Circular RNA-ZNF532 regulates diabetes-induced retinal pericyte degeneration and vascular dysfunction
Qin Jiang, … , Chen Zhao, Biao Yan
Qin Jiang, … , Chen Zhao, Biao Yan
Published April 28, 2020
Citation Information: J Clin Invest. 2020;130(7):3833-3847. https://doi.org/10.1172/JCI123353.
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Research Article Ophthalmology

Circular RNA-ZNF532 regulates diabetes-induced retinal pericyte degeneration and vascular dysfunction

Abstract

Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults. Vascular pericyte degeneration is the predominant clinical manifestation of DR, yet the mechanism governing pericyte degeneration is poorly understood. Circular RNAs (circRNAs) play important roles in multiple biological processes and disease progression. Here, we investigated the role of circRNA in pericyte biology and diabetes-induced retinal vascular dysfunction. cZNF532 expression was upregulated in pericytes under diabetic stress, in the retinal vessels of a diabetic murine model, and in the vitreous humor of diabetic patients. cZNF532 silencing reduced the viability, proliferation, and differentiation of pericytes and suppressed the recruitment of pericytes toward endothelial cells in vitro. cZNF532 regulated pericyte biology by acting as a miR-29a-3p sponge and inducing increased expression of NG2, LOXL2, and CDK2. Knockdown of cZNF532 or overexpression of miR-29a-3p aggravated streptozotocin-induced retinal pericyte degeneration and vascular dysfunction. By contrast, overexpression of cZNF532 or inhibition of miR-29a-3p ameliorated human diabetic vitreous–induced retinal pericyte degeneration and vascular dysfunction. Collectively, these data identify a circRNA-mediated mechanism that coordinates pericyte biology and vascular homeostasis in DR. Induction of cZNF532 or antagonism of miR-29a-3p is an exploitable therapeutic approach for the treatment of DR.

Authors

Qin Jiang, Chang Liu, Chao-Peng Li, Shan-Shan Xu, Mu-Di Yao, Hui-Min Ge, Ya-Nan Sun, Xiu-Miao Li, Shu-Jie Zhang, Kun Shan, Bai-Hui Liu, Jin Yao, Chen Zhao, Biao Yan

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Figure 6

cZNF532-miR-29a-3p-NG2/LOXL2/CDK2 signaling regulates retinal pericyte function and vascular integrity in vivo.

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cZNF532-miR-29a-3p-NG2/LOXL2/CDK2 signaling regulates retinal pericyte f...
(A and B) Diabetic C57BL/6 mice (3 months old, male) received an intravitreous injection of miR-29a-3p agomir or negative control (NC) agomir, or were left untreated (Ctrl). Pericyte coverage was quantified by staining the whole-mount retinas with Isolectin IB4 and NG2 after 2 months, 4 months, and 6 months of treatment (n = 8; scale bar: 100 μm). The statistical result and representative images after 6 months of treatment are shown. (C and D) The above-mentioned mice were infused with EB dye for 2 hours. The tile-scanning images of entire retinal vessels were taken using a ×4 lens with identical gain settings. The representative images of flat-mounted retinas after 6 months of treatment (C, n = 10; scale bar: 500 μm) and statistical result of EB extravasation are shown (D). The red fluorescence indicates EB signal. (E–G) Retinal trypsin digestion and PAS staining were conducted to detect the number of microaneurysms (E, n = 8 per mm2 retina), acellular capillaries (F, n = 8 per mm2 retina), and pericyte ghosts (G, n = 8 per mm2 retina). The blood glucose levels of diabetic mice were above 300 mg/dL. The significant difference was evaluated by Kruskal-Wallis’s test followed by Bonferroni’s post hoc test. Error bar indicates SD. *P < 0.05.