Erythropoietin production by PDGFR-β+ cells

PDGFR-beta-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-beta-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-beta(+) 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-beta. Amongst a variety of extrarenal organs only adrenal glands showed significant EPO mRNA expression after Vhl deletion in PDGFR-beta(+) cells. EPO mRNA, plasma EPO, and hematocrit fell to subnormal values if HIF-2 alpha, but not HIF-1 alpha, was deleted either alone or in combination with Vhl in PDGFR-beta(+) 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-1 alpha in PDGFR-beta(+) cells but exerted no effect in mice lacking HIF-2 alpha in PDGFR-beta(+) cells. These findings suggest that PDGFR-beta(+) 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-beta(+) cells elaborating EPO might arise from the metanephric mesenchyme, rather than from the neural crest.