LncRNA HOXA11-AS regulates calcium oxalate crystal-induced renal inflammation via miR-124-3p/MCP-1

Long noncoding RNA (lncRNA) has been suggested to play an important role in a variety of diseases over the past decade. In a previous study, we identified a novel lncRNA, termed HOXA11-AS, which was significantly up-regulated in calcium oxalate (CaOx) nephrolithiasis. However, the biological function of HOXA11-AS in CaOx nephrolithiasis remains poorly defined. Here, we demonstrated that HOXA11-AS was significantly up-regulated in CaOx nephrolithiasis both in vivo and in vitro. Gain-/loss-of-function studies revealed that HOXA11-AS inhibited proliferation, promoted apoptosis and aggravated cellular damage in HK-2 cells exposed to calcium oxalate monohydrate (COM). Further investigations showed that HOXA11-AS regulated monocyte chemotactic protein 1 (MCP-1) expression in HK-2 cell model of CaOx nephrolithiasis. In addition, online bioinformatics analysis and dual-luciferase reporter assay results showed that miR-124-3p directly bound to HOXA11-AS and the 3'UTR of MCP-1. Furthermore, rescue experiment results revealed that HOXA11-AS functioned as a competing endogenous RNA to regulate MCP-1 expression through sponging miR-124-3p and that overexpression of miR-124-3p restored the inhibitory effect of proliferation, promotion effects of apoptosis and cell damage induced by HOXA11-AS overexpression. Taken together, HOXA11-AS mediated CaOx crystal-induced renal inflammation via the miR-124-3p/MCP-1 axis, and this outcome may provide a good potential therapeutic target for nephrolithiasis.

在过去十年中，长链非编码RNA（lncRNA）被认为在多种疾病中发挥着重要作用。在先前的一项研究中，我们发现了一种新型的lncRNA，称为HOXA11 - AS，它在草酸钙（CaOx）肾结石中显著上调。然而，HOXA11 - AS在草酸钙肾结石中的生物学功能仍不明确。在此，我们证明了在体内和体外的草酸钙肾结石中HOXA11 - AS均显著上调。功能获得/缺失研究表明，HOXA11 - AS抑制了暴露于草酸钙一水合物（COM）的HK - 2细胞的增殖，促进了其凋亡并加重了细胞损伤。进一步的研究显示，在草酸钙肾结石的HK - 2细胞模型中，HOXA11 - AS调节单核细胞趋化蛋白1（MCP - 1）的表达。此外，在线生物信息学分析和双荧光素酶报告基因检测结果表明，miR - 124 - 3p直接与HOXA11 - AS以及MCP - 1的3'非翻译区（3'UTR）结合。而且，挽救实验结果显示，HOXA11 - AS作为一种竞争性内源性RNA，通过吸附miR - 124 - 3p来调节MCP - 1的表达，并且miR - 124 - 3p的过表达恢复了因HOXA11 - AS过表达而诱导的增殖抑制作用、凋亡促进作用以及细胞损伤。综上所述，HOXA11 - AS通过miR - 124 - 3p/MCP - 1轴介导草酸钙晶体诱导的肾脏炎症，这一结果可能为肾结石提供一个良好的潜在治疗靶点。