CTRP6 alleviates endometrial fibrosis by regulating Smad3 pathway in intrauterine adhesion

Jul 10, 2024Biology of reproduction

CTRP6 may reduce womb lining scarring by controlling the Smad3 pathway in uterine adhesions

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Abstract

CTRP6 expression is significantly downregulated in the endometrial tissues of individuals with intrauterine adhesion (IUA).

CTRP6 is associated with modulating fibrosis processes in various diseases.
In vitro studies show that CTRP6 levels decrease in TGF-β1-treated human endometrial stromal cells (HESCs).
CTRP6 inhibits the expression of fibrosis markers, including α-smooth muscle actin and collagen I, in TGF-β1-treated HESCs.
CTRP6 activates key signaling pathways (AMPK and AKT) in HESCs, contributing to its anti-fibrotic effects.
Inhibition of AMPK or AKT disrupts the protective effects of CTRP6 against TGF-β1-induced fibrosis.
CTRP6 treatment reduces fibrosis in the endometrium in animal models, suggesting its potential as a therapeutic target.

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Intrauterine adhesion (IUA) is manifestations of endometrial fibrosis and excessive extracellular matrix deposition. C1q/tumor necrosis factor-related protein-6 (CTRP6) is a newly identified adiponectin paralog which has been reported to modulate the fibrosis process of several diseases; however, the endometrial fibrosis function of CTRP6 remains unknown. Our study aimed to assess the role of CTRP6 in endometrial fibrosis and further explore the underlying mechanism. Here, we found that the expression of CTRP6 was downregulated in the endometrial tissues of IUA. In vitro experiments demonstrated the reduced level of CTRP6 in facilitated transforming growth factor-β1 (TGF-β1)-induced human endometrial stromal cells (HESCs). In addition, CTRP6 inhibited the expression of α-smooth muscle actin (α-SMA) and collagen I in TGF-β1-treated HESCs. Mechanistically, CTRP6 activated the AMP-activated protein kinase (AMPK) and protein kinase B (AKT) pathway in HESCs, and AMPK inhibitor (AraA) or PI3K inhibitor (LY294002) pretreatment abolished the protective effect of CTRP6 on TGF-β1-induced fibrosis. CTRP6 markedly decreased TGF-β1-induced Smad3 phosphorylation and nuclear translocation, and AMPK or AKT inhibition reversed these effects. Notably, CTRP6-overexpressing treatment alleviated the fibrosis of endometrium in vivo. Therefore, CTRP6 ameliorates endometrial fibrosis, among which AMPK and AKT are essential for the anti-fibrotic effect of CTRP6 via the Smad3 pathway. Taken together, CTRP6 may be a potential therapeutic target for the treatment of intrauterine adhesion.

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CTRP6 alleviates endometrial fibrosis by regulating Smad3 pathway in intrauterine adhesion

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