Format

Send to

Choose Destination
FASEB J. 2018 Sep 5:fj201701355RR. doi: 10.1096/fj.201701355RR. [Epub ahead of print]

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

Liu T1,2,3, Liu L1,2, Liu M1,2, Du R4, Dang Y5, Bai M1,2, Zhang L1,2, Ma F1, Yang X1, Ning X2,6, Sun S1,2.

Author information

1
Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
2
State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China.
3
Department of Nephrology, Guangren Hospital of Xi'an Jiaotong University, Xi'an, China.
4
Department of Radiation Oncology, Navy General Hospital, Beijing, China.
5
Department of Anesthesiology, Children Hospital of Xi'an, Xi'an, China.
6
Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.

Abstract

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 microRNA are involved in this regulation. We compared microRNA expression between hypoxia and normoxia in HK2 cells and found 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.

KEYWORDS:

HIF-1α; chronic kidney injury; hypoxia; tubular cell

PMID:
30183377
DOI:
10.1096/fj.201701355RR

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center