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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 Article has an altmetric score of 1

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

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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 5

cZNF532 regulates pericyte function by acting as a miRNA sponge in vitro.

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cZNF532 regulates pericyte function by acting as a miRNA sponge in vitro...
(A) HEK293T cells were transfected with pGL3-Basic (Ctrl) or LUC-cZNF532 with different miRNA mimic and pRL-TK vector. pRL-TK vector was transfected as the internal transfection control. Luciferase assays were conducted 48 hours after transfection using the Dual-Luciferase Reporter Assay kit. Normalized value of luciferase activity for Ctrl group was set to 1 (n = 4). (B) LUC-cZNF532 or LUC-cZNF532-mutant was cotransfected without or with miRNA mimic and pRL-TK vector. Luciferase assays were conducted 48 hours after transfection. Normalized value of luciferase activity was set to 1 in cells transfected with LUC-cZNF532 and pRL-TK (n = 4). (C and D) Relative expression abundance of cZNF532, miR-29a-3p, miR-498, and miR-758 was detected by qRT-PCR in pericytes (C, n = 4) and mouse retinas (D, n = 6). (E) Expression distribution of cZNF532 and miR-29a-3p in pericytes was detected by RNA-FISH assay (scale bar: 20 μm). (F) The schematic figure shows the putative binding sites of miR-29a-3p on cZNF532 transcript. (G and H) Luciferase reporter with perfect miR-29a-3p target site (G) or entire cZNF532 sequence was constructed (H). The constructed reporter was transfected with 40 ng empty vector (vector, pcDNA3), 40 ng cZNF532-ir (pcDNA3-cZNF532-ir), 40 ng cZNF532 (pcDNA3-cZNF532), 5 nM anti–miR-29a-3p (anti–miR-29a-3p), or 5 nM anti–miRNA control (anti-Ctl), together with 20 ng pJEBB-miR-29a-3p or pJEBB-miR-21 expression plasmid. Meanwhile, pRL-TK vector was transfected as the internal control. The normalized value of luciferase activity was set to 1 in cells transfected with the constructed Luc reporter, pcDNA3 (vector), pJEBB-miR-21, and pRL-TK. Luciferase activity was detected at 48 hours after transfection (n = 4, *P < 0.05 vs. miR-29a-3p plus vector). (I) Pericytes were transfected with miR-29a-3p mimic or miR-29a-3p inhibitor, or left untreated (Ctrl) for 48 hours. The expression of cZNF532 and ZNF532 mRNA was detected by qRT-PCR (n = 4). The significant difference was determined by 1-way ANOVA followed by Bonferroni’s post hoc test. Error bar indicates SD. *P < 0.05.

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