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.

CircRNA Is a Rising Star in Researches of Ocular Diseases

“…ECs, which were verified to antagonize the diabetes-induced disruption to vascular homeostasis (Liu et al, 2019;Jiang et al, 2020). And the severity of DR was also correlated to rising levels of cZNF532 in the vitreous (Jiang et al, 2020).…”

“…ECs, which were verified to antagonize the diabetes-induced disruption to vascular homeostasis (Liu et al, 2019;Jiang et al, 2020). And the severity of DR was also correlated to rising levels of cZNF532 in the vitreous (Jiang et al, 2020). The SP1, a transcription factor activated in diabetic condition, could bind to the promoter of cZNF532 and take charge of increasing cZNF532 expression (Jiang et al, 2020).…”

“…The SP1, a transcription factor activated in diabetic condition, could bind to the promoter of cZNF532 and take charge of increasing cZNF532 expression (Jiang et al, 2020). In pericytes, cZNF532 can promote the expression of CSPG4, LOXL2, and CDK2 by sequestering the miR-29a-3p binding sites, which results in increased cell viability, proliferation, and recruitment toward HRVECs, ameliorated diabetic stress-induced cell apoptosis, and decreased the macromolecular permeability (Figure 2; Jiang et al, 2020). However, manipulating the cZNF532 expression had almost no effect on HRVECs (Jiang et al, 2020).…”

“…In pericytes, cZNF532 can promote the expression of CSPG4, LOXL2, and CDK2 by sequestering the miR-29a-3p binding sites, which results in increased cell viability, proliferation, and recruitment toward HRVECs, ameliorated diabetic stress-induced cell apoptosis, and decreased the macromolecular permeability (Figure 2; Jiang et al, 2020). However, manipulating the cZNF532 expression had almost no effect on HRVECs (Jiang et al, 2020). cPWWP2A had similar effects to those of cZNF532 on the regulation of pericyte functions via a different network-cPWWP2A-miR-579-angiopoietin1/occludin/SIRT1, but, unlike cZNF532, it was able to indirectly modulate HRVEC angiogenic activities and pericyte-EC crosstalk through a paracrine approach in exosomes from pericytes (Figure 2; Liu et al, 2019).…”

Emerging roles of non‐coding RNAs in retinal diseases: A review

“…130 In the current study, knockdown of cZNF532 by Cre-dependent AAV injection-induced pericyte degeneration and retinal vascular dysfunction. 131…”