Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
Emergency Medicine and Difficult Diseases Institute, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
Cell Death Dis. 2022 Mar 4;13(3):207. doi: 10.1038/s41419-022-04612-3.
Circular RNAs (circRNAs) are involved in the pathogenesis of certain renal diseases, however, the function and mechanism of them in renal fibrosis remains largely unknown. In the present study, RNA expression data in unilateral ureteral obstruction (UUO) kidneys was obtained from our previous circRNA Microarray and public Gene Expression Omnibus datasets to construct a ceRNA network. The effects of target circRNA as long as the homologous human circRNA on renal fibrosis was examined in vitro and in vivo. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was further performed among genes regulated by the human circRNA. We found that circRNA_37492, showing well connection degree in the ceRNA network, was abundant expression and high sequence conservation. We observed that the expression of circRNA_37492 was induced by the TGF-β1 or UUO in BUMPT cells and C57BL/6 mice, respectively. In vitro, cytoplasmic circRNA_37492 inhibited type I, III collagen and fibronectin deposition by sponging miR-7682-3p and then upregulated its downstream target Fgb. In vivo, overexpression of circRNA_37492 attenuated fibrotic lesions in the kidneys of UUO mice via targeting miR-7682-3p/Fgb axis. Furthermore, hsa_circ_0012138, homologous with circRNA_37492, may potentially target miR-651-5p/FGB axis in human renal fibrosis. Not only that, GO and KEGG enrichment revealed that hsa_circ_0012138-regulated genes were previously demonstrated to related to the fibrosis. In conclusion, we for the first time demonstrated that circRNA_37492 attenuated renal fibrosis via targeting miR-7682-3p/Fgb axis, and the homologous hsa_circRNA_0012138 was speculated as a possible ceRNA to regulate multiple gene expressions and involve in human renal fibrosis, suggesting that circRNA_37492/hsa_circ_0012138 may serve as potent therapy target for obstructive renal fibrosis disease.
环状 RNA（circRNAs）参与某些肾脏疾病的发病机制，但它们在肾纤维化中的功能和机制在很大程度上仍然未知。在本研究中，我们从前circRNA 微阵列和公共基因表达综合数据集获得单侧输尿管梗阻（UUO）肾脏的 RNA 表达数据，以构建 ceRNA 网络。我们在体外和体内检查了作为长链非编码 RNA 的目标 circRNA 以及同源的人类 circRNA 对肾纤维化的影响。进一步对受人类 circRNA 调控的基因进行了基因本体论（GO）和京都基因与基因组百科全书（KEGG）富集分析。我们发现，在 ceRNA 网络中具有良好连接度的 circRNA_37492 表达丰富且序列高度保守。我们观察到，circRNA_37492 的表达分别由 TGF-β1 或 UUO 在 BUMPT 细胞和 C57BL/6 小鼠中诱导。在体外，细胞质 circRNA_37492 通过海绵 miR-7682-3p 抑制 I 型、III 型胶原和纤维连接蛋白的沉积，然后上调其下游靶标 Fgb。在体内，过表达 circRNA_37492 通过靶向 miR-7682-3p/Fgb 轴减轻 UUO 小鼠肾脏的纤维化病变。此外，与 circRNA_37492 同源的 hsa_circ_0012138 可能在人类肾纤维化中靶向 miR-651-5p/FGB 轴。不仅如此，GO 和 KEGG 富集分析表明，hsa_circ_0012138 调控的基因以前被证明与纤维化有关。总之，我们首次证明 circRNA_37492 通过靶向 miR-7682-3p/Fgb 轴减轻肾纤维化，同源的 hsa_circ_0012138 被推测为可能的 ceRNA 以调节多个基因表达并参与人类肾纤维化，提示 circRNA_37492/hsa_circ_0012138 可能作为阻塞性肾纤维化疾病的潜在治疗靶点。
