Circular RNA-ZNF532 regulates diabetes-induced retinal pericyte degeneration and vascular dysfunction
Qin Jiang1,2, Chang Liu2, Chao-Peng Li3
1Affiliated Eye Hospital and.
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.
Insights
Circular RNA cZNF532 is upregulated in diabetic retinopathy (DR), impairing retinal pericyte function. Targeting cZNF532 or miR-29a-3p offers a potential therapeutic strategy for DR treatment.
Area of Science:
- Ophthalmology
- Molecular Biology
- Vascular Biology
Background:
- Diabetic retinopathy (DR) is a leading cause of blindness in working-age adults.
- Vascular pericyte degeneration is a key feature of DR, but its underlying mechanisms are unclear.
- Circular RNAs (circRNAs) are implicated in various biological processes and disease progression.
Purpose of the Study:
- To investigate the role of circRNAs in pericyte biology within the context of diabetic retinopathy.
- To elucidate the specific function of circRNA cZNF532 in retinal pericyte dysfunction and vascular health during diabetes.
Main Methods:
- Examined cZNF532 expression in pericytes under diabetic stress, in a diabetic murine model, and in human vitreous humor.
- Assessed the impact of cZNF532 silencing on pericyte viability, proliferation, differentiation, and recruitment in vitro.
- Investigated the molecular mechanism involving cZNF532 as a miR-29a-3p sponge, affecting downstream gene expression (NG2, LOXL2, CDK2).
- Utilized knockdown and overexpression strategies for cZNF532 and miR-29a-3p in both in vitro and in vivo models of DR.
Main Results:
- cZNF532 expression was significantly upregulated in diabetic conditions and DR patient samples.
- Silencing cZNF532 impaired pericyte function and suppressed their recruitment to endothelial cells.
- cZNF532 acts as a sponge for miR-29a-3p, leading to increased expression of NG2, LOXL2, and CDK2.
- Modulating cZNF532 or miR-29a-3p levels significantly impacted retinal pericyte degeneration and vascular dysfunction in diabetic models.
Conclusions:
- A circRNA-mediated mechanism involving cZNF532 and miR-29a-3p plays a crucial role in regulating pericyte biology and vascular homeostasis in diabetic retinopathy.
- Induction of cZNF532 or inhibition of miR-29a-3p represents a promising therapeutic avenue for treating diabetic retinopathy.
