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/db200203
复制
发表时间：
2020-11-17
期刊：
影响因子：
7.7
通讯作者：
Long, Haibo
中科院分区：
文献类型：
--
作者：
Peng, Fenfen;Gong, Wangqiu;Long, Haibo
糖尿病肾病（DN）是糖尿病的一种血管并发症，是糖尿病患者死亡的主要原因。异常表达的环状RNA在体内对糖尿病肾病的作用尚不清楚。采用综合比较环状RNA微阵列分析技术检测了db/db小鼠糖尿病肾脏中环状RNA的表达。我们发现circRNA_010383在糖尿病肾脏、高糖培养的系膜细胞和肾小管上皮细胞中的表达显著下调。circRNA_010383与微小RNA - 135a（miR - 135a）共定位，并通过直接结合miR - 135a抑制其功能。在体外，circRNA_010383的敲低促进了细胞外基质（ECM）蛋白的积累，并下调了瞬时受体电位阳离子通道C亚家族成员1（TRPC1）的表达，TRPC1是miR - 135a的靶蛋白。此外，circRNA_010383的过表达在体外有效抑制了高糖诱导的ECM积累并提高了TRPC1水平。更重要的是，circRNA_010383过表达靶向肾脏可抑制db/db小鼠的蛋白尿和肾纤维化。从机制上讲，我们发现circRNA_010383的缺失通过作为miRNA - 135a的海绵作用促进了糖尿病肾病中的蛋白尿和肾纤维化。这项研究表明，circRNA_010383可能是未来糖尿病肾病的一个新的治疗靶点。
Diabetic nephropathy (DN), a vascular complication of diabetes mellitus, is the leading cause of death in diabetic patients. The contribution of aberrantly expressed circRNAs to diabetic nephropathy 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 microRNA-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 (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 miRNA-135a. This study reveals that circRNA_010383 may be a novel therapeutic target for DN in the future.