miR-155 Derived from Bone Marrow Mesenchymal Stem Cell-Secreted Exosomes Reduces Kidney Rejection in Rat Allogeneic Transplantation Model via SDF-1/CXCR4

Abstract

Aberrantly expressed miR-155 is associated with renal rejection after allogeneic transplantation. This study mainly explored the mechanism of miR-155 derived from bone marrow mesenchymal stem cell-secreted exosomes (BMSC-exo) in renal rejection after allogeneic transplantation. Thirty Fischer rats and 40 Lewis rats were used as donors and recipients, respectively. The Lewis rats were randomized into 4 groups (10 rats per group): Control group, miR-155 group, positive control group and CXCR4 agonist group. The following indicators were monitored in BMSC-exo: miR-155 expression, serum creatinine level, renal histopathological changes, CADI score, number of cells that were positive for TGF-β, Smad3 and α-SMA, as well as the protein levels of Smad3, TGF-β, CXCR4 and SDF-1. miR-155 expression in BMSC-exo was significantly higher than that in HKb-20 cells. On the 7th day after surgery, the serum creatinine levels of rats in the miR-155 group and positive control group reduced significantly, while decreasing slowly in the control group and CXCR4 agonist group. The CADI scores of rats in the miR-155 group and positive control group were significantly higher than those in the control group and CXCR4 agonist group (P < 0.05). No significant difference was found either between the miR-155 group and positive control group, or between the control group and CXCR4 agonist group (P > 0.05). Rats in the control group and CXCR4 agonist group had more cells that were positive for TGF-β, Smad3 and α-SMA, while those in the miR-155 group and positive control group showed less. The Smad3, TGF-β, CXCR4 and SDF-1 proteins were weakly expressed in the miR-155 group and positive control group, but strongly expressed in the control group and CXCR4 agonist group. No significant difference in the protein levels was found either between the miR-155 group and positive control group, or between the control group and CXCR4 agonist group (P > 0.05). miR-155 derived from BMSC-exo is protective against allogeneic kidney transplantation. Specifically, BMSC-exo-derived miR-155 blocked the activity of SDF-1/CXCR4 and TGF-β/Smad3 pathways, thereby downregulating the expression of α-SMA. As a result, it ameliorated renal fibrosis and alleviated renal dysfunction, ultimately leading to the prevention and reduction of renal rejection following allograft transplantation.