Ang II Controls the Expression of Mapkap1 by miR-375 and Affects the Function of Islet β Cells.

Abstract

The RAS system is involved in the regulation of islet function, but its regulation remains unclear. This study investigates the role of an islet-specific miR-375 in the effect of RAS system on islet β-cells. miR-375 mimics and inhibitors were transfected into insulin-secreting MIN6 cells in the presence or absence of RAS component. Compared to control, in Ang II-treated MIN6 cells, miR-375 mimic transfection results in a decrement in cell viability and Akt-Ser levels (0.739±0.05 vs. 0.883±0.06 and 0.40±0.04 vs. 0.79±0.04, respectively), while the opposite occurred in miR-375 inhibitor-transfected cells (1.032±0.11 vs. 0.883±0.06 and 0.98±0.05 vs. 0.79±0.04, respectively, P<0.05). Mechanistically, transfection of miR- 375 mimics into Ang II-treated MIN6 cells significantly reduced the expression of Mapkap1 protein (0.97±0.15 vs. 0.63±0.06, P<0.05); while miR-375 inhibitor-transfected cells elevated Mapkap1 expression level (0.35±0.11 vs. 0.90±0.05, P<0.05), without changes in mRNA expression. Transfection of miR-375 specific inhibitors TSB-Mapkap1 could elevate Mapkap1 (1.62±0.02 vs. 0.68±0.01, P<0.05), while inhibition of Mapkap1 could significantly reduce the level of Akt-Ser473 phosphorylation (0.60±0.14 vs. 1.80±0.27, P<0.05). The effects of Ang II on mouse islet β cells were mediated by miR-375 through miR- 375/Mapkap 1 axis. This targeted regulation may occur by affecting Akt phosphorylation of β cells. These results may provide new ideas and a scientific basis for further development of miRNA-targeted islet protection measures.