Androgens Increase Accumulation of Advanced Glycation End Products in Granulosa Cells by Activating ER Stress in PCOS

Abstract

Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism, and we previously found that androgens activate endoplasmic reticulum (ER) stress in granulosa cells from patients with PCOS. In addition, recent studies demonstrated the accumulation of advanced glycation end products (AGEs) in granulosa cells from PCOS patients, which contribute to the pathology. Therefore, we hypothesized that androgens upregulate the receptor for AGEs (RAGE) expression in granulosa cells by activating ER stress, thereby increasing the accumulation of AGEs in these cells and contributing to the pathology. In the present study, we show that testosterone increases RAGE expression and AGE accumulation in cultured human granulosa-lutein cells (GLCs), and this is reduced by pretreatment with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor in clinical use. Knockdown of the transcription factor C/EBP homologous protein (CHOP), an unfolded protein response factor activated by ER stress, inhibits testosterone-induced RAGE expression and AGE accumulation. The expression of RAGE and the accumulation of AGEs are upregulated in granulosa cells from PCOS patients and dehydroepiandrosterone-induced PCOS mice. Administration of the RAGE inhibitor FPS-ZM1 or TUDCA to PCOS mice reduces RAGE expression and AGE accumulation in granulosa cells, improves their estrous cycle, and reduces the number of atretic antral follicles. In summary, our findings indicate that hyperandrogenism in PCOS increases the expression of RAGE and accumulation of AGEs in the ovary by activating ER stress, and that targeting the AGE-RAGE system, either by using a RAGE inhibitor or a clinically available ER stress inhibitor, may represent a novel approach to PCOS therapy.

Electroacupuncture alleviates polycystic ovary syndrome-like symptoms through improving insulin resistance, mitochondrial dysfunction, and endoplasmic reticulum stress via enhancing autophagy in rats

“…Additionally, overexpression of key autophagy regulatory protein mechanistic target of rapamycin kinase (mTOR) can lead to insulin resistance during the pathological development of PCOS (Liu et al 2018;Song et al 2018). Besides, mitochondrial dysfunction and ER stress have been shown to participate in the pathogenesis of PCOS (Azhary et al 2020;Zeng et al 2020). Previous studies suggested that autophagy was closely related to mitochondrial dysfunction (Go et al 2015) and ER stress (Lee et al 2015).…”

TMT-based proteomic and bioinformatic analyses of human granulosa cells from obese and normal-weight female subjects

“…In patients with PCOS, advanced glycation endproduct (AGE) levels were significantly increased compared with those in matched normal-weight controls [53,54]. AGEs can alter insulin receptor substrate and AKT phosphorylation, thereby stimulating the downstream PI3K signaling cascade and compromising the effects of insulin signaling [55,56].…”

Androgens impair β-cell function in a mouse model of polycystic ovary syndrome by activating endoplasmic reticulum stress

“…28-day old C57BL/6J female mice were purchased from Wenzhou medical University and divided into three groups: control, dehydroepiandrosterone (DHEA)-induced PCOS, and DHEA+flutamide (Flut, an AR antagonist). PCOS mouse model was created by the administration of DHEA as described previously ( 22 , 23 ). Briefly, control mice were subcutaneously injected with sesame oil and, and implanted subcutaneously with an empty pellet; PCOS mice were subcutaneously injected with DHEA (Sigma-Aldrich) and implanted subcutaneously with an empty pellet; DHEA+Flut mice were subcutaneously injected with sesame oil and implanted subcutaneously with a pellet containing 20 mg flutamide (Innovative Research of America, Sarasota, FL, USA).…”