Elucidating the role of pigment epithelium-derived factor (PEDF) in metabolic PCOS models

in Journal of Endocrinology
Authors:
Michal Silber Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Department of OB/GYN, Meir Medical Center, Kfar Saba, Israel
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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Irit Miller Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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Hadas Bar-Joseph Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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Ido Ben-Ami IVF and Fertility Unit, Department of OB/GYN, Shaare Zedek Medical Center, Jerusalem, Israel
The Hebrew University Medical School of Jerusalem, Jerusalem, Israel

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Ruth Shalgi Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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Correspondence should be addressed to R Shalgi: shalgir@tauex.tau.ac.il

*(I Ben-Ami and R Shalgi contributed equally to this work)

DOI:
https://doi.org/10.1530/JOE-19-0297
Volume/Issue:
Volume 244: Issue 2
Article Type:
Research Article
Page Range:
297–308
Online Publication Date:
Feb 2020
Copyright:
© 2020 Society for Endocrinology 2020
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PCOS is the most common endocrinopathy in women; associated with obesity and insulin resistance (IR). IR leads to accumulation of advanced-glycation-end-products (AGEs) and their receptor, RAGE. PCOS patients have increased levels of vascular endothelial growth factor (VEGF), interleukin 6/8 (IL-6/8) and anti-Mϋllerian-hormone (AMH). PEDF is a secreted-glycoprotein known for its anti-angiogenic and anti-inflammatory properties. We aimed to elucidate the role of PEDF in the pathogenesis and treatment of PCOS. We used a prenatal PCOS mouse model and fed the female offspring a high-fat diet, inducing metabolic PCOS (met.PCOS) characteristics. Female offspring were divided into three groups: control; met.PCOS; met.PCOS + recombinant PEDF (rPEDF). Met.PCOS mice gained more weight, had elevated serum IL-6 and higher mRNA levels of AMH, PEDF and RAGE in their granulosa cells (GCs) than met.PCOS + rPEDF mice. An in vitro Met.PCOS model in human GCs (KGN) line was induced by prolonged incubation with insulin/AGEs, causing development of IR. Under the same conditions, we observed an elevation of VEGF, IL-6/8 mRNAs, concomitantly with an increase in PEDF mRNA, intracellular protein levels, and an elevation of PEDF receptors (PEDF-Rs) mRNA and protein. Simultaneously, a reduction in the secretion of PEDF from GCs, was measured in the medium. The addition of rPEDF (5 nM) activated P38 signaling, implying that PEDF-Rs maintained functionality, and negated AGE-induced elevation of IL-6/8 and VEGF mRNAs. Decreased PEDF secretion may be a major contributor to hyperangiogenesis and chronic inflammation, which lie at the core of PCOS pathogenesis. rPEDF treatment may restore physiological angiogenesis inflammatory balance, thus suggesting a potential therapeutic role in PCOS.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2020 Society for Endocrinology 2020
Page(s):
12
Article Type:
Research Article
Received Date:
21 Sep 2019
Accepted Date:
29 Oct 2019
Print Publication Date:
01 Feb 2020
Online Publication Date:
Feb 2020
Keywords:
PCOS; PEDF; insulin resistance; advanced glycation end-products; KGN; IL-6; IL-8; VEGF

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