Emerging role of circular RNAs in diabetic retinopathy

Hyunjong Kim; Juhee Ryu

doi:10.4196/kjpp.24.389

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Kim and Ryu: Emerging role of circular RNAs in diabetic retinopathy

Review Article

Korean J. Physiol. Pharmacol. 2025;29(4):385-397.

Published online: 15 May 2025

DOI: https://doi.org/10.4196/kjpp.24.389

Emerging role of circular RNAs in diabetic retinopathy

Hyunjong Kim^1,², Juhee Ryu^1,^2,^*

¹Vessel-Organ Interaction Research Center, College of Pharmacy, Kyungpook National University, Daegu 41566, Korea

²College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea

^*Correspondence Juhee Ryu, E-mail: juheeryu@knu.ac.kr

Supported by:

Author contributions: H.K. collected the available literature. H.K. and J.R. analyzed and interpreted the literature. H.K. wrote the first draft. J.R. revised the manuscript. J.R. acquired funding.

Received 24 November 2024 Revised 10 April 2025 Accepted 10 April 2025

(open-access):

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Diabetic retinopathy (DR), a significant complication that affects the retina of individuals with diabetes, poses a severe threat to their visual health. DR is classified into stages ranging from non-proliferative to proliferative forms. As the disease progresses, pathological neovascularization and hemorrhage in the retina or vitreous can occur, potentially leading to vision impairment or blindness. Current treatments for DR include intravitreal injections of anti-vascular endothelial growth factor drugs and surgical interventions such as laser photocoagulation. However, these treatments are associated with various complications and side effects. Therefore, cellular and epigenetic studies are necessary to better understand the pathogenesis of DR, which may lead to the development of novel therapeutic strategies. Several studies have demonstrated the role of circular RNAs (circRNAs) in the pathogenesis and progression of DR. CircRNAs have been shown to regulate the expression of genes involved in the proliferation, differentiation, or angiogenesis of different retinal cells, thereby influencing their function. Therefore, this review aims to investigate the role of circRNAs in different retinal cell types in DR and evaluate their potential as diagnostic and therapeutic targets for the disease.

Keywords: Circular RNA, Diabetic retinopathy, Endothelial cells, Noncoding RNA, Retinal pigment epithelial cell

DIABETIC RETINOPATHY (DR)

DR is a vision-threatening complication of diabetes mellitus that can lead to blindness [1]. It primarily affects individuals aged 20–70 years, with recent studies estimating 9.6 million DR patients in the United States, representing 26% of the diabetic population [2,3]. The progression of DR is closely associated with prolonged diabetes duration, chronic hyperglycemia, hypertension, and other risk factors, such as dyslipidemia, obesity, and smoking [4]. Although DR is a leading cause of vision loss in working-age adults, current diagnostic methods often fail to detect DR at its early stages [2]. Moreover, existing therapies such as anti-vascular endothelial growth factor (anti-VEGF) injections and laser therapy may be insufficient to slow disease progression [5,6]. Therefore, it is critical to develop novel biomarkers and therapeutic targets for DR.

DR is classified into two types: non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR) (Fig. 1) [7,8]. NPDR represents the early stage of DR and it is further classified as mild, moderate, or severe based on the extent of retinal damage. The initial manifestation involves the formation of microaneurysms, which are dilated blood vessels with weakened walls. As the disease advances, retinal hemorrhages, venous beading, cotton wool spots, and intraretinal microvascular anomalies develop [7,9]. PDR is characterized by neovascularization originating from the optic disc and retinal vessels, resulting in vision loss due to preretinal and vitreous hemorrhage or retinal detachment [10].

Early diagnosis of DR is crucial for preventing permanent vision loss [11 -14]. Common diagnostic methods include fundus photography, which captures detailed images of the interior of the eye, and fluorescein angiography (FA), which visualizes the retinal vasculature using a fluorescent dye [15 -17]. Recent advancements in diagnostic technology have introduced methods such as optical coherence tomography (OCT), ultra-widefield imaging, and optical coherence tomography angiography as valuable tools for diagnosing DR [18 -22]. However, these diagnostic methods may not adequately detect DR before structural changes in the retina occur. Additionally, diagnostic techniques such as FA may be invasive as they require dye injections. Therefore, identifying novel diagnostic biomarkers capable of detecting DR before visible retinal changes, alongside the development of non-invasive biomarkers such as those found in tears, is crucial.

