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促凋亡长链非编码RNA lincRNA-p21在狼疮性肾炎中表达上调并增强细胞凋亡

Up-Regulated Expression of Pro-Apoptotic Long Noncoding RNA lincRNA-p21 with Enhanced Cell Apoptosis in Lupus Nephritis.

作者信息

Chen Yi-Cheng, Kuo Pin-Yu, Chou Yu-Chi, Chong Hao-Earn, Hsieh Yu-Tung, Yang Mei-Lin, Wu Chao-Liang, Shiau Ai-Li, Wang Chrong-Reen

机构信息

Department of Internal Medicine, National Cheng Kung University Medical College and Hospital, Tainan 70403, Taiwan.

Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan 70101, Taiwan.

出版信息

Int J Mol Sci. 2020 Dec 30;22(1):301. doi: 10.3390/ijms22010301.

DOI:10.3390/ijms22010301
PMID:33396699
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7795010/
Abstract

Accelerated cell apoptosis with dysregulated long noncoding RNAs is the crucial pathogenesis in lupus nephritis (LN). Pro-apoptotic lincRNA-p21 was studied in LN patients, cell lines with lentivirus-mediated overexpression and CRISPR interference (CRISPRi)-conducted repression, and a mouse model. Clinical samples were from patients and age/sex-matched controls. Expression of lincRNA-p21 and endogenous RNA target miR-181a, were examined in mononuclear and urine cells. Guide RNA sequences targeting lincRNA-p21 were cloned into CRISPRi with dCas9/ Krüppel-associated box (KRAB) domain. LincRNA-p21-silened transfectants were investigated for apoptosis and miR-181a expression. LincRNA-p21-overexpressed cells were evaluated for apoptosis and p53-related down-stream molecules. Balb/C mice were injected with pristane to induce LN and examined for apoptosis and lincRNA-p21. Higher lincRNA-p21 levels were found in LN mononuclear and urine cells, positively correlated with activity. There were lower miR-181a levels in LN mononuclear cells, negatively correlated with activity. Doxorubicin-induced apoptotic cells had up-regulated lincRNA-p21 levels. CRISPRi with dCas9/KARA domain showed efficient repression ability on transcription initiation/elongation. CRISPRi-conducted lincRNA-p21-silenced transfectants displayed reduced apoptosis with up-regulated miR-181a levels, whereas lentivirus-mediated lincRNA-p21-overexpressed cells revealed enhanced apoptosis with up-regulated downstream PUMA/Bax expression. LN mice had glomerular apoptosis with progressive increased lincRNA-p21 levels. Our results demonstrate up-regulated lincRNA-p21 expression in LN, implicating a potential diagnostic marker and therapeutic target.

摘要

长链非编码RNA失调导致的细胞凋亡加速是狼疮性肾炎（LN）的关键发病机制。在LN患者、经慢病毒介导过表达和CRISPR干扰（CRISPRi）抑制的细胞系以及小鼠模型中研究了促凋亡的lincRNA-p21。临床样本来自患者和年龄/性别匹配的对照。检测了单核细胞和尿液细胞中lincRNA-p21以及内源性RNA靶标miR-181a的表达。将靶向lincRNA-p21的引导RNA序列克隆到带有dCas9/克勒ppel相关框（KRAB）结构域的CRISPRi中。研究了lincRNA-p21沉默的转染子的细胞凋亡和miR-181a表达。评估了lincRNA-p21过表达细胞的细胞凋亡和p53相关下游分子。给Balb/C小鼠注射 pristane以诱导LN，并检测细胞凋亡和lincRNA-p21。在LN单核细胞和尿液细胞中发现lincRNA-p21水平较高，与活性呈正相关。LN单核细胞中miR-181a水平较低，与活性呈负相关。阿霉素诱导的凋亡细胞中lincRNA-p21水平上调。带有dCas9/KARA结构域的CRISPRi对转录起始/延伸显示出有效的抑制能力。CRISPRi介导的lincRNA-p21沉默转染子显示细胞凋亡减少，miR-181a水平上调，而慢病毒介导的lincRNA-p21过表达细胞显示细胞凋亡增强，下游PUMA/Bax表达上调。LN小鼠出现肾小球细胞凋亡且lincRNA-p21水平逐渐升高。我们的结果表明LN中lincRNA-p21表达上调，提示其可能是一种潜在的诊断标志物和治疗靶点。

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