title: Effect of erythropoietin on the migration of bone marrow-derived mesenchymal stem cells to the acute kidney injury microenvironment.
abstract: Bone marrow-derived mesenchymal stem cells (BMSCs) preferentially migrate to the injured tissue but with limited efficiency. Here we investigated the effect of erythropoietin (EPO) treatment on the BMSC migration to the acute kidney injury (AKI) microenvironment. The possible mechanisms were also discussed. A hypoxia/re-oxygenation (HR) model of renal tubular epithelial cells (RTECs) was established to generate AKI in vitro, and a chemotaxis experiment was conducted using the transwell chamber. EPO treatment enhanced the BMSC migration to the HR-RTEC culturing chamber in a SDF-1 level-dependent manner, which was fully inhibited by the treatment of anti-SDF-1 antibody. The BMSC migration could also be partly blocked by LY294002 (phosphoinositide 3-kinase (PI3K) inhibitor) and PD98059 (MAPK inhibitor). Western blot analysis showed that phosphorylated Akt and phosphorylated MAPK in BMSCs were enhanced by EPO treatment. In the in vivo experiment, BMSCs were transplanted into the AKI mice and EPO was subcutaneously injected. The results showed that EPO injection increased the SDF-1 protein expression and BMSC accumulation in the renal tissue, which was consistent with a decent improvement of renal function. In addition, the BMSC accumulation in the renal tissue was blocked by anti-SDF-1 antibody, LY294002 or PD98059. Our data suggest that AKI microenvironment had a directional chemotactic effect on BMSCs, which could be further enhanced by the EPO treatment. The increased SDF-1 level in the AKI microenvironment and the activations of PI3K/AKT and MAPK in BMSCs were the possible mechanisms for the effect of EPO. Therefore, BMSC transplantation combined with EPO injection can be a novel and effective approach for AKI repair.
authors.affiliation: Department of Nephrology, Changzheng Hospital affiliated to the Second Military Medical University, Shanghai 200003 China; Department of Nephrology, the 455th hospital of PLA, Shanghai 200052 China.
authors.forename: Nanmei
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Nephrology, the 455th hospital of PLA, Shanghai 200052 China.
authors.forename: Jun
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Nephrology, the 455th hospital of PLA, Shanghai 200052 China.
authors.forename: Jin
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Nephrology, the 455th hospital of PLA, Shanghai 200052 China. Electronic address: zhangjinyuan455@gmail.com.
authors.forename: Jinyuan
authors.initials: J
authors.lastname: Zhang
mesh_terms: D058186:Acute Kidney Injury / Q000473:pathology*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D060833:Cellular Microenvironment / Q000187:drug effects* / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D004921:Erythropoietin / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D004921:Erythropoietin
keywords: Acute kidney injury; Bone marrow-derived mesenchymal stem cells; Erythropoietin; Hypoxia/re-oxygenation; Migration