The poor prognosis of LN is still a seriously clinical and economic problem, as the mechanisms of LN remain indistinct. Thus, the identification of novel treatment targets for LN would be very desirable. CircRNA is a special class of endogenous RNAs with multiple functions. Many studies have revealed the abnormal circRNAs were associated with several renal diseases ,such as AKI, carcinoma[8, 20]. However, the role of circRNA in LN was rarely reported. In the present study, we conducted integrative analysis using circRNA sequencing in renal tissues and identified 159 circRNAs with significantly differential expression, of which 73 were upregulated and 86 downregulated. Hsa_circ_0123190 maybe act as a sponge for hsa-miR-483-3p, which regulates APLNR expression in LN. In addition, peripheral blood hsa_circ_0123190 would be a biomarker for patients with LN.
Special attention must be paid to the type of specimen since circRNAs were highly expressed in a cell type-specific or tissue-specific manner[4, 5]. Ouyang et al discovered that upregulated plasma circRNA_002453 level in LN patients was associated with the severity of renal involvement and served as a novel biomarker for LN patient diagnosis . Luan et al, showed that circHLA-C played an important role in the pathogenesis by sponging miR-150 in single class IV of LN. These data are not consistent across researches due to different samples and methods. The profiling of circRNAs from this study may provide a novel database and new view to study mechanisms of LN.
Over the last few years, many functions of circRNAs have been elucidated. CircRNAs can act as gene expression regulators via different regulatory modes,such as “sponges” miRNAs resulting in the expression of target mRNAs. The interaction network of circRNA in LN was slightly shed in the current study. The circRNA hsa_circ_0123190 was downregulated in renal tissues of patients with LN, and the expression of hsa-miR-483-3p had a significantly opposite direction. Bioinformatic analysis and luciferase reporter assay discovered that hsa_circ_0123190 directly bind to hsa-miR-483-3p, which serves as a miRNA sponge. There have been several reports that increased hsa-miR-483-3p impair endothelial cell survival to limit vascular repair capacity upon injury in cancer and metabolic diseases [24–26]. However, the role of hsa-miR-483-3p has been unreported in LN, which also has vascular lesion. This suggests that the downregulated hsa_circ_0123190 might sponge hsa-miR-483-3p in LN to promote kidney vascular damage.
In addition, hsa-miR-483-3p was only interacted with APLNR in this study, which was decreased in renal tissues of LN. APLNR is the orphan G protein-coupled apelin receptor, which could be expressed in various organ and tissues. Hus-Citharel et al discovered that the APLNR mRNA were widely expressed in rat kidney, and the level of APLNR in all nephron segments was lower than the glomeruli. There are multiple functions of APLNR and apelin, such as regulation of blood pressure, immune response and anti-inflammatory effect. They also play an important role in organ fibrosis. Renal fibrosis is a major feature of chronic kidney disease including LN. Collagen, α-SMA, TGF-β are considered to be important fibrosis-related proteins. In the present study, Masson-trichome staining laterally demonstrated that renal fibrosis is a typical pathological manifestation of LN kidney. A large amount of studies on kidney diseases indicates that APLNR and apelin can improve renal interstitial fibrosis by restraining the expression of TGF-β1.TGF-β participates in chronic renal inflammation and renal fibrosis through the Smad signaling pathway, protein kinase C pathway and mitogen-activated protein kinase pathway. A research on mice with complete unilateral ureteral obstruction (UUO) illustrated that apelin treatment could significantly reduce the expression of α-SMA, TGF-β1 and its receptor. In this study, we found that the expression of TGF-β1 was significantly increased in LN, which was opposite to APLNR. Therefore, we tentatively hypothesized APLNR may be involved in renal fibrosis of LN by regulating TGF-β1.
The expression of peripheral blood hsa_circ_0123190 was downregulated and negatively associated with serum creatine level in LN, which indicated that it might be involved in renal injury in patients with LN. Moreover, we ensured the clinal value of this circRNA as a diagnostic biomarker for LN through performing ROC curve analysis. These results indicated that hsa_circ_0123190 in peripheral blood could be a novel promising diagnostic and non-invasive biomarker of LN patients.
There are some limitations in our study. First of all, our sample sizes were comparatively small. The examination of circRNAs in kidneys and blood samples in larger cohorts of LN patients may define its clinical value as a diagnostic biomarker. Secondly, the mechanisms of hsa_circ_0123190 in the development and pathogenesis of LN has not yet been completely studied. Thus, further experiments in vitro and in vivo are needed. Thirdly, the expression of hsa_circ_0123190 in T cells, B cells and other immune cells will be detected and compared in the next step.