Department of Obstetrics and Gynecology, Division of Reproductive Biology, New York University School of Medicine, 4 Columbus Circle, Fourth Floor, New York, NY 10019, USA.
Department of Obstetrics & Gynecology and Womens' Health, Division of Reproductive Endocrinology and Infertility, Montefiore's Institute for Reproductive Medicine and Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Mol Hum Reprod. 2018 Jun 1;24(6):318-326. doi: 10.1093/molehr/gay014.
Does vitamin D attenuate the adverse effects of advanced glycation end products (AGEs) on steroidogenesis by human granulosa cells (GCs)?
AGEs alter the expression of genes important in steroidogenesis while 1,25-dihydroxyvitamin D3 (vit D3) in vitro attenuates some of the actions of AGEs on steroidogenic gene expression, possibly by downregulating the expression of the pro-inflammatory cell membrane receptor for AGEs (RAGE).
Vitamin D attenuates the pro-inflammatory effects of AGEs in non-ovarian tissues.
STUDY DESIGN, SIZE, DURATION: Women who were undergoing IVF were enrolled. Follicular fluid samples (n = 71) were collected and cumulus GCs (n = 12) were treated in culture.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Follicular fluid levels of the anti-inflammatory soluble RAGE (sRAGE), AGEs and 25-hydroxyvitamin D (25-OHD) were quantified for possible correlations. GCs of each participant were split equally and treated with either media alone (control) or with human glycated albumin (HGA as a precursor for AGEs) with or without vit D3 after which RT-PCR and immunofluorescence were performed and cell culture media estradiol (E2) levels were compared.
In follicular fluid, sRAGE levels were positively correlated with 25-OHD levels. HGA treatment (i) increased CYP11A1 (by 48%), 3β-HSD (by 38%), StAR (by 42%), CYP17A1 (by 30%) and LHR (by 37%) mRNA expression levels (P < 0.05 for all) but did not alter CYP19A1 or FSHR mRNA expression levels; and (ii) increased E2 release in cell culture media (P = 0.02). Vit D3 treatment (i) downregulated RAGE mRNA expression by 33% and RAGE protein levels by 44% (P < 0.05); (ii) inhibited the HGA-induced increase in CYP11A1, StAR, CYP17A1 and LHR mRNA levels, but not the increase in 3β-HSD mRNA levels; and (iii) did not inhibit the HGA-induced E2 release in cell culture media.
This study used luteinized GCs that were collected from women who received gonadotropins thus the results obtained may not fully extrapolate to non-luteinized GCs in vivo.
This study suggests that there is a relationship between AGEs and their receptors (RAGE and sRAGE) with vitamin D. Understanding the interaction between AGEs and vitamin D in ovarian physiology could lead to a more targeted therapy for the treatment of ovarian dysfunction.
STUDY FUNDING/COMPETING INTEREST(S): Funding was received from NIH (R01 NS045940), American Society for Reproductive Medicine, Ferring Pharmaceuticals Inc., and University of Vermont College of Medicine Bridge Funds. All authors have nothing to disclose.
维生素 D 是否能减弱晚期糖基化终产物 (AGEs) 对人卵巢颗粒细胞 (GCs) 甾体生成的不良影响？
AGEs 改变了甾体生成中重要基因的表达，而 1,25-二羟维生素 D3（vit D3）在体外减弱了 AGEs 对甾体生成基因表达的部分作用，可能是通过下调促炎细胞表面 AGEs 受体 (RAGE) 的表达。
维生素 D 可减弱非卵巢组织中 AGEs 的促炎作用。
研究设计、规模、持续时间：招募正在接受 IVF 的女性。采集卵泡液样本（n = 71），并培养卵丘 GCs（n = 12）。
参与者/材料、设置、方法：对每位参与者的卵泡液进行抗炎症可溶性 RAGE（sRAGE）、AGEs 和 25-羟维生素 D（25-OHD）水平的定量，以确定可能的相关性。将每个参与者的 GCs 平均分成两部分，分别用培养基（对照）或用人糖化白蛋白（HGA，AGEs 的前体）处理，然后进行 RT-PCR 和免疫荧光检测，并比较细胞培养上清液中的雌二醇（E2）水平。
在卵泡液中，sRAGE 水平与 25-OHD 水平呈正相关。HGA 处理（i）增加 CYP11A1（增加 48%）、3β-HSD（增加 38%）、StAR（增加 42%）、CYP17A1（增加 30%）和 LHR（增加 37%）mRNA 表达水平（所有 P 值均<0.05），但不改变 CYP19A1 或 FSHR mRNA 表达水平；（ii）增加细胞培养上清液中的 E2 释放（P = 0.02）。vit D3 处理（i）使 RAGE mRNA 表达下调 33%，RAGE 蛋白水平下调 44%（P < 0.05）；（ii）抑制 HGA 诱导的 CYP11A1、StAR、CYP17A1 和 LHR mRNA 水平增加，但不抑制 3β-HSD mRNA 水平增加；（iii）不抑制 HGA 诱导的细胞培养上清液中的 E2 释放。
本研究使用了从接受促性腺激素治疗的女性中收集的黄体化 GCs，因此获得的结果可能不完全外推到体内未黄体化的 GCs。
该研究表明，AGEs 及其受体（RAGE 和 sRAGE）与维生素 D 之间存在关系。了解 AGEs 和维生素 D 在卵巢生理学中的相互作用，可能为治疗卵巢功能障碍提供更有针对性的治疗方法。
研究资金/竞争利益：本研究得到 NIH（R01 NS045940）、美国生殖医学学会、费森尤斯制药公司和佛蒙特大学医学院桥梁基金的资助。所有作者均无利益冲突。