DR treatments include non-pharmacologic therapy, such as pan-retinal photocoagulation (PRP) and vitrectomy, along with pharmacologic therapies, including anti-VEGF drugs [23 -25]. In PRP, laser treatment is used to target neovascular areas in the retina and is commonly used to treat PDR or severe NPDR [26]. In cases where DR cannot be managed with laser therapy and complications occur, vitrectomy may be considered. A vitrectomy can be performed to remove blood or scar tissue caused by abnormal blood vessel formation in patients with DR [27]. However, PRP can induce an increase in intraocular pressure, lead to macular edema, and cause vision loss. Additionally, vitrectomy carries a high risk of retinal detachment and cataract formation [28,29]. Pharmacologic therapy for DR involves the use of anti-VEGF drugs, which target VEGF to reduce angiogenesis [23,30]. Currently, the U.S. Food and Drug Administration has approved two anti-VEGF drugs for the treatment of DR: aflibercept and ranibizumab. However, anti-VEGF drugs can cause side effects, such as retinal and ocular hemorrhage, endophthalmitis, and retinal detachment [11]. Therefore, developing novel therapies that offer superior therapeutic efficacy and fewer side effects than current treatments is important.

CIRCULAR RNA (CIRCRNA)

Noncoding RNAs (ncRNAs), constituting most transcriptomes, have been shown to regulate various biological processes, such as gene expression regulation and cell division [31 -40]. Recent studies demonstrate the involvement of ncRNAs, including circRNAs, microRNAs (miRNAs), and long ncRNAs, in the pathophysiology of pathological angiogenesis in the retina [41]. circRNAs are transcripts in which the 3' and 5' ends of a single strand are covalently linked through backsplicing to form a circular structure, making them resistant to degradation by RNase R [42,43]. circRNAs have been reported to influence retinal vascular diseases by modulating several biological processes, including gene expression regulation, signal transduction, and cell survival and function [44 -47].

circRNAs are synthesized through a process called backsplicing, where the 5' splice site (donor site) and 3' splice site (acceptor site) of an exon covalently bind to form a closed-loop structure. circRNAs are classified into three types: exonic circRNAs (ecircRNAs), composed exclusively of exons; exon-intron circRNAs (EIciRNAs), containing both exons and introns; and circular intronic RNAs (ciRNAs), consisting solely of introns [48 -51] (Fig. 2).

Several studies have revealed diverse functions of circRNAs, with the most extensively researched being their ability to bind to proteins or miRNAs. circRNA can act as miRNA sponge, inhibiting miRNAs from suppressing their target mRNA [52,53]. When circRNAs bind to proteins, they can perform several functions, including acting as a sponge to inhibit the activity of the protein, serving decoys to facilitate interaction between proteins and miRNAs, and functioning as a scaffold to recruit and bind multiple proteins [54 -58]. Furthermore, circRNAs can interact with RNA polymerase II (Pol II) and U1 small nuclear ribonucleoprotein (U1snRNP) in the nucleus, playing crucial roles in gene transcription [59]. For some circRNAs, they can be translated into peptides in a cap-independent manner or via internal ribosome entry sites [60,61] (Fig. 2). Elucidating the role of circRNAs in DR pathogenesis may facilitate the development of early diagnostic biomarkers based on their expression. Furthermore, identifying the pathological mechanisms involving circRNAs can lead to more fundamental treatment strategies and personalized prognostic predictions for patients.

ROLE OF CIRCRNA IN DR

Several studies have been conducted to elucidate the role of circRNAs in the pathogenesis and progression of DR (Table 1). These studies were conducted using endothelial cells, pericytes, and retinal pigment epithelial (RPE) cells in cellular models of DR, alongside DR animal models such as streptozotocin (STZ)-induced mice or rats and clinical specimens from patients with diabetes. Studies on circRNAs involving pathophysiological mechanisms such as angiogenesis, vascular dysfunction, inflammation, and apoptosis are included.

