The tubular compartment of the nephron displays a high regenerative ability. We previously isolated CD133+ stem/progenitor cells in the tubular compartment of the human kidney(1-3). However, their possible contribution to repair is unknown. We here evaluated the possible modulation of CD133+ cells by the hypoxic environment, the molecular mechanisms involved and their possible involvement in renal regeneration. CD133+ progenitors cultured under hypoxia (1%O2) showed increased proliferation and clonogenic ability. When injected in vivo, CD133+ hypoxic progenitors showed ability to differentiate in structures resembling the different segments of the nephron. Moreover, hypoxia up-regulated Oct-4 isoforms in CD133+ cells via regulation of the Oct4 promoter. In parallel, hypoxia downregulated microRNA-145, known to act as an Oct4 transcriptional repressor. Epithelial differentiation increased microRNA-145 and reduced Oct4 level, suggesting a balance between Oct4 and microRNA-145. Labelled CD133+ progenitors localized into the injured kidneys in a model of acute renal damage and promoted renal functional regeneration. In addition, modulation of the HIF pathway through PHD2 inhibitors increase EPO production by CD133+ cells. These results suggest that hypoxia may direct CD133+ progenitors toward a more stem phenotype via Oct4A/miR145 balance. The plasticity of renal CD133+ cells could be exploited in renal regeneration after hypoxic damage. Among the mechanisms that may be involved in the regenerative properties of CD133+ cells, release of growth factors and of microvescicles were investigated. Results show that hypoxic CD133+ cells release microvescicles enriched in microRNA and that exosome injection may directly mediate their in vivo effect in a model of acute kidney injury.