Activation of Endoplasmic Reticulum Stress in Granulosa Cells from Patients with Polycystic Ovary Syndrome Contributes to Ovarian Fibrosis

Yasushi Hirota,Shunichi Shimasaki,Miyuki Harada,Osamu Wada-Hiraike,Gentaro Izumi,Chisato Kunitomi,Tomoyuki Fujii,Yutaka Osuga,Nozomi Takahashi,Kaori Koga,Osamu Yoshino,Tetsuya Hirata,Hiroshi Koike,Emi Nose,Jerilee Mk Azhary,R Jeffrey Chang

doi:10.1038/s41598-017-11252-7

Abstract

Recent studies report the involvement of intra-ovarian factors, such as inflammation and oxidative stress, in the pathophysiology of polycystic ovary syndrome (PCOS), the most common endocrine disorder of reproductive age women. Endoplasmic reticulum (ER) stress is a local factor that affects various cellular events during a broad spectrum of physiological and pathological conditions. It may also be an important determinant of pro-fibrotic remodeling during tissue fibrosis. In the present study, we showed that ER stress was activated in granulosa cells of PCOS patients as well as in a well-established PCOS mouse model. Pharmacological inducers of ER stress, tunicamycin and thapsigargin, were found to increase the expression of pro-fibrotic growth factors, including transforming growth factor (TGF)-β1, in human granulosa cells, and their expression also increased in granulosa cells of PCOS patients. By contrast, treatment of PCOS mice with an ER stress inhibitor, tauroursodeoxycholic acid or BGP-15, decreased interstitial fibrosis and collagen deposition in ovaries, accompanied by a reduction in TGF-β1 expression in granulosa cells. These findings suggest that ER stress in granulosa cells of women with PCOS contributes to the induction of pro-fibrotic growth factors during ovarian fibrosis, and that ER stress may serve as a therapeutic target in PCOS.

Highlights

Polycystic ovary syndrome (PCOS), the most common endocrine disorder among reproductive age women, affects 6−10% of them, and it is the most common cause of anovulatory infertility[1]
Our results show that Endoplasmic reticulum (ER) stress was activated in granulosa cells of both PCOS patients and the DHEA-treated PCOS mouse model
XBP1(S) expression is induced by the activation of inositol-requiring enzyme 1 (IRE1), and C/EBP homologous protein (CHOP) is induced by the activation of protein kinase-like ER kinase (PERK), while HSPA5 lies downstream of both IRE1 and PERK16, 21

Summary

Introduction

Polycystic ovary syndrome (PCOS), the most common endocrine disorder among reproductive age women, affects 6−10% of them, and it is the most common cause of anovulatory infertility[1]. Recent studies reveal the essential roles of transforming growth factor (TGF)-β1 and connective tissue growth factor (CTGF), a downstream factor mediating the pro-fibrotic actions of TGF-β1, in granulosa cells during extracellular matrix remodeling in the ovary[11,12,13,14] Consistent with this notion, a higher serum level and an increased ovarian expression of TGF-β1 in PCOS patients supports the involvement of TGF-β1 in the pathogenesis of PCOS14, 15, neither the mechanism www.nature.com/scientificreports/. These findings suggest that ER stress and UPR are important regulators of physiological events in granulosa cells Based on these findings, we hypothesize that ER stress is activated in granulosa cells of PCOS patients, and that activated ER stress induces ovarian fibrosis by modulating pro-fibrotic growth factor expression in granulosa cells. It is a hydroxylamine derivative that amplifies the endogenous stress response by altering the organization of cholesterol-rich membrane domains to target stressed cells and a pharmacological co-inducer of the chaperone HSP7232, 33

Methods

Results

Conclusion