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长链非编码RNA KCNQ1OT1通过调控miR-93-5p/ROCK2轴促进糖尿病肾病的发展。

LncRNA KCNQ1OT1 promotes the development of diabetic nephropathy by regulating miR-93-5p/ROCK2 axis.

作者信息

Zhao Li, Chen Huaqian, Wu Lin, Li Zhengdong, Zhang Ren, Zeng Yan, Yang Tao, Ruan Hualing

机构信息

Department of Nephrology, Affiliated Dongfeng Hospital, Hubei University of Medicine, Shiyan, Hubei, People's Republic of China.

Department of Nephrology, Sinopharm Hanjiang Hospital, Hubei University of Medicine, Shiyan, Hubei, People's Republic of China.

出版信息

Diabetol Metab Syndr. 2021 Oct 15;13(1):108. doi: 10.1186/s13098-021-00726-4.

DOI:10.1186/s13098-021-00726-4
PMID:34654473
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8518197/
Abstract

BACKGROUND

Long non-coding RNAs (lncRNAs) have been reported to play vital roles in diabetic nephropathy (DN). The aim of this study was to explore the function of mechanism of lncRNA KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) in DN.

METHODS

DN cell models were established using high glucose (HG) treatment in human glomerular mesangial cells (HGMC) and human renal glomerular endothelial cells (HRGEC). The expression levels of KCNQ1OT1, microRNA-93-5p (miR-93-5p), and Rho associated coiled-coil containing protein kinase 2 (ROCK2) mRNA was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell Counting Kit-8 (CCK-8) assay and flow cytometry were used to detect cell proliferation and apoptosis, respectively. ROCK2 and apoptosis/fibrosis-related protein levels were examined by western blot. The predicted interaction between miR-93-5p and KCNQ1OT1 or ROCK2 was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay.

RESULTS

KCNQ1OT1 was upregulated in DN patients and DN cell models. KCNQ1OT1 knockdown inhibited cell proliferation and fibrosis and induced apoptosis in DN cell models. MiR-93-5p was a direct target of KCNQ1OT1, and miR-93-5p inhibition restored the KCNQ1OT1 knockdown-mediated effects on cell proliferation, fibrosis and apoptosis in DN cell models. In addition, ROCK2 was identified as a target of miR-93-5p, and miR-93-5p overexpression suppressed cell proliferation and fibrosis and accelerated apoptosis by targeting ROCK2 in DN cell models. Moreover, KCNQ1OT1 regulated ROCK2 expression by binding to miR-93-5p.

CONCLUSION

KCNQ1OT1 knockdown inhibited cell proliferation and fibrosis and induced apoptosis in DN by regulating miR-93-5p/ROCK2 axis, providing potential value for the treatment of DN.

摘要

背景

长链非编码RNA（lncRNAs）已被报道在糖尿病肾病（DN）中发挥重要作用。本研究旨在探讨lncRNA KCNQ1反义链/反义转录本1（KCNQ1OT1）在DN中的作用机制。

方法

采用高糖（HG）处理人肾小球系膜细胞（HGMC）和人肾小球内皮细胞（HRGEC）建立DN细胞模型。通过定量实时聚合酶链反应（qRT-PCR）检测KCNQ1OT1、微小RNA-93-5p（miR-93-5p）和含Rho相关卷曲螺旋蛋白激酶2（ROCK2）mRNA的表达水平。分别用细胞计数试剂盒-8（CCK-8）法和流式细胞术检测细胞增殖和凋亡。通过蛋白质印迹法检测ROCK2和凋亡/纤维化相关蛋白水平。通过双荧光素酶报告基因检测和RNA免疫沉淀（RIP）检测验证miR-93-5p与KCNQ1OT1或ROCK2之间的预测相互作用。

结果

KCNQ1OT1在DN患者和DN细胞模型中上调。KCNQ1OT1敲低抑制DN细胞模型中的细胞增殖和纤维化并诱导细胞凋亡。MiR-93-5p是KCNQ1OT1的直接靶点，miR-93-5p抑制恢复了KCNQ1OT1敲低介导的对DN细胞模型中细胞增殖、纤维化和凋亡的影响。此外，ROCK2被鉴定为miR-93-5p的靶点，miR-93-5p过表达通过靶向DN细胞模型中的ROCK2抑制细胞增殖和纤维化并加速细胞凋亡。此外，KCNQ1OT1通过与miR-93-5p结合调节ROCK2表达。

结论

KCNQ1OT1敲低通过调节miR-93-5p/ROCK2轴抑制DN中的细胞增殖和纤维化并诱导细胞凋亡，为DN的治疗提供了潜在价值。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1e/8518197/ad5d42a1b3bb/13098_2021_726_Fig8_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1e/8518197/cbbe8fcde171/13098_2021_726_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1e/8518197/07f9a865e51a/13098_2021_726_Fig5_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1e/8518197/44ac35d45afe/13098_2021_726_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1e/8518197/ad5d42a1b3bb/13098_2021_726_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1e/8518197/67db28552c02/13098_2021_726_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1e/8518197/dca06e5c15f6/13098_2021_726_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1e/8518197/29d8945fad5f/13098_2021_726_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1e/8518197/cbbe8fcde171/13098_2021_726_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1e/8518197/07f9a865e51a/13098_2021_726_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1e/8518197/bdb8eec3093f/13098_2021_726_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1e/8518197/44ac35d45afe/13098_2021_726_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1e/8518197/ad5d42a1b3bb/13098_2021_726_Fig8_HTML.jpg

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