Androgens Increase Accumulation of Advanced Glycation End Products in Granulosa Cells by Activating ER Stress in PCOS
Androgens Increase Accumulation of Advanced Glycation End Products in Granulosa Cells by Activating ER Stress in PCOS
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DOI：
10.1210/endocr/bqaa015
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发表时间：
2020-02-01
期刊：
影响因子：
4.8
通讯作者：
Osuga, Yutaka
中科院分区：
文献类型：
--
作者：
Azhary, Jerilee M. K.;Harada, Miyuki;Osuga, Yutaka
多囊卵巢综合征（PCOS）与高雄激素血症有关，我们以前发现雄激素激活PCOS患者颗粒细胞的内质网（ER）应激。此外，最近的研究表明，晚期糖基化终末产物（AGEs）在PCOS患者的颗粒细胞中积累，这有助于病理学。因此，我们假设雄激素通过激活ER应激上调颗粒细胞中AGEs受体（AGEs）的表达，从而增加AGEs在这些细胞中的积累并导致病理学改变。在本研究中，我们表明睾酮会增加培养的人颗粒黄素细胞（GLC）中RAGE的表达和AGE的积累，并且通过临床使用的ER应激抑制剂牛磺熊去氧胆酸（TUDCA）预处理可以减少这种情况。转录因子C/EBP同源蛋白（CHOP），一个未折叠的蛋白质反应因子激活的ER压力，抑制睾酮诱导的表达和AGE的积累。PCOS患者和去氢表雄酮诱导的PCOS小鼠颗粒细胞中AGEs的积累和表达上调。PCOS小鼠给予AGEs抑制剂FPS-ZM 1或TUDCA可降低AGEs表达和颗粒细胞中AGE的积累，改善其发情周期，并减少闭锁的窦状卵泡数量。总之，我们的研究结果表明，PCOS高雄激素血症增加表达的AGEs和积累的卵巢通过激活ER应激，并针对AGE-AGEs系统，无论是通过使用AGEs抑制剂或临床上可用的ER应激抑制剂，可能代表一种新的方法来治疗PCOS。
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.