Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
Diabetes. 2021 Feb;70(2):603-615. doi: 10.2337/db20-0203.
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 / 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 / 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.
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（circRNA）在体内对 DN 的作用知之甚少。本研究采用整合比较环状 RNA 微阵列分析，研究了 / 鼠糖尿病肾脏中 circRNA 的表达。结果发现，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表达明显下调。circRNA_010383 与 miRNA-135a（miR-135a）共定位，并通过直接结合 miR-135a 抑制 miR-135a 功能。在体外，circRNA_010383 的敲低促进细胞外基质（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（TRPC1）的表达，TRPC1 是 miR-135a 的靶蛋白。此外，circRNA_010383 的过表达可有效抑制高糖诱导的 ECM 积累和体外 TRPC1 水平升高。更重要的是，circRNA_010383 的过表达可抑制 / 鼠肾脏中的蛋白尿和肾纤维化。机制上，我们发现 circRNA_010383 通过作为 miR-135a 的海绵，促进 DN 中的蛋白尿和肾纤维化。本研究表明，circRNA_010383 可能成为未来治疗 DN 的一个新靶点。