Pathological angiogenesis in DR

Circ0004805 is implicated in the pathophysiology of DR [62]. Studies on circ0004805 have involved high-glucose (HG)-induced human retinal microvascular endothelial cells (HRMECs) and STZ-induced rat models. Circ0004805 exhibits high expression in aqueous humor samples from patients with proliferative DR and in HG-induced HRMEC. Its overexpression enhanced cell proliferation, wound healing, and angiogenesis. Bioinformatics analysis indicates miR-149-5p as a circ0004805 target. In HRMECs, overexpression of miR-149-5p inhibits angiogenesis, DNA synthesis, and cell division. Previous studies suggest that transforming growth factor beta 2 (TGFB2) interacts with miR-149-5p. The expression levels of TGFB2, proliferating cell nuclear antigen (PCNA), and phosphorylated mothers against decapentaplegic homolog 2 (SMAD2), which are elevated in HG-induced HRMEC, are reduced following circ0004805 siRNA (small interfering RNA) transfection. In vivo experiments and bioinformatics analyses demonstrate that miR-149-5p is conserved between rats and humans. These findings reveal that injection of miR-149-5p agomir into rats with diabetes reduces DR-induced albumin expression, vascular leakage, and the acellular capillaries area in the retina. Furthermore, the expression levels of TGFB2, PCNA, and fibronectin are reduced, suggesting that the overexpression of miR-149-5p could mitigate the pathophysiological processes associated with DR. Therefore, this study highlights the involvement of the circ0004805/miR-149-5p/TGFB2 axis in the pathological angiogenesis observed in DR.

CircCOL1A2 exacerbates the pathogenesis of DR by promoting angiogenesis [63]. Its expression increases in HG-treated HRMECs and STZ-induced DR mouse models. Silencing circCOL1A2 downregulates the expression of VEGF, phosphorylated VEGFR2, matrix metalloproteinase-2 (MMP-2), and MMP-9, resulting in the suppression of cell proliferation, migration, and angiogenesis. In STZ-induced DR mouse models, silencing circCOL1A2 reduces the number of blood vessels compared to that in the control group and reduces the expression levels of VEGF and MMPs. Subsequently, bioinformatic database analyses indicate that miR-29b could interact with circCOL1A2 and VEGF. miR-29b knockdown increases the expression of VEGF, MMP-2, MMP-9, while the overexpression of miR-29b decreases the expression of these markers. These findings suggest that circCOL1A2 promotes cell proliferation, migration, and angiogenesis by targeting miR-29b/VEGF axis.

CircZNF609 has been identified as a factor involved in angiogenesis in HG-treated human umbilical vein endothelial cells (HUVECs) and STZ-induced diabetic mice [64]. Its expression was significantly upregulated in HG-treated HUVECs and STZ-induced diabetic mice alongside the fibrovascular membranes and plasma of patients with diabetes. Silencing circZNF609 enhanced endothelial cell viability, proliferation, migration, and tube formation. Additionally, inhibiting circZNF609 reduced retinal vascular leakage and inflammation in STZ-induced diabetic mice. Bioinformatics analysis subsequently identified miR-615-5p as a potential target of circZNF609. Overexpression of miR-615-5p inhibited apoptosis while promoting cell migration and tube formation in HUVECs. Furthermore, overexpression of miR-615-5p decreased retinal vascular leakage and the number of acellular capillaries in diabetic mice. Bioinformatics analysis further predicted Myocyte-specific enhancer factor 2A (MEF2A) as a gene potentially targeted by miR-615-5p. Overexpression of MEF2A restored the antiapoptotic effects observed after circZNF609 silencing. These findings indicate that circZNF609 contributes to endothelial and vascular dysfunction by regulating MEF2A through its interaction with miR-615-5p. These findings suggest that circZNF609 may induce pathological angiogenesis by regulating endothelial cell function through the miR-615-5p/MEF2A axis.

