微小RNA-6516-3p介导的系膜细胞内源性基质金属蛋白酶-9抑制剂RECK的下调可能会加重狼疮性肾炎。

miR-6516-3p-mediated downregulation of the endogenous MMP-9 inhibitor RECK in mesangial cells might exacerbate lupus nephritis.

作者信息

Tomita Hiroyuki, Hayakawa Kunihiro, Ikeda Keigo, Tsushima Hiroshi, Shinoura Marina, Fujishiro Maki, Kataoka Yuko, Yamaji Ken, Takamori Kenji, Tamura Naoto, Sekigawa Iwao, Morimoto Shinji

机构信息

Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Tomioka Urayasu-Shi, Chiba, 279-0021, Japan.

Department of Internal Medicine and Rheumatology, Juntendo University Urayasu Hospital, Chiba, Japan.

出版信息

Mol Med. 2025 Mar 5;31(1):84. doi: 10.1186/s10020-025-01124-6.

DOI:10.1186/s10020-025-01124-6

PMID:40045202

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11881388/

Abstract

BACKGROUND

MicroRNAs (miRNAs) regulate biological processes by inhibiting translation and causing mRNA degradation. In this study, we identified the miRNAs involved in the development and progression of lupus nephritis (LNs) and verified their roles.

METHODS

Total RNA, extracted from PBMCs collected from patients with LNs before and after treatment, was used for miRNA array analysis to identify miRNAs whose expression was significantly altered. The results of this analysis were confirmed using qRT-PCR. The identified miRNAs were transfected into normal human mesangial cells (NHMCs), human renal proximal tubule epithelial cells (RPTECs), human umbilical vein endothelial cells (HUVECs), and THP-1-derived macrophages (THP1-Mφ) to investigate their biological functions.

RESULTS

Three miRNAs were altered in PBMCs before and after treatment of LNs. Among these miRNAs, hsa-miR-6516-3p promoted TNF-α-induced expression of MMP-9 in NHMCs. Moreover, hsa-miR-6516-3p downregulated the expression of RECK, an endogenous inhibitor of MMP-9. However, in NHMCs, endogenous hsa-miR-6516-3p was not present in functional amounts under inflammatory environment; therefore, we performed analysis using an experimental system considering extracellular influences of mesangial cells under LNs. The expression of hsa-miR-6516-3p was increased in HUVECs under inflammatory conditions and in activated macrophages.

CONCLUSIONS

hsa-miR-6516-3p increases MMP9 expression by suppressing RECK, and might, thereby, exacerbate LNs.

摘要

背景

微小RNA（miRNA）通过抑制翻译和导致mRNA降解来调节生物学过程。在本研究中，我们鉴定了参与狼疮性肾炎（LN）发生发展的miRNA，并验证了它们的作用。

方法

从LN患者治疗前后采集的外周血单个核细胞（PBMC）中提取总RNA，用于miRNA芯片分析以鉴定表达有显著变化的miRNA。使用qRT-PCR确认该分析结果。将鉴定出的miRNA转染到正常人系膜细胞（NHMC）、人肾近端小管上皮细胞（RPTEC）、人脐静脉内皮细胞（HUVEC）和THP-1衍生的巨噬细胞（THP1-Mφ）中，以研究它们的生物学功能。

结果

LN治疗前后PBMC中有三种miRNA发生了变化。在这些miRNA中，hsa-miR-6516-3p促进了NHMC中TNF-α诱导的MMP-9表达。此外，hsa-miR-6516-3p下调了MMP-9的内源性抑制剂RECK的表达。然而，在NHMC中，在炎症环境下内源性hsa-miR-6516-3p不存在功能量；因此，我们使用考虑LN下系膜细胞细胞外影响的实验系统进行了分析。在炎症条件下的HUVEC和活化的巨噬细胞中，hsa-miR-6516-3p的表达增加。