Document Type

Article

Publication Date

10-9-2024

Identifier

DOI: 10.3390/cells13191667; PMCID: PMC11476440

Abstract

Chronic kidney disease (CKD) is a leading cause of morbidity and mortality globally. Maternal obesity during pregnancy is linked to systemic inflammation and elevated levels of the pro-inflammatory cytokine interleukin-6 (IL-6). In our previous work, we demonstrated that increased maternal IL-6 during gestation impacts intrauterine development in mice. We hypothesized that IL-6-induced inflammation alters gene expression in the developing fetus. To test this, pregnant mice were administered IL-6 or saline during mid-gestation. Newborn mouse kidneys were analyzed using mRNA-seq, miRNA-seq and whole-genome bisulfite-seq (WGBS). A multi-omics approach was employed to quantify mRNA gene expression, miRNA expression and DNA methylation, using advanced bioinformatics and data integration techniques. Our analysis identified 19 key genes present in multiple omics datasets, regulated by epigenetics and miRNAs. We constructed a regulatory network for these genes, revealing disruptions in pathways such as Mannose type O-glycan biosynthesis, the cell cycle, apoptosis and FoxO signaling. Notably, the Atp7b gene was regulated by DNA methylation and miR-223 targeting, whereas the Man2a1 gene was controlled by DNA methylation affecting energy metabolism. These findings suggest that these genes may play a role in fetal programming, potentially leading to CKD later in life due to gestational inflammation.

Journal Title

Cells

Volume

13

Issue

19

MeSH Keywords

Animals; Kidney; Female; Mice; Interleukin-6; DNA Methylation; Pregnancy; Disease Models, Animal; MicroRNAs; Gene Regulatory Networks; Mice, Inbred C57BL; Animals, Newborn; RNA, Messenger; Multiomics

Keywords

chronic kidney disease (CKD); co-expression; epigenetics; interleukin-6 (IL-6); miRNA regulation; multi-omics

Comments

Grants and funding

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Publisher's Link: https://www.mdpi.com/2073-4409/13/19/1667

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