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miR-30a-5p 通过 DNMT1 介导的高甲基化促进高同型半胱氨酸血症下肾小球足细胞凋亡。

miR-30a-5p promotes glomerular podocyte apoptosis via DNMT1-mediated hypermethylation under hyperhomocysteinemia.

机构信息

Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan 750004, China.

Department of Clinical Medicine, General Hospital of Ningxia Medical University, Yinchuan 750004, China.

出版信息

Acta Biochim Biophys Sin (Shanghai). 2022 Jan 25;54(1):126-136. doi: 10.3724/abbs.2021005.

DOI:10.3724/abbs.2021005
PMID:35130620
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9909319/
Abstract

Abnormal elevation of homocysteine (Hcy) level is closely related to the development and progression of chronic kidney disease (CKD), with the molecular mechanisms that are not fully elucidated. Given the demonstration that miR-30a-5p is specifically expressed in glomerular podocytes, in the present study we aimed to investigate the role and potential underlying mechanism of miR-30a-5p in glomerular podocyte apoptosis induced by Hcy. We found that elevated Hcy downregulates miR-30a-5p expression in the mice and Hcy-treated podocytes, and miR-30a-5p directly targets the 3'-untranslated region (3'-UTR) of the forkhead box A1 (FOXA1) and overexpression of miR-30a-5p inhibits FOXA1 expression. By nMS-PCR and MassARRAY quantitative methylation analysis, we showed the increased DNA methylation level of miR-30a-5p promoter both and . Meanwhile, dual-luciferase reporter assay showed that the region between --1400 and --921 bp of miR-30a-5p promoter is a possible regulatory element for its transcription. Mechanistic studies indicated that DNA methyltransferase enzyme 1 (DNMT1) is the key regulator of miR-30a-5p, which in turn enhances miR-30a-5p promoter methylation level and thereby inhibits its expression. Taken together, our results revealed that epigenetic modification of miR-30a-5p is involved in glomerular podocyte injury induced by Hcy, providing a diagnostic marker candidate and novel therapeutic target in CKD induced by Hcy.

摘要

同慢性肾脏病（CKD）的发展和进展密切相关的是同型半胱氨酸（Hcy）水平的异常升高，但其分子机制尚未完全阐明。鉴于 miR-30a-5p 特异性表达于肾小球足细胞的证明，本研究旨在探讨 miR-30a-5p 在 Hcy 诱导的肾小球足细胞凋亡中的作用及其潜在的作用机制。我们发现，升高的 Hcy 下调了小鼠和 Hcy 处理的足细胞中 miR-30a-5p 的表达，并且 miR-30a-5p 直接靶向叉头框 A1（FOXA1）的 3'-非翻译区（3'-UTR），而过表达 miR-30a-5p 抑制 FOXA1 的表达。通过 nMS-PCR 和 MassARRAY 定量甲基化分析，我们显示 miR-30a-5p 启动子的 DNA 甲基化水平均增加。同时，双荧光素酶报告基因检测表明 miR-30a-5p 启动子的 --1400 到 --921 bp 之间的区域是其转录的可能调节元件。机制研究表明，DNA 甲基转移酶 1（DNMT1）是 miR-30a-5p 的关键调节因子，它反过来增强 miR-30a-5p 启动子的甲基化水平，从而抑制其表达。总之，我们的研究结果表明，miR-30a-5p 的表观遗传修饰参与了 Hcy 诱导的肾小球足细胞损伤，为 Hcy 诱导的 CKD 提供了一个诊断标志物候选和新的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/beb3/9909319/283f61078376/21430-t8.jpg
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