MicroRNA-493 targets STMN-1 and promotes hypoxia-induced epithelial cell cycle arrest in G2/M and renal fibrosis

Abstract

Hypoxia plays an important role in the development of renal fibrosis.G2/Marrest in renal tubular cells is an important pathway in the development of chronic kidney disease. It is unknown whether hypoxia leads to renal fibrosis via the regulation of G2/M arrest in renal tubular epithelial cells. For the first time, to our knowledge, we showedthat hypoxia inducesG2/Marrest in renal tubular cells leading to renal fibrosis, andmicroRNAs are involved in this regulation. We compared microRNA expression between hypoxia and normoxia in HK2 cells and found microRNA (miR)-493 to be highly expressed at 24 and 48 h after hypoxia.The overexpression of miR-493 reduced the expression of the cell cycle regulator, Stathmin (STMN)-1, and increased the percentage of G2/M phase cells and profibrotic factors inHK2cells.Targeting STMN-1with short hairpinRNAproduced an effect similar to that ofmiR- 493 overexpression. On contrast, the miR-493 inhibitor reversed these effects in vitro. Consistent with these results, miR-493 sponge adeno-associated virus reduced the expression of profibrotic factors and increased STMN-1 in vivo. In summary, these results suggest that the miR-493-STMN-1 pathway contributes to hypoxia-induced tubular epithelial cellG2/M arrest and renal fibrosis. AbrogatingG2/M arrest and blocking the miR-493-STMN-1 pathwaywill provide further insight for thedevelopment of antifibrosis therapy.