MicroRNA-145 protects follicular granulosa cells against oxidative stress-induced apoptosis by targeting Krüppel-like factor 4

Mol Cell Endocrinol. 2017 Sep 5;452:138-147. doi: 10.1016/j.mce.2017.05.030. Epub 2017 May 28.

Abstract

Oxidative stress-induced follicular granulosa cell (GC) apoptosis plays an essential role in abnormal follicular atresia, which may trigger ovarian dysfunction. To investigate the role of microRNA (miR)-145 in the regulation of GC apoptosis and modulation of the apoptotic pathway in the setting of oxidative stress, we employed an H2O2-induced in vitro model and a 3-nitropropionic acid (NP)-induced in vivo model of ovarian oxidative stress. We demonstrated in vitro that miR-145 expression was significantly down-regulated in KGN cells and mouse granulosa cells (mGCs) treated with H2O2, whereas miR-145 over-expression attenuated H2O2-induced apoptosis in GCs. Moreover, miR-145 protected GCs against H2O2-induced apoptosis by targeting KLF4, which promoted H2O2-induced GC apoptosis via the BAX/BCL-2 pathway. Importantly, decreased miR-145 expression in the in vivo ovarian oxidative stress model promoted apoptosis by up-regulating KLF4 expression, whereas GC-specific miR-145 over-expression attenuated apoptosis by targeting KLF4. In conclusion, miR-145 protects GCs against oxidative stress-induced apoptosis by targeting KLF4.

Keywords: Apoptosis; Granulosa cell; KLF4; Oxidative stress; miR-145.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis* / genetics
  • Female
  • Follicular Atresia / metabolism
  • Gene Expression Regulation
  • Granulosa Cells / metabolism*
  • HEK293 Cells
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Nitro Compounds / pharmacology
  • Oxidative Stress*
  • Primary Cell Culture
  • Primary Ovarian Insufficiency / metabolism*
  • Propionates / pharmacology

Substances

  • Apoptosis Regulatory Proteins
  • GKLF protein
  • Kruppel-Like Transcription Factors
  • MIRN145 microRNA, mouse
  • MicroRNAs
  • Nitro Compounds
  • Propionates
  • Hydrogen Peroxide
  • 3-nitropropionic acid