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

Hypoxia plays an important role in the development of renal fibrosis. G2/M arrest 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 showed that hypoxia induces G2/M arrest in renal tubular cells leading to renal fibrosis, and microRNAs 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 in HK2 cells. Targeting STMN-1 with short hairpin RNA produced an effect similar to that of miR-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 cell G2/M arrest and renal fibrosis. Abrogating G2/M arrest and blocking the miR-493-STMN-1 pathway will provide further insight for the development of antifibrosis therapy.-Liu, T., Liu, L., Liu, M., Du, R., Dang, Y., Bai, M., Zhang, L., Ma, F., Yang, X., Ning, X., Sun, S. MicroRNA-493 targets STMN-1 and promotes hypoxia-induced epithelial cell cycle arrest In G2/M and renal fibrosis.