title: 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-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-2α 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.
authors: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy. benedetta.bussolati@unito.it
authors: Benedetta
authors: B
authors: Bussolati
authors: Carola
authors: C
authors: Lauritano
authors: Aldo
authors: A
authors: Moggio
authors: Federica
authors: F
authors: Collino
authors: Massimiliano
authors: M
authors: Mazzone
authors: Giovanni
authors: G
authors: Camussi
mesh_terms: D015720:5'-Nucleotidase / Q000032:analysis; D000071916:AC133 Antigen; D015703:Antigens, CD / Q000032:analysis; D004921:Erythropoietin / Q000378:metabolism*; D058851:GPI-Linked Proteins / Q000032:analysis; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007679:Kidney Medulla / Q000378:metabolism*; D010455:Peptides / Q000032:analysis; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D058851:GPI-Linked Proteins; D006023:Glycoproteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000606023:PROM1 protein, human; D010455:Peptides; D004921:Erythropoietin; D011393:Procollagen-Proline Dioxygenase; D015720:5'-Nucleotidase; C548241:NT5E protein, human
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