Vascular dysfunction in DR

CircRNA DNMT3B (circDNMT3B) has been reported to mitigate retinal vascular dysfunction in HG-treated HRMECs and STZ-induced DR rat models [65]. The expression of circDNMT3B was downregulated in HG-treated HRMECs. Overexpression of circDNMT3B inhibited cell proliferation, migration, and tube formation in HG-treated HRMECs while improving retinal vascular function in STZ-induced DR rat models. Bioinformatics analysis identified miR-20b as a potential target of circDNMT3B. In contrast to circDNMT3B, the expression of miR-20b expression is upregulated in HG-treated HRMECs and the retinas of diabetic rats. Inhibiting miR-20b expression enhanced the levels of tight junction-related proteins, including Zonula occludens-1 (ZO-1), occludin, and claudin-5, while inhibiting cell proliferation, migration, and tube formation in HG-treated HRMECs. Additionally, bioinformatic analysis was performed to predict an mRNA target of miR-20b, BAMBI (BMP and activin membrane bound inhibitor). circDMNT3B overexpression led to decreased and increased expression of miR-20b and BAMBI, respectively. Therefore, this study reveals that circDNMT3B may influence retinal vascular function through its interaction with the miR-20b/BAMBI axis.

CircEHMT1 interacts with the RNA-binding protein elF4A3, playing a crucial role in regulating endothelial dysfunction in DR [66]. circEHMT1 expression is reduced in HG-treated retinal microvascular endothelial cells and STZ-induced diabetic rat model. circEHMT1 overexpression upregulates the expression of tight junction-related proteins such as ZO-1, occludin, and claudin-5 and inhibits tube formation. Furthermore, bioinformatics analysis revealed that circEHMT1 can bind to elF4A3. In HG-induced microvascular endothelial cells, the expression of elF4A3 and binding of circEHMT1 to elF4A3 is reduced. Overexpression of elF4A3 resulted in increased expression of ZO-1, occludin, and claudin-5 while simultaneously decreasing VEGF expression and inhibiting tube formation in HG-induced microvascular endothelial cells. Similarly, the overexpression of eIF4A3 reduced retinal vascular distribution in the STZ-induced diabetic rat model, suggesting that circEHMT1 may regulate retinal vascular function through its interaction with eIF4A3.

Inflammatory response and oxidative stress in DR

CircMAP4K2 has been revealed to involve in inflammatory responses and angiogenesis [67]. Its expression is significantly expressed in HG-induced human retinal vascular endothelial cells (HRVECs) and STZ-induced diabetic mice. The inhibition of circMAP4K2 suppresses cell proliferation, migration, and angiogenesis in HG-induced HRVECs. Furthermore, the silencing of circMAP4K2 in mice with diabetes results in a reduction in the expression of inflammatory markers, such as interleukin (IL)-2, IL-6, and tumor necrosis factor-alpha (TNF-α), along with an improvement in retinal vascular leakage. In contrast, the overexpression of circMAP4K2 produces opposite effects. Subsequently, TargetScan, a bioinformatics database, was used to identify miR-377 as a target miRNA of circMAP4K2. VEGFA was predicted as the mRNA target of miR-377. The interaction between miR-377 and VEGFA was further confirmed using a luciferase assay. Additionally, the role of miR-377 was examined in HRVECs. Overexpression of miR-377 reduces cell survival, motility, and angiogenesis; however, these effects are partially reversed after VEGFA overexpression. Additionally, circMAP4K2 exhibits higher expression in the vitreous samples of patients with DR, suggesting its potential as a diagnostic biomarker for the disease. This study confirms that circMAP4K2 may contribute to DR by inducing inflammatory responses and pathological angiogenesis through its interaction with the miR-377-VEGFA axis.

