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

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

SUBMITTER: Bussolati B 

PROVIDER: S-EPMC3736703 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature