Interference of AGE-RAGE signaling with steroidogenic enzyme action in human ovarian cells

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 554-573-Ovarian & Uterine Function I
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-556
Evanthia Diamanti-Kandarakis*1, Christina Piperi2, Sarantis Livadas3, Eleni A Kandaraki2, Efstathia Papageorgiou4 and Michael Koutsilieris5
1Medical School University of Athens, Athens, Greece, 2University of Athens Medical School, Athens, Greece, 3Unit of Endocrinology, Metabolism and Diabetes, Athens, Greece, 4University of Athens, Medical school, 5Med Sch/Univ of Athens, Athens, Greece
Introduction: Advanced glycation end products (AGEs) and their receptor RAGE have been found elevated in serum and localized in the granulosa cell layer of women with infertility disorders such as PCOS. AGE-RAGE intracellular signaling commonly involves ERK1/2 MAPKs activation that have been proposed as key regulators of cell proliferation and differentiation as well as oocyte maturation in culture. Recent findings demonstrate that the Luteinizing Hormone (LH) also acts via activation of ERK1/2 to induce oocyte resumption of meiosis, ovulation, and luteinization in mice. In addition it may serve as an intrafollicular mediator to stimulate the cumulus cell-oocyte complex expansion and oocyte maturation via induction of EGF/ERK1/2 pathway.

It was thus hypothesized that AGE-RAGE signaling could interfere or attenuate LH action via ERK1/2 activation in human granulosa cells. The effect of human glycated albumin (HGA) either alone or in combination with LH was investigated in human ovarian granulosa cells (KGN) relative to ERK1/2 activation.

Methods: KGN cells were cultured with LH (0.2μg/ml-2μg/ml) or HGA (0.2mg/ml) and LH combined with HGA for 0-2hours. Activation of ERK1/ERK2 was assessed in all conditions by Western immunoblotting.

Results: LH treatment significantly increased p-ERK1/2 levels after 5 to 60 min exposure in human granulosa cells compared to basal levels (P<0.001). The combined treatment of LH and HGA increased p-ERK1/2 levels by 2.5 fold and attenuated ERK1/2 activation over 2 hours.

Conclusions: AGEs presence in the ovary interfere with LH action leading to a sustained activation of ERK1/2 in granulosa cells that is crucial for directing normal follicle development and initiating the ovulation process. Inappropriate activation of ERK1/2 in granulosa cells may block the granulosa cell differentiation pathway and /or impair follicular responses to hormones, leading to ovulation failure that characterizes PCOS.

Nothing to Disclose: ED, CP, SL, EAK, EP, MK

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