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circRNA_010383 acts as a sponge for miR-135a and its downregulated expression contributes to renal fibrosis in diabetic nephropathy

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posted on 17.11.2020, 22:53 by Ada Admin, Fenfen Peng, Wangqiu Gong, Shuting Li, Bohui Yin, Chen Zhao, Wenting Liu, Xiaowen Chen, Congwei Luo, Qianying Huang, Ting Chen, Lingzhi Sun, Shun Fang, Weidong Zhou, Zhijian Li, Haibo Long
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.

Funding

This work was supported by the National Natural Science Foundation of China (NSFC, no. 81600624, no. 81673792, no. 81873346, no. U1801288, no. 81900607 and 82071563), the Natural Science Foundation of Guangdong Province, China (no. 2017A030313708 and no. 2014A030310065), the Science and Technology Planning Project of Guangdong Province, China (no. 2017A020215158), and the Science and Technology Planning Project of Guangzhou, China (no. 201707010286).

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