CircUBXN7 promotes macrophage infiltration and renal fibrosis associated with the IGF2BP2-dependent SP1 mRNA stability in diabetic kidney disease.
CircUBXN7 promotes macrophage infiltration and renal fibrosis associated with the IGF2BP2-dependent SP1 mRNA stability in diabetic kidney disease.
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CircuBxn7促进了与糖尿病肾脏疾病中IGF2BP2依赖性SP1 mRNA稳定性相关的巨噬细胞浸润和肾纤维化。
DOI：
10.3389/fimmu.2023.1226962
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发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
炎症细胞浸润是糖尿病肾病（DKD）的新标志，部分是由活化的巨噬细胞引起的。巨噬细胞与小管上皮细胞的通讯可能在肾纤维化中起重要作用。环状rna （circRNAs）在包括DKD在内的巨噬细胞活化的各种人类疾病的发病机制中已被报道。然而，circRNAs在巨噬细胞浸润和DKD肾纤维化中的确切机制尚不清楚。在我们的研究中，利用微阵列技术在DKD患者中发现了一种新的环状rna cirbxn7。采用qRT-PCR、western blot、免疫荧光等方法研究cirbxn7在体外和体内的功能。最后，通过双荧光素酶报告基因实验、ChIP、RNA下拉、RNA免疫沉淀和抢救实验来研究cirbxn7的作用机制。我们证明cirbxn7在DKD患者血浆中的表达显著上调，且与肾功能相关，可能作为DKD患者的独立生物标志物。研究表明，异位表达cirbxn7在体外促进巨噬细胞活化、EMT和纤维化，在体内增加巨噬细胞浸润、EMT、纤维化和蛋白尿。从机制上讲，在DKD中，cirbxn7被转录因子SP1上调转录，并通过直接结合m6a读取器IGF2BP2，相互促进SP1 mRNA的稳定性和激活。cirbxn7在DKD患者中高表达，可能为DKD提供潜在的生物标志物和治疗靶点。
Inflammatory cell infiltration is a novel hallmark of diabetic kidney disease (DKD), in part, by activated macrophages. Macrophage-to-tubular epithelial cell communication may play an important role in renal fibrosis. Circular RNAs (circRNAs) have been reported in the pathogenesis of various human diseases involving macrophages activation, including DKD. However, the exact mechanism of circRNAs in macrophage infiltration and renal fibrosis of DKD remains obscure. In our study, a novel circRNA circUBXN7 was identified in DKD patients using microarray. The function of circUBXN7 in vitro and in vivo was investigated by qRT-PCR, western blot, and immunofluorescence. Finally, a dual-luciferase reporter assay, ChIP, RNA pull-down, RNA immunoprecipitation and rescue experiments were performed to investigate the mechanism of circUBXN7. We demonstrated that the expression of circUBXN7 was significantly upregulated in the plasma of DKD patients and correlated with renal function, which might serve as an independent biomarker for DKD patients. According to investigations, ectopic expression of circUBXN7 promoted macrophage activation, EMT and fibrosis in vitro, and increased macrophage infiltration, EMT, fibrosis and proteinuria in vivo. Mechanistically, circUBXN7 was transcriptionally upregulated by transcription factor SP1 and could reciprocally promote SP1 mRNA stability and activation via directly binding to the m6A-reader IGF2BP2 in DKD. CircUBXN7 is highly expressed in DKD patients may provide the potential biomarker and therapeutic target for DKD.
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