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.

• Authors: Katharina Gerl, Karen A Nolan, Christian Karger, Michaela Fuchs, Roland H Wenger, Claus C Stolt, Carsten Willam, Armin Kurtz, Birgül Kurt
• Journal: Pflugers Archiv : European journal of physiology (Pflugers Arch) Vol. 468 Issue 8 Pg. 1479-87 (08 2016) ISSN: 1432-2013 [Electronic] Germany
• PMID: 27220347 (Publication Type: Journal Article)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Hypoxia-Inducible Factor 1, alpha Subunit
• Prolyl-Hydroxylase Inhibitors
• RNA, Messenger
• Erythropoietin
• endothelial PAS domain-containing protein 1
• Von Hippel-Lindau Tumor Suppressor Protein
• Receptor, Platelet-Derived Growth Factor beta

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Erythropoietin (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Kidney (diagnostic imaging, metabolism)
• Mice
• Prolyl-Hydroxylase Inhibitors (pharmacology)
• RNA, Messenger (metabolism)
• Receptor, Platelet-Derived Growth Factor beta (metabolism)
• Von Hippel-Lindau Tumor Suppressor Protein (metabolism)