Department of Biochemistry and Molecular Biology, Dalian Medical University, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian 116044, China.
Centre for Auxiliary Human Reproduction, Shengjing Hospital of China Medical University, Shenyang 110004, China.
Cell Death Dis. 2017 Oct 26;8(10):e3145. doi: 10.1038/cddis.2017.494.
Polycystic ovary syndrome (PCOS) is a complicated reproductive endocrine disease characterized by polycystic ovaries, hyperandrogenism and anovulation. It is one of the main causes of infertility. RU486 is an antagonist of progesterone receptor, and most commonly used as a contraceptive. However, whether RU486 is correlated with PCOS remains unclear. Atrial natriuretic peptide (ANP) is a small peptide with natriuretic and diuretic functions, and its availability to be used in PCOS treatment is unknown. Here, we showed that the serum ANP level was lower in PCOS patients than that in healthy women, and it was also decreased in the serum and ovarian tissues of RU486-induced PCOS rats compared with the control rats. We also found that RU486 inhibited the proliferation and promoted the apoptosis of human KGN ovarian granulosa cells by downregulating progesterone receptor membrane component 1 (PGRMC1). Meantime, ANP promoted the proliferation and inhibited the apoptosis of KGN cells through upregulating ANP receptor A (NPRA). The promotive effects of ANP on ovarian functions were mediated through the formation of an NPRA/PGRMC1/EGFR complex, which further activated MAPK/ERK signaling and transcription factor AP1. Moreover, ANP treatment reversed the PCOS symptoms, and improved the fertility of RU486-induced PCOS rats. Collectively, these findings highlight that RU486 is associated with the pathogenesis of PCOS, and ANP treatment may be a promising therapeutic option for PCOS.
多囊卵巢综合征（PCOS）是一种复杂的生殖内分泌疾病，其特征是多囊卵巢、高雄激素血症和排卵障碍。它是不孕的主要原因之一。RU486 是孕激素受体拮抗剂，最常用于避孕。然而，RU486 是否与 PCOS 相关尚不清楚。心钠肽（ANP）是一种具有利钠和利尿功能的小肽，其在 PCOS 治疗中的应用尚不清楚。在这里，我们发现 PCOS 患者的血清 ANP 水平低于健康女性，并且与对照组大鼠相比，RU486 诱导的 PCOS 大鼠的血清和卵巢组织中的 ANP 水平也降低。我们还发现，RU486 通过下调孕激素受体膜成分 1（PGRMC1）抑制人 KGN 卵巢颗粒细胞的增殖并促进其凋亡。同时，ANP 通过上调 ANP 受体 A（NPRA）促进 KGN 细胞的增殖并抑制其凋亡。ANP 对卵巢功能的促进作用是通过形成 NPRA/PGRMC1/EGFR 复合物介导的，该复合物进一步激活 MAPK/ERK 信号转导和转录因子 AP1。此外，ANP 治疗可逆转 PCOS 症状，提高 RU486 诱导的 PCOS 大鼠的生育能力。综上所述，这些发现表明 RU486 与 PCOS 的发病机制有关，ANP 治疗可能是 PCOS 的一种有前途的治疗选择。
