circRNA_010383 Acts as a Sponge for miR-135a, and Its Downregulated Expression Contributes to Renal Fibrosis in Diabetic Nephropathy
circRNA_010383 Acts as a Sponge for miR-135a, and Its Downregulated Expression Contributes to Renal Fibrosis in Diabetic Nephropathy
复制标题
circRNA_010383 作为 miR-135a 的海绵，其表达下调导致糖尿病肾病的肾纤维化
DOI：
10.2337/db20-0203
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发表时间：
2021-02-01
期刊：
影响因子：
7.7
通讯作者：
Long, Haibo
中科院分区：
文献类型：
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作者：
Peng, Fenfen;Gong, Wangqiu;Long, Haibo
糖尿病肾病（DN）是糖尿病的血管并发症，是糖尿病患者死亡的主要原因。异常表达的环状RNA（circRNA）在体内对DN的贡献知之甚少。使用整合的比较circRNA微阵列分析来检查db/db小鼠的糖尿病肾脏中circRNA的表达。我们发现，circRNA_010383的表达显着下调糖尿病肾脏，系膜细胞，肾小管上皮细胞在高糖条件下培养。circRNA_010383与miRNA-135 a（miR-135 a）共定位，并通过直接结合miR-135 a来抑制miR-135 a功能。在体外，敲低circRNA_010383促进细胞外基质（ECM）蛋白的积累，并下调瞬时受体电位阳离子通道，亚家族C，成员1（TRPC 1）的表达，这是miR-135 a的靶蛋白。此外，在体外，circRNA_010383过表达有效地抑制高糖诱导的ECM积累并增加TRPC 1水平。更重要的是，circRNA_010383过表达的肾脏靶点抑制db/db小鼠的蛋白尿和肾纤维化。在机制上，我们确定了circRNA_010383的缺失通过充当miR-135 a的海绵而促进DN中的蛋白尿和肾纤维化。该研究表明，circRNA_010383可能是未来DN治疗的新靶点。
Diabetic nephropathy (DN), a vascular complication of diabetes, is the leading cause of death in patients with diabetes. The contribution of aberrantly expressed circular RNAs (circRNAs) to DN in vivo is poorly understood. Integrated comparative circRNA microarray profiling was used to examine the expression of circRNAs in diabetic kidney of db/db mice. We found that circRNA_010383 expression was markedly downregulated in diabetic kidneys, mesangial cells, and tubular epithelial cells cultured in high-glucose conditions. circRNA_010383 colocalized with miRNA-135a (miR-135a) and inhibited miR-135a function by directly binding to miR-135a. In vitro, the knockdown of circRNA_010383 promoted the accumulation of extracellular matrix (ECM) proteins and downregulated the expression of transient receptor potential cation channel, subfamily C, member 1 (TRPC1), which is a target protein of miR-135a. Furthermore, circRNA_010383 overexpression effectively inhibited the high-glucose–induced accumulation of ECM and increased TRPC1 levels in vitro. More importantly, the kidney target of circRNA_010383 overexpression inhibited proteinuria and renal fibrosis in db/db mice. Mechanistically, we identified that a loss of circRNA_010383 promoted proteinuria and renal fibrosis in DN by acting as a sponge for miR-135a. This study reveals that circRNA_010383 may be a novel therapeutic target for DN in the future.