CircPWWP2A has been found to be transferred from pericytes to endothelial cells via exosomes, where it regulates endothelial cell function [46]. circPWWP2A expression is increased in HG-treated human pericytes, the retinas of STZ-induced mice (a type I diabetes model), db/db mice (a type II diabetes model), and the fibrovascular membrane of patients with diabetes. Silencing circPWWP2A in HG-treated human pericytes increases the expression of inflammation-related markers and enhances the activation of apoptotic markers, caspase-3/7 and decreased pericyte maker levels, including platelet-derived growth factor receptor (PDGF)-β, α-smooth muscle actin (α-SMA), desmin, and neuron-glial antigen 2 (NG2). In the STZ-induced diabetic mouse model, silencing circPWWP2A leads to reduced pericytes and aggravated retinal vascular leakage. This suggests that circPWWP2A protects pericytes from HG-induced stress. Bioinformatics analysis further indicates that circPWWP2A and miR-579 could interact with each other, with angiopoietin, occludin, and silent mating type information regulation 2 homolog 1 (SIRT1) identified as potential targets of miR-579. miR-579 overexpression in cell models decreases pericyte marker expression and increases apoptosis in HG-induced human pericytes. Moreover, treatment with miR-579 agomir downregulates the mRNA expression of its target—angiopoietin, occludin, and SIRT1—and leads to the increased acellular capillary, pericyte ghosts, and microaneurysm in the STZ-induced diabetic mouse model. Inhibiting exosome production with GW4869 also reduces the transfer of circPWWP2A from pericytes to endothelial cells, indicating that circPWWP2A is expressed in pericytes and transported to endothelial cells via exosomes. When endothelial cells are incubated with the medium from HG-treated pericytes, their migration and tube formation abilities are enhanced. This suggests that pericytes regulate endothelial cell function through a paracrine circPWWP2A-mediated signaling pathway. Therefore, circPWWP2A overexpression under HG conditions can regulate retinal vascular dysfunction by affecting the biology of pericytes and endothelial cells. In conclusion, circPWWP2A may protect pericytes from DR-related damage, such as inflammation, through the miR-579/angiopoietin, occludin, and SIRT signaling axes.

CircZNF532 plays a protective role in shielding pericytes from inflammatory stimuli under HG environment [68]. CircZNF532 expression is upregulated in HG-treated pericytes, a STZ-induced diabetic mouse model, and vitreous samples from patients with DR. Silencing circZNF532 increases the expression of inflammation-related factors, such as IL-2, IL-6, and TNF-α, while decreasing the expression of pericyte-associated markers, including PDGF-β, α-SMA, desmin, and NG2. This suggests that circZNF532 may play a role in regulating pericyte survival. CircZNF532 inhibition reduces pericyte recruitment to endothelial cells and increases apoptosis under HG conditions. In diabetic mice, silencing circZNF532 results in decreased pericyte coverage and accelerated retinal vascular leakage. Bioinformatics analysis further revealed miR-29a-3p as a target of circZNF532, with NG2, lysyl oxidase-like 2 (LOXL2), cyclin-dependent kinase 2 (CDK2) identified as targets of miR-29a-3p. In diabetic mice, miR-29a-3p overexpression results in decreased NG2, LOXL2, and CDK2 expression, which are involved in cell differentiation, proliferation, and migration. This leads to decreased pericyte coverage, increased vascular leakage, and a higher number of microaneurysm and acellular capillaries. Therefore, circZNF532 regulates the expression of NG2, LOXL2, and CDK2 by interacting with miR-29a-3p, thereby protecting pericytes from inflammation-induced damage under DR conditions.

CircRSU1 may influence endothelial cell function in response to inflammation associated with DR [69]. Its expression is significantly elevated in HG-treated HRVECs and plasma samples from patients with diabetes. Transfection with circRSU1 siRNA transfection leads to a decrease in VEGF expression, alongside reductions in cell viability, proliferation, migration, and invasion. In contrast, overexpression of circRSU1 showed opposite effects. The findings suggest that circRSU1 promotes angiogenesis and endothelial cell dysfunction in HG-treated HRVECs. Bioinformatics analysis identified miR-345-3p as the target miRNA of circRSU1 and TAZ (transcriptional coactivator with PDZ-binding motif) as the corresponding mRNA target. The role of circRSU1 as a miR-345-3p sponge was confirmed using luciferase assays and RNA immunoprecipitation. Silencing circRSU1 or overexpressing miR-345-3p reduced TAZ expression, suggesting that circRSU1 regulates TAZ expression by sponging miR-345-3p. Knockdown of TAZ downregulates cell viability, migration, invasion, and angiogenesis. In STZ-induced rats, inhibiting circRSU1 leads to a decrease in acellular capillaries, while VEGF and inflammation-related factors, such as IL-1β, IL-2, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1, are downregulated. In contrast, inhibition of miR-345-3p expression reverses the effects of decreased circRSU1 expression. These findings suggest that circRSU1 may serve as a potential biomarker for diagnosing DR. These findings suggest that the circRSU1/miR-345-3p/TAZ axis is associated with DR-related inflammation, indicating that circRSU1 may serve as a potential biomarker for DR.

