Erythropoietin production by PDGFR-$ β^{+} $ cells
Abstract PDGFR-β-expressing cells of the kidneys are considered as a relevant site of erythropoietin (EPO) production. The origin of these cells, their contribution to renal EPO production, and if PDGFR-β-positive cells in other organs are also capable to express EPO are less clear. We addressed these questions in mice, in which hypoxia-inducible transcription factors were stabilized in PDGFR-$ β^{+} $ cells by inducible deletion of the von Hippel-Lindau (Vhl) protein. Vhl deletion led to a 600-fold increase of plasma EPO concentration, 170-fold increase of renal EPO messenger RNA (mRNA) levels, and an increase of hematocrit values up to 70 %. Intrarenal localization of EPO-expressing cells coincided with the zonal heterogeneity and distribution of cells expressing PDGFR-β. Amongst a variety of extrarenal organs only adrenal glands showed significant EPO mRNA expression after Vhl deletion in PDGFR-$ β^{+} $ cells. EPO mRNA, plasma EPO, and hematocrit fell to subnormal values if HIF-2α, but not HIF-1α, was deleted either alone or in combination with Vhl in PDGFR-$ β^{+} $ cells. Treatment of mice with a prolyl-hydroxylase inhibitor caused an increase of EPO mRNA abundance and plasma EPO concentrations in wild-type mice and in mice lacking HIF-1α in PDGFR-$ β^{+} $ cells but exerted no effect in mice lacking HIF-2α in PDGFR-$ β^{+} $ cells. These findings suggest that PDGFR-$ β^{+} $ cells are the only relevant site of EPO expression in the kidney and that HIF-2 is the essential transcription factor triggering EPO expression therein. Moreover, our findings suggest that PDGFR-$ β^{+} $ cells elaborating EPO might arise from the metanephric mesenchyme, rather than from the neural crest..
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2016 |
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| Erschienen: |
2016 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:468 |
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| Enthalten in: |
Pflügers Archiv - 468(2016), 8 vom: 25. Mai, Seite 1479-1487 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gerl, Katharina [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| Themen: |
Adrenal gland |
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| Anmerkungen: |
© Springer-Verlag Berlin Heidelberg 2016 |
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| doi: |
10.1007/s00424-016-1829-2 |
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OLC2056824078 |
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| 520 | |a Abstract PDGFR-β-expressing cells of the kidneys are considered as a relevant site of erythropoietin (EPO) production. The origin of these cells, their contribution to renal EPO production, and if PDGFR-β-positive cells in other organs are also capable to express EPO are less clear. We addressed these questions in mice, in which hypoxia-inducible transcription factors were stabilized in PDGFR-$ β^{+} $ cells by inducible deletion of the von Hippel-Lindau (Vhl) protein. Vhl deletion led to a 600-fold increase of plasma EPO concentration, 170-fold increase of renal EPO messenger RNA (mRNA) levels, and an increase of hematocrit values up to 70 %. Intrarenal localization of EPO-expressing cells coincided with the zonal heterogeneity and distribution of cells expressing PDGFR-β. Amongst a variety of extrarenal organs only adrenal glands showed significant EPO mRNA expression after Vhl deletion in PDGFR-$ β^{+} $ cells. EPO mRNA, plasma EPO, and hematocrit fell to subnormal values if HIF-2α, but not HIF-1α, was deleted either alone or in combination with Vhl in PDGFR-$ β^{+} $ cells. Treatment of mice with a prolyl-hydroxylase inhibitor caused an increase of EPO mRNA abundance and plasma EPO concentrations in wild-type mice and in mice lacking HIF-1α in PDGFR-$ β^{+} $ cells but exerted no effect in mice lacking HIF-2α in PDGFR-$ β^{+} $ cells. These findings suggest that PDGFR-$ β^{+} $ cells are the only relevant site of EPO expression in the kidney and that HIF-2 is the essential transcription factor triggering EPO expression therein. Moreover, our findings suggest that PDGFR-$ β^{+} $ cells elaborating EPO might arise from the metanephric mesenchyme, rather than from the neural crest. | ||
| 650 | 4 | |a Inducible deletion of Vhl | |
| 650 | 4 | |a Kidney | |
| 650 | 4 | |a Adrenal gland | |
| 650 | 4 | |a PDGFR-β-expressing cells | |
| 650 | 4 | |a Erythropoietin | |
| 650 | 4 | |a HIF-2 | |
| 700 | 1 | |a Nolan, Karen A. |4 aut | |
| 700 | 1 | |a Karger, Christian |4 aut | |
| 700 | 1 | |a Fuchs, Michaela |4 aut | |
| 700 | 1 | |a Wenger, Roland H. |4 aut | |
| 700 | 1 | |a Stolt, Claus C. |4 aut | |
| 700 | 1 | |a Willam, Carsten |4 aut | |
| 700 | 1 | |a Kurtz, Armin |4 aut | |
| 700 | 1 | |a Kurt, Birgül |4 aut | |
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