembrane box1 domain). 15,16 JAK2, as activated via a Y1007 phosphorylation loop, 17 next stimulates 2 separable signal transduction pathways. First, JAK2 interestingly can support steady-state erythropoiesis via EPOR-PY-independent routes that, in part, may involve MEK1,2 and ERK1,2 stimulation. 18 Second, JAK2 also mediates the phosphorylation of 8 conserved EPOR cytoplasmic PY sites, which can then form a scaffold for the binding of up to 20 SH2-or PTB-domain encoding signal transduction factors and molecular adaptors. [6][7][8][19][20][21] Among conserve...

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Erythropoietin production by interstitial cells of hypoxic monkey kidneys

Cited by 81 publications

References 21 publications

Superoxide dismutase-3 promotes full expression of the EPO response to hypoxia

Superoxide dismutase-3 promotes full expression of the EPO response to hypoxia

17β-Estradiol decreases hypoxic induction of erythropoietin gene expression

EPO receptor circuits for primary erythroblast survival

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