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Microvesicles (MVs) from mesenchymal stem cells (MSCs) have been reported as a new communicated way between cells. This study evaluated the influence and underlying mechanism of MVs-shuttled miR-451a on renal fibrosis and epithelial mesenchymal transformation (EMT) in diabetic nephropathy (DN) with hyperuricemia. MVs were isolated from MSCs-cultured medium by gradient ultracentrifugation. The level of miR-451a in MSCs and MVs was analyzed by qPCR. The changes of miR-451a, E-cadherin, α-SMA, P15INK4b (P15), and P19INK4d (P19) were measured in hyperglycosis and hyperuricemia-induced cell (HK-2) and mouse models. The changes of cell cycle were analyzed by flow cytometry. The ability of proliferation and viability was measured by BrdU and CCK8, respectively. Dual-luciferase reporter assays were conducted to determine the target binding sites. The renal function and histological changes of mice were analyzed. MVs showed the same surface markers as MSCs but much higher miR-451a expression (4.87 ± 2.03 fold higher than MSCs). miR-451a was decreased to 26% ± 11% and 6.7% ± 0.82% in injured HK-2 cells and kidney, respectively. MV-miR-451a enhanced the HK2 cells proliferation and viability in vitro, and decreased the morphologic and functional injury of kidney in vivo. Moreover, infusion of MV-miR-451a reduced the level of α-SMA and raised E-cadherin expression. These effects were responsible for the improved arrested cell cycle and down-regulation of P15 and P19 via miR-451a targeting their 3′-UTR sites. This study demonstrated that MSC–MV-miR-451a could inhibit cell cycle inhibitors P15 and P19 to restart the blocked cell cycle and reverse EMT in vivo and in vitro, and thus miR-451a is potentially a new target for DN therapy.    Impact statement   The mechanism of MSCs repairing the injured kidney in diabetic nephropathy is not yet clear. In the research, MVs showed the same surface markers as MSCs but much higher MiR-451a expression. miR-451a was decreased in both injured HK-2 cells and kidneys. MV-miR-451a stimulated the cell proliferation and viability in vitro and promoted structural and functional improvements of injured kidney in vivo. Infusion of MV-miR-451a ameliorated EMT by reducing α-SMA and increasing E-cadherin. These effects relied on the improved cell cycle arrest and the down-regulation of P15 and P19 via miR-451a binding to their 3′-UTR region. This study demonstrated that MSC–MV-miR-451a could specifically inhibit cell cycle inhibitors to restart the blocked cell cycle and reverse EMT in vivo and in vitro. Therefore, miR-451a may be a new target for DN therapy.

Mesenchymal stem cells–microvesicle-miR-451a ameliorate early diabetic kidney injury by negative regulation of P15 and P19