Circ-ITCH restrains the expression of MMP-2, MMP-9 and TNF-alpha in diabetic retinopathy by inhibiting miR-22

Diabetic retinopathy (DR), the most frequent complication of diabetes mellitus, is the principal cause of acquired blindness worldwide. Although the roles of circRNAs have been extensively explored, the detailed physiological and pathological functions of circRNAs in DR are less understood. Here, we studied the biological effects of circ-ITCH in diabetic retinal pigment epithelial cells (RPEs) and explored the underlying mechanisms. As our results shown, the RNA expression of circ-ITCH was significantly lower in RPEs isolated from diabetic rats than they were in those isolated from normal rats. While diabetes induced an increase in MMP-2, MMP-9 and TNF-alpha in RPEs, circ-ITCH overexpression exerted an inhibitory on these increases and knockdown of circ-ITCH reversed the inhibitory. In addition, increased expression of miR-22 in RPEs correlated with diabetes and downregulation of circ-ITCH. Remarkably, in the presence of miR-22 mimics, the effects of circ-ITCH on the MMP-2 and MMP-9 were both antagonized. Collectively, our data supports a cellular signaling cascade in which circ-ITCH-inhibited miR-22 activity modulates the expression of MMP-2, MMP-9 and TNF-alpha in DR.

Automated summary

In diabetic retinopathy, the decreased expression of circ-ITCH in retinal pigment epithelial cells correlates with increased levels of MMP-2, MMP-9, and TNF-alpha, which is reversed by circ-ITCH overexpression. Additionally, the inhibitory effects of circ-ITCH on MMP-2 and MMP-9 are antagonized by miR-22 mimics, indicating a regulatory role of circ-ITCH-inhibited miR-22 activity in DR pathogenesis.