HOXA11-OS participates in lupus nephritis by targeting miR-124-3p mediating Cyr61 to regulate podocyte autophagy.
HOXA11-OS participates in lupus nephritis by targeting miR-124-3p mediating Cyr61 to regulate podocyte autophagy.
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HOXA11-OS通过靶向miR-124-3p介导Cyr61调节足细胞自噬参与狼疮肾炎
DOI：
10.1186/s10020-022-00570-w
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发表时间：
2022-11-22
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
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作者：
最近发现了长链非编码RNA HOXA11-OS。越来越多的研究表明，HOXA11-OS对胃癌、前列腺癌和多种肾脏疾病的基因具有调控作用，但对其在系统性红斑狼疮中的作用尚缺乏研究。本研究旨在探讨HOXA11-OS在狼疮性肾炎(LN)发病过程中足细胞自噬的调控作用及其可能的分子机制。用实时定量聚合酶链式反应、免疫印迹和免疫荧光检测靶基因Cyr61的mRNA和蛋白表达。用狼疮患者血清免疫球蛋白G(Ig G)诱导小鼠足细胞，用细胞计数试剂盒-8法检测其存活率。用双荧光素酶报告基因分析miR-124-3p与HOXA11-OS和Cyr61的相互作用。采用酶联免疫吸附试验检测血清自身抗体水平。用苏木精-伊红染色和高碘酸席夫染色检测肾组织的病理改变。两组间比较采用独立样本t检验，多组间比较采用单因素方差分析。HOXA11-OS在LN组织、血清和细胞中高表达，一些关键自噬因子和Cyr61的表达显著增加，而miR-124-3p的表达显著降低。在体外，LN-Ig G以时间和剂量依赖的方式抑制足细胞活性，增加自噬和Cyr61的表达，加重足细胞损伤。HOXA11-OS作为miR-124-3p的竞争性内源性RNA，可促进Cyr61的表达，从而增强LN-Ig G诱导的自噬增加，加重足细胞损伤。HOXA11-OS基因的敲除则起到相反的作用。MIR-124-3p模拟或Cyr61基因敲除可恢复HOXA11-OS过表达诱导的自噬因子和Cyr61的高表达，减轻足细胞损伤。进一步的体内实验表明，注射SH-HOXA11-OS腺相关病毒下调了HOXA11-OS的表达，并显着减轻了狼疮小鼠的肾脏损害。HOXA11-OS通过miR-124-3p/Cyr61海绵作用调节足细胞自噬，参与LN的发生发展，可能为LN提供一个潜在的治疗靶点。
The long chain non-coding RNA HOXA11-OS was recently identified. Increasing studies have shown that HOXA11-OS has regulatory effects on genes in gastric cancer, prostate cancer, and various kidney diseases, but research on its role in systemic lupus erythematosus is still lacking. The present study aimed to investigate the role of HOXA11-OS in the regulation of podocyte autophagy in the development of lupus nephritis (LN) and its potential molecular mechanism. mRNA and protein expression of the target gene (i.e., Cyr61) was detected by quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence. Mouse podocytes were induced using serum immunoglobulin G (IgG) from patients with lupus and their viability was detected using the cell counting kit-8 assay. The interaction of miR-124-3p with HOXA11-OS and Cyr61 was analyzed by double luciferase reporter gene assay. Serum autoantibody levels were detected by enzyme-linked immunosorbent assay. Pathological lesions in the kidney tissue were detected by hematoxylin–eosin and periodate-Schiff staining. The independent samples t-test was used for comparing two groups, and one-way analysis of variance for comparing multiple groups. HOXA11-OS was highly expressed in LN tissues, serum, and cells, and the expression of some key autophagy factors and Cyr61 was significantly increased, while miR-124-3p expression was significantly decreased. In vitro, LN-IgG inhibited podocyte activity, increased autophagy and Cyr61 expression, and aggravated podocyte injury in a time- and dose-dependent manner. As a competitive endogenous RNA of miR-124-3p, HOXA11-OS promoted the expression of Cyr61, thus enhancing the autophagy increase induced by LN-IgG and aggravating podocyte injury. Knockdown of HOXA11-OS had the opposite effect. miR-124-3p mimic or Cyr61 knockdown restored the high expression of autophagy factors and Cyr61 induced by HOXA11-OS overexpression and alleviated podocyte injury. Further in vivo experiments showed that injection of sh-HOXA11-OS adeno-associated virus downregulated HOXA11-OS and significantly alleviated renal damage in lupus mice. HOXA11-OS is involved in the occurrence and development of LN by regulating podocyte autophagy through miR-124-3p/Cyr61 sponging, which may provide a good potential therapeutic target for LN.
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