Metformin exhibits its therapeutic effect in the treatment of pre-eclampsia via modulating the Met/H19/miR-148a-5p/P28 and Met/H19/miR-216-3p/EBI3 signaling pathways.

Abstract

Metformin (Met) has been found to modify the methylation of H19 and to alter its expression. In addition, IL-27, one of the downstream factors in the H19 signaling pathway, plays an important role in the pathogenesis of pre-eclampsia (PE). In this study, we investigated the molecular mechanism underlying the therapeutic effect of Met in the management of PE both in vivo and in vitro. The role of H19 signaling pathway in PE was validated using online bioinformatics tools, luciferase assays, real-time PCR and Western Blot. A tail-cuff method was used to examine the blood pressures in PE rats with or without Met treatment. Cells exhibited a dose-dependent increase of H19 methylation, which inhibited the expression of H19. Additionally, upon the Met treatment, levels of miR-148-5p and miR-216-3p were both elevated in a dose-dependent manner while levels of p28 mRNA and EBI3 mRNA were both inhibited by Met treatment. Also, H19 was found to regulate the expression of miR-148a-5p and miR-216-3p, while P28 and EBI3 were respectively identified as target genes of miR-148a-5p and miR-216-3p. Therefore, the Met/H19/miR-148a-5p/P28 and Met/H19/miR-216-3p/EBI3 signaling pathways were implicated in the pathogenesis of PE. Met was implicated in the pathogenesis of PE via modulating the H19 signaling pathway. The methylation of H19 reduced H19 expression, which in turn could up-regulate the expression of miR-148-5p/miR-216-3p. And the expressions of subunits of IL-27, P28 and EBI3, were thus suppressed. Therefore, Met-induced inhibition of H19 also led to the reduction of IL-27 expression, TNF-α and IL-6 in vivo.

• Authors: Chang Shu, Dongmei Yan, Chen Chen, Yanxiang Mo, Linlin Wu, Jishuang Gu, Neelam Kumari Shah, Jin He, Shuai Dong
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 74 Pg. 105693 (Sep 2019) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 31203154 (Publication Type: Journal Article)
• Copyright: Copyright © 2019. Published by Elsevier B.V.

Chemical References

• EBI3 protein, rat
• Il27 protein, rat
• Interleukin-6
• Interleukins
• MIRN216 microRNA, rat
• MicroRNAs
• Minor Histocompatibility Antigens
• RNA, Long Noncoding
• Tumor Necrosis Factor-alpha
• Metformin

Topics

• Animals
• Cells, Cultured
• DNA Methylation
• Female
• Gene Expression Regulation
• Interleukin-6 (genetics, metabolism)
• Interleukins (genetics, metabolism)
• Metformin (therapeutic use)
• MicroRNAs (genetics)
• Minor Histocompatibility Antigens (genetics, metabolism)
• Pre-Eclampsia (drug therapy)
• Pregnancy
• RNA, Long Noncoding (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• Tumor Necrosis Factor-alpha (genetics, metabolism)