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 2 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-2a (HIF-2a) expression and erythropoietin transcription. Moreover, under hypoxic conditions, inhibition of prolyl hydroxylase significantly increased erythropoietin release by CD133 + progenitors. Finally, blockade of HIF-2a 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-HIF2a 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.

Human CD133+ Renal Progenitor Cells Induce Erythropoietin Production and Limit Fibrosis After Acute Tubular Injury

“…CD133 + cells were previously shown to release EPO under hypoxia12, and we have also here confirmed their capacity with respect to human fibroblasts, that were used as controls in our study. The role of CD133 + cells in physiological EPO synthesis within the nephron is unclear, as EPO production has been reported to occur in the peritubular interstitial fibroblasts464748.…”

“…We have previously reported EPO production by CD133 + cells from the medulla under hypoxia in a HIF-2 dependent manner12. In culture, CD133 + cells but not fibroblasts secreted EPO (Fig.…”

“…Using optical imaging, our group also showed that CD133 + cells isolated from the renal medulla localized into the injured renal tissue within a short interval of time after injury10. Of interest, CD133 + cells isolated from renal medulla were previously shown to possess the ability to release erythropoietin (EPO) under hypoxia through a hypoxia inducible factor-2 dependent activation12.…”

DNA methyltransferase inhibition restores erythropoietin production in fibrotic murine kidneys

“…REPCs, which have long projections between tubules and blood vessels, are detected in the interstitium (8)(9)(10)(11)(12)(13). Lineage-tracing studies have revealed that the majority of REPCs in the healthy kidney are derived from myelin protein 0-expressing (P0-expressing) cells, which are positive for CD73 (also known as ecto-5′-nucleotidase), PDGFRβ, and p75 nerve growth factor receptor and negative for PECAM-1 (also known as CD31) (11).…”

Concise Review: Stem/Progenitor Cells for Renal Tissue Repair: Current Knowledge and Perspectives

“…Experiments on the administration of CD133 + cells in murine models of glycerol‐induced acute kidney injury and of adriamycin‐induced glomerular damage showed improvement of the renal function, suggesting the feasibility of cell therapy with human isolated CD133 + renal progenitors [56, 57, 61, 62]. However, at present, the possible application of these cells cannot be envisaged, for several reasons such as the scarce availability of the cells, the need for compatibility among patients, and the availability of other sources of effective cells as MSCs.…”