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01.12.2018 | Research | Ausgabe 1/2018 Open Access

Journal of Ovarian Research 1/2018

DHEA-induced ovarian hyperfibrosis is mediated by TGF-β signaling pathway

Zeitschrift:
Journal of Ovarian Research > Ausgabe 1/2018
Autoren:
Daojuan Wang, Wenqing Wang, Qiao Liang, Xuan He, Yanjie Xia, Shanmei Shen, Hongwei Wang, Qian Gao, Yong Wang
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s13048-017-0375-7) contains supplementary material, which is available to authorized users.

Abstract

Background

The polycystic ovary syndrome (PCOS) is a common metabolic and endocrine disorder with pathological mechanisms remain unclear. The following study investigates the ovarian hyperfibrosis forming via transforming growth factor-β (TGF-β) signaling pathway in Dehydroepiandrosterone (DHEA)- induced polycystic ovary syndrome (PCOS) rat model. We furthermore explored whether TGF-βRI inhibitor (SB431542) decreases ovarian fibrosis by counterbalancing the expression of fibrotic biomarkers.

Methods

Thirty female Sprague-Dawley rats were randomly divided into Blank group (n = 6), Oil group (n = 6), and Oil + DHEA-induced model group (n = 6 + 12). The model groups were established by subcutaneous injection of DHEA for 35 consecutive days. The 12 successful model rats were additionally divided in vehicle group (n = 6) and SB431542-treated group (n = 6). Vehicle group and SB431542-treated group, served as administration group and were intraperitoneally injected with DMSO and SB431542 for additional 14 consecutive days. Ovarian morphology, fibrin and collagen localization and expression in ovaries were detected using H&E staining, immunohistochemistry and Sirius red staining. The ovarian protein and RNA were examined using Western blot and RT-PCR.

Results

In DHEA-induced ovary in rat, fibrin and collagen had significantly higher levels, while the main fibrosis markers (TGF-β, CTGF, fibronectin, a-SMA) were obviously upregulated. SB431542 significantly reduced the expression of pro-fibrotic molecules (TGF-β, Smad3, Smad2, a-SMA) and increased anti-fibrotic factor MMP2.

Conclusion

TGF-βRI inhibitor (SB431542) inhibits the downstream signaling molecules of TGF-β and upregulates MMP2, which in turn prevent collagen deposition. Moreover, ovarian hyperfibrosis in DHEA-induced PCOS rat model could be improved by TGF-βRI inhibitor (SB431542) restraining the transcription of accelerating fibrosis genes and modulating EMT mediator.
Zusatzmaterial
Additional file 1: Figure S1. The serum testosterone (T) and (Estrogen) E2/T levels in control, DHEA and SB431542-treated rats. *p ≤ 0.05, ***p ≤ 0.002. Data are shown as mean ± SEM. Figure S2. The estrous cycle of DHEA-induced PCOS rats disordered. (A) The estrous cycle of the Blank group, Oil group and Oil + DHEA group rats. The abscissa indicates the age of rats. In the proestrus, many nucleated epithelial cells (NEC) were observed. In the estrus, high number of corneous cells (CC) were detected. In the metestrus, visible nucleated epithelial cells, corneous cells and leucocyte (L) were discovered. In the diestrus, a mass of leucocyte can be seen in the field of view. (B) Microscopic examination of vaginal smears stained by toluidine blue. × 200.. D = diestrus; P = proestrus; E = estrus; M = metestrus. Figure S3. The hormone levels after SB431542 treatment. (A) Serum total T levels; (B) E2/T of serum. (DOCX 467 kb)
13048_2017_375_MOESM1_ESM.docx
Additional file 2: Table S1. The serum hormonal levels in Vehicle and SB431542 treated rats. ∆p ≤ 0.05, ∆∆p ≤ 0.01, significantly different from Oil + DHEA; #p ≤ 0.05, significantly different from Vehicle. Dates are mean ± SEM. (XLSX 11 kb)
13048_2017_375_MOESM2_ESM.xlsx
Literatur
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