Up-regulation of microRNA-135 or silencing of PCSK6 attenuates inflammatory response in preeclampsia by restricting NLRP3 inflammasome

Xiaolan Zhao,Jie Mei,Zhao Wu,Xun Zhang,Yujue Wang,Lingling Li

doi:10.1186/s10020-021-00335-x

Abstract

ObjectiveNumerous studies have confirmed the correlation of microRNAs (miRNAs) with human disease, yet few have explored the role of miR-135 in preeclampsia (PE). This study intends to discuss miR-135’s function in inflammatory response in PE by modulating proprotein convertase subtilisin/kexin-6 (PCSK6) and NLR pyrin domain containing 3 (NLRP3).MethodsThe venous blood and placental tissues were collected from PE pregnant women and 25 normal ones. The levels of miR-135, PCSK6 and NLRP3 in placenta tissues of patients were detected. Hypoxia/reoxygenation HTR-8/SVneo and HPT-8 models were established to mimic PE in vitro, and cell proliferation, colony formation, apoptosis rate, invasion, migration and inflammation were detected through gain-of and loss-of-function assays.ResultsMiR-135 was down-regulated, and PCSK6 and NLRP3 were up-regulated in PE patients. Up-regulating miR-135 or silencing PCSK6 strengthened colony formation ability, viability, invasion and migration ability, and weakened apoptosis and inflammation of H/R-treated HTR-8/SVneo and HPT-8 cells. Inhibition of NLRP3 negated the effects of silenced PCSK6 in H/R-treated HTR-8/SVneo and HPT-8 cells.ConclusionsAltogether, we demonstrate that up-regulated miR-135 or reduced PCSK6 attenuates inflammatory response in PE by restricting NLRP3 inflammasome, which provides novel therapy for PE treatment.

Highlights

Preeclampsia (PE) refers to a pregnancy-specific syndrome which influences 3–5 % of pregnancies and usually appears when a woman presents hypertension and proteinuria after about 20 weeks of gestation (Mol et al 2016; Sircar et al 2015)
MiR‐135 is down‐regulated and proprotein convertase subtilisin/kexin-6 (PCSK6) and NLR pyrin domain containing 3 (NLRP3) are up‐regulated in placenta tissues of PE patients In addition to that, we conducted HE staining (Fig. 1A) with placenta tissues and observed that placenta tissues in the control group showed mature villi, uniform matrix, full morphology, less mesenchyme, abundant blood vessels, and orderly arranged nuclei of syncytiotrophoblast cells
The results demonstrated that miR-135 expression enhanced while PCSK6 and NLRP3 expression decreased in the H/R + miR-135 mimic group versus the H/R + mimic negative control (NC) group (Fig. 3A, B)

Summary

Introduction

Preeclampsia (PE) refers to a pregnancy-specific syndrome which influences 3–5 % of pregnancies and usually appears when a woman presents hypertension and proteinuria after about 20 weeks of gestation (Mol et al 2016; Sircar et al 2015). MicroRNA (miRNAs), a collection of small, endogenous non-coding RNAs with approximately 21–24 nucleotides, have the capacity to modulate gene expression by regulating mRNAs’s stability, govern the translation rates, and modulate protein synthesis (Zaheer et al 2019). MiR-135, a significant member of miRNA cluster, has been documented to suppress glycolysis in pancreatic ductal adenocarcinoma and regulate proliferation and epithelial-mesenchymal transition in breast cancer (Yang et al 2019; Jiang et al 2019). Zhang et al have demonstrated that miR-942 expression falls prior to 20 weeks gestation in PE women and is related with the pathophysiology of PE in vitro (Zhang et al 2017a, b)

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Discussion

Conclusion