CircUBAP2 has been identified as a contributor to the progression of DR by promoting pathological angiogenesis and oxidative stress [70]. Its expression was significantly upregulated in HG-induced HRMECs and the vitreous humor of patients with DR compared to the controls. Suppression of circUBAP2 reduced the levels of malondialdehyde (MDA), which were elevated under HG conditions, while the expression of antioxidative genes, such as nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and superoxide dismutase-1 (SOD-1), was restored. Additionally, circUBAP2 inhibition led to decreased cell viability, migration, and angiogenesis. Furthermore, bioinformatics analysis identified miR-589-5p as a target of circUBAP2. Luciferase assays, along with cell viability, migration, and tube formation, demonstrated that circUBAP2 acts as a sponge for miR-589-5p. Bioinformatics databases predicted early growth response 1 (EGR1) as an mRNA target of miR-589-5p. Overexpression of EGR1 decreases intracellular levels of Nrf2, HO-1, and SOD-1 proteins, thereby promoting angiogenesis and enhancing cellular survival. These results suggest that circUBAP2 may influence DR progression by regulating antioxidant gene expression through interaction with the miR-589-5p/EGR1 axis.

Apoptosis in DR

CircMKLN1 has been identified as a regulator of autophagy in DR [71]. Studies were conducted in HG-treated and methylglyoxal (MG)-treated HRMECs, along with STZ-induced mice with diabetes. MG, a reactive metabolite that accumulates in DR, plays a significant role in the disease. Additionally, circMKLN1 exhibits high expression in the serum of patients with diabetes. In MG-treated HRMECs, the expression levels of BCL2-associated X protein (Bax), a pro-apoptotic protein, and microtubule-associated proteins 1A/1B light chain 3B (LC3B)-II, an autophagy marker, are elevated. Conversely, the levels of B-cell lymphoma-extra Large (Bcl-xl), an antiapoptotic protein, and p62, an adapter protein, are downregulated. The reduced expression of tight junction markers, such as ZO-1, occludin, and p62, is restored, while the elevated expression of LC3B-II is attenuated in MG-treated HRMECs after circMKLN1 siRNA transfection. The role of circMKLN1 is associated with autophagy-modulated cell viability. A bioinformatics analysis was performed to identify the miRNA/mRNA axis associated with circMKLN1 and confirmed that circMKLN1 might interact with the miR-26a-5p/Rab11a axis. Overexpression of miR-26a-5p reduces the autophagy flux that had been elevated through MG therapy. Additionally, Rab11a expression is significantly increased in the retinal vessels of a diabetic mouse model. Transfection with Rab11a siRNA inhibits apoptosis and restores endothelial cell function. Furthermore, the suppression of circMKLN1 improves microvascular dysfunction, vascular leakage, and pericyte loss in the retina of STZ-induced mice with diabetes. In conclusion, the circMKLN1/miR-26a-5p/Rab11a axis may facilitate autophagy dysfunction in DR.

circNNT relieves DR by suppressing apoptosis and inflammation [72]. The effect was confirmed using HG-induced ARPE-19 cells, where circNNT expression was low. In these cells, overexpression led to upregulation of B-cell leukemia/lymphoma 2 (Bcl-2), an antiapoptotic protein, and PCNA, a marker of DNA replication and the cell cycle, are reduced, whereas cleaved-PARP and Bax, apoptotic proteins, are elevated. Overexpression of circNNT upregulates PCNA and Bcl-2 while promoting cell proliferation and DNA synthesis activity. Conversely, Bax, cleaved-PARP, and inflammation markers, such as IL-6 and TNF-α, are downregulated. Bioinformatics analysis indicates that miR-320b predictably binds to circNNT, which is consistent with findings via luciferase assay. miR-320 overexpression reverses the protective effects of circNNT, leading to increased apoptosis and inflammatory responses. Additionally, bioinformatics analysis suggests that TIMP metallopeptidase inhibitor 3 (TIMP3) interacts with miR-320b—a finding confirmed via luciferase assay. circNNT overexpression leads to increased expression of TIMP3, whereas co-overexpression of circNNT and miR-320b reduces TIMP3 levels. Suppression of miR-320b downregulates apoptosis and inflammation, whereas inhibition of miR-320b and TIMP upregulates apoptosis and inflammation. These findings suggest that the circNNT/miR-320/TIMP3 axis regulates the pathological processes and the apoptotic and inflammatory reactions associated with DR.

