Exosomal circDNAJB6 derived from decidual macrophages promotes preeclampsia progression via the miR-670-5p/TOB2 axis and by subsequently regulating the PPARγ/NF-κB pathway.

PURPOSE: Exosomes and circular RNAs (circRNAs) have been strongly implicated in the development of preeclampsia (PE). This study aimed to investigate the function and regulatory mechanism of exosomal circRNAs derived from decidual macrophages (DMφ) in PE. PATIENTS AND

METHODS

DMφ and exosomes derived from DMφ (PE-DMφ-exo and normal-DMφ-exo) were obtained from PE patients and normal pregnant patients. The effects of DMφ-exo on the biological function of trophoblasts were assessed. Microarray analysis and qRT‒PCR were used to identify the differentially expressed circRNAs between PE-DMφ-exo and normal-DMφ-exo. The effects of exosomal circDNAJB6 on the biological function of trophoblasts were then explored. The regulatory relationships among circDNAJB6, miR-670-5p, and TOB2 were verified by dual-luciferase reporter assays. The effect of the circDNAJB6/miR-670-5p/TOB2 axis on the PPARγ/NF-κB pathway was then assessed. The function of exosomal circDNAJB6 in vivo was confirmed in a PE rat model.

RESULTS

PE-DMφ-exo inhibited trophoblasts proliferation, migration, invasion and human umbilical vein endothelial cell (HUVEC) angiogenesis and increased trophoblasts apoptosis. circDNAJB6 was upregulated in PE-DMφ-exo and transported from DMφ to trophoblasts via the exosomal pathway. Exosomal circDNAJB6 inhibited trophoblasts activity and HUVEC tube formation. CircDNAJB6 was found to act as a competing endogenous RNA (ceRNA) of miR-670-5p and thereby upregulate TOB2. miR-670-5p overexpression or TOB2 knockdown reversed the inhibitory effect of exosomal circDNAJB6 on trophoblasts. Moreover, the circDNAJB6/miR-670-5p/TOB2 axis activated the NF-κB pathway by downregulating PPARγ. Finally, in vivo experiments demonstrated that the upregulation of circDNAJB6 in PE-DMφ-exo increased blood pressure and 24-h urine protein levels, thereby exacerbating PE.

CONCLUSIONS

Our study revealed that exosomal circDNAJB6 derived from DMφ regulated the miR-670-5p/TOB2/PPARγ/NF-κB pathway and thereby promoted PE progression, which provides novel insights into PE development.