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).