期刊
EXPERIMENTAL BIOLOGY AND MEDICINE
卷 243, 期 15-16, 页码 1233-1242出版社
SAGE PUBLICATIONS LTD
DOI: 10.1177/1535370218819726
关键词
Mesenchymal stem cells; microvesicles; miR-451a; cell cycle; epithelial mesenchymal transformation
资金
- National Natural Science Foundation of China [81370824, 31571474]
- Hospital foundation of Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital [30305030864]
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, alpha-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 alpha-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.
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