CircPSEN1 facilitates ferroptosis, an iron-dependent form of programmed cell death triggered by DR [73]. In HG-treated ARPE-19 cells, the expression of circPSEN1, intracellular iron levels, and MDA-a lipid peroxidation marker-are upregulated, whereas glutathione (GSH), an antioxidant, is downregulated, indicating increased ferroptosis. circPSEN1 knockdown decreases MDA and intracellular iron levels while increasing GSH levels and cell survival, indicating anti-ferroptosis effects. miR-200b-3p is also identified as a target of circPSEN1. miR-200b-3p expression level is low in HG-induced ARPE-19. miR-200b-3p inhibition leads to the downregulation of anti-ferroptosis genes, including glutathione peroxidase 4 and SLC7A11. Furthermore, inhibition of circPSEN1 alongside miR-200b-3p raises MDA and intracellular iron ion levels while reducing GSH expression levels and cell viability. Bioinformatics analysis indicates that cofilin-2 (CFL2) is a target of miR-200b-3p. CFL2 expression is elevated in HG-induced ARPE-19. CFL2 overexpression reduces GSH levels while promoting MDA and intracellular iron levels that are upregulated after miR-200b-3p mimic administration. These findings suggest that modulating the circPSEN1/miR-200b-3p/CFL2 axis may offer a novel approach to control ferroptosis induced in DR.

APPLICATION OF CIRCRNA IN TREATING DR

Traditional diagnostic method for DR such as FA is invasive, requiring administration of contrast agent and anesthetics, and may cause side effects such as nausea and allergic reactions [74]. OCT is also frequently used, but it may not evaluate the retinal periphery as effectively as FA [75]. Therefore, novel diagnostic methods need to be developed to overcome the limitations of current approaches. One potential approach is utilizing disease-specific biomarkers as non-invasive tools for early diagnosis. Biomarkers such as proteins, nucleic acids, and metabolites are indicators of disease onset or severity [76,77]. Among these, RNA-based biomarkers offer greater sensitivity and specificity than protein biomarkers and are being actively studied for various diseases, including cancer. Recently, ncRNAs have shown promise as biomarkers for retinal diseases, including DR. For example, miR-146a-5p has been investigated in patients with diabetes. The findings indicate downregulation of miR-146a-5p in those with DR [78]. Additionally, serum miR-126 is reduced in patients with NPDR and PDR, highlighting its potential as a biomarker for DR [79]. lncRNA metastasis-associated lung adenocarcinoma transcript 1 is significantly increased in the aqueous humor and fibrovascular membranes of patients with DR [80]. circMET is significantly increased in the vitreous specimen of patients with DR, and it strongly correlates with the severity of diabetes-related retinal vascular complications [81]. Given the potential of these ncRNAs as biomarkers for diagnosis and prognosis, further clinical trials are warranted to evaluate their applicability in clinical settings.

Currently, clinical trials using ncRNAs to explore their application as therapeutics for DR remain uninvestigated. However, RNA-based agents are being explored to treat retinal diseases. PF-04523655, a siRNA-based drug targeting the RTP801 gene (associated with hypoxia-inducible factor-1), has undergone Phase II clinical trials to assess its efficacy in treating various retinal diseases including DR, age-related macular degeneration (AMD), and diabetic macular edema (DME). Administration of PF-04523655 improves best-corrected visual acuity in patients with AMD [82,83]. Bevasiranib, a siRNA-based drug targeting VEGF, completