Renal CD133+/CD73+ progenitors produce erythropoietin under hypoxia and prolyl hydroxylase inhibition

The identity of the peritubular population of cells with mesenchymal phenotype thought responsible for producing erythropoietin in humans remains unclear.Here, renalCD133+/CD73+ progenitor cells, isolated from the human renal inner medulla and described as a population of mesenchymal progenitors, released erythropoietin under hypoxic conditions. CD73- 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-2α (HIF-2α) expression and erythropoietin transcription. Moreover, under hypoxic conditions, inhibition of prolyl hydroxylase significantly increased erythropoietin release by CD133 + progenitors. Finally, blockade of HIF-2α 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-HIF- 2a 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.