The Effect and Possible Mechanism of Kallistatin in Protecting against Endometrial Fibrosis

Xing-Yu Luo, Li Zhuan, Qin Xu, Ji-Wen Tian, Yan-Ping Ma

Article ID: 7351
Vol 37, Issue 6, 2023
DOI: https://doi.org/10.23812/j.biol.regul.homeost.agents.20233706.295
Received: 9 July 2023; Accepted: 9 July 2023; Available online: 9 July 2023; Issue release: 9 July 2023

Abstract

Objective: This study aimed to investigate the effect and possible mechanism of kallistatin (KS) in protecting against endometrial fibrosis. Methods: Human endometrial tissues from patients with intrauterine adhesions and normal uterine cavities were collected, and the expression of KS was analyzed. Fibrosis was induced in human endometrial epithelial (AN3CA) cells and human endometrial stromal cells (HESCs) using transforming growth factor beta 1 (TGF-β1). The cells were cultured with the KS protein, and the expression of fibronectin (FN) was assessed. Kallistatin expression was knocked down in the AN3CA cells, and the cells proliferation activity, apoptosis rate, and migration rate, along with the expression of related fibrosis factors, were tested. A rat intrauterine adhesion model was established, treatment was provided to each group of rats, and the pregnancy outcomes of the rats were noted. Results: Compared with the control group, the KS expression of the human endometrium in the adhesion group decreased. After treatment with TGF-β1, the FN expression of the AN3CA cells and HESCs increased. However, compared with the TGF-β1 treatment, the FN expression decreased after the culture with the KS protein. The knockout (KO) of KS expression in the AN3CA cells resulted in decreased cellular proliferation activity, an increased cellular apoptosis rate, and a decreased cellular migration rate. There was an increase in the expression of FN, TGF-β1, mothers against decapentaplegic homolog 3 (SMAD3), phosphorylated-p38 mitogen-activated protein kinase (p-p38 MAPK), and phospho-nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha. After uterine curettage, the rat endometrium became thinner, the number of glandular organs decreased, the expression of TGF-β1, SMAD3, and FN increased, and the number of embryos from pregnancy decreased. Endometrial fibrosis occurred after KS expression KO, and the overexpression of KS improved intrauterine adhesion to some extent. Conclusions: Kallistatin exhibited a protective effect on intrauterine adhesion. Kallistatin regulated and controlled TGF-β1 expression by inhibiting the p-p38 MAPK and nuclear factor kappa B pathways, which reduced endometrial fibrosis and improved pregnancy outcomes in rats.


Keywords

kallistatin;intrauterine adhesion;endometrial fibrosis;pregnancy rate


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