NOX4 deficiency improves the impaired viability, inhibited the apoptosis and suppressed autophagy of DHEA-treated ovarian granulosa cells through inhibiting endoplasmic reticulum stress via inactivating PERK/ATF4 pathway

Abstract

Background

PCOS is the most prevalent endocrine and metabolic problem in women of reproductive age. This current study was formulated to thoroughly expound the ovary-protecting effects of NOX4 deficiency in PCOS and probe into the intrinsic mechanisms underlying the protective effects of NOX4 deficiency against DHEA injury in ovarian GCs.

Methods

KGN cells were subjected to 20 nM DHEA for 48 h to establish PCOS cellular model. For loss-of-function experiments, KGN cells were transfected with si-NOX4. In addition, to investigate the biological roles of ERS and PERK/ATF4 pathway in the ovary-protecting effects of NOX4 deficiency in DHEA-treated ovarian GCs, KGN cells were pretreated with ERS agonist TM or PERK agonist CCT020312.

Results

NOX4 was highly expressed in DHEA-treated ovarian GCs. NOX4 deficiency improved the impaired viability, inhibited the apoptosis and suppressed autophagy of DHEA-treated ovarian GCs. Besides, NOX4 deficiency inactivated PERK/ATF4 pathway in DHEA-treated ovarian GCs. NOX4 deficiency repressed DHEA-induced ERS of ovarian GCs through inactivating PERK/ATF4 pathway. Pretreatment with ERS agonist TM or pretreatment with PERK agonist CCT020312 can both reduced the viability, promoted the apoptosis and strengthened autophagy of ovarian GCs, partially abolishing the ovary-protecting effects of NOX4 deficiency in DHEA-treated ovarian GCs. In general, NOX4 deficiency could improve the impaired viability, inhibited the apoptosis and suppressed autophagy of DHEA-treated ovarian GCs through repressing ERS depending on inactivation of PERK/ATF4 pathway.

Conclusion

To conclude, downregulation of NOX4 could exert ovary-protecting effects in DHEA-induced PCOS cellular model through repressing ERS via inactivating PERK/ATF4 pathway.