Upregulated autophagy in sertoli cells of ethanol-treated rats is associated with induction of inducible nitric oxide synthase (iNOS), androgen receptor suppression and germ cell apoptosis

Akio Horibe, Nabil Eid, Yuko Ito, Hitomi Hamaoka, Yoshihisa Tanaka, Yoichi Kondo

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

Abstract

This study was conducted to investigate the autophagic response of Sertoli cells (SCs) to acute ethanol toxicity using in vivo and in vitro models. Adult Wistar rats were intraperitoneally injected with either 5 g/kg ethanol or phosphate-buffered saline (for the control group) and sacrificed 0, 3, 6 and 24 h after injection. Compared to the control group, enhanced germ cell apoptosis was observed in the ethanol-treated rats (ETRs) in association with upregulation of iNOS and reduced expression of androgen receptor protein levels in SCs, which were resistant to apoptosis. Meanwhile, autophagy was upregulated in ETR SCs (peaking at 24 h) compared to the control group, as evidenced by transcription factor EB (TFEB) nuclear translocation, enhanced expression of microtubule-associated protein 1 light chain3-II (LC3-II), lysosome-associated membrane protein-2 (LAMP-2), pan cathepsin protein levels and reduced expression of p62. This upregulation of SC autophagy was confirmed ultrastructurally by enhanced formation of autophagic vacuoles and by immunofluorescent double labelling of autophagosomal and lysosomal markers. Study of cultured SCs confirmed enhanced autophagic response to ethanol toxicity, which was cytoprotective based on decreased viability of SCs upon blocking autophagy with 3-methyladenine (3-MA). The results highlighted the molecular mechanisms of prosurvival autophagy in ETR SCs for the first time, and may have significant implications for male fertility.

Original languageEnglish
Article number1061
JournalInternational journal of molecular sciences
Volume18
Issue number5
DOIs
Publication statusPublished - May 15 2017
Externally publishedYes

Keywords

  • Androgen receptor (AR)
  • Apoptosis
  • Autophagy
  • Ethanol
  • Inducible nitric oxide synthase (iNOS)
  • Sertoli
  • Transcription factor EB (TFEB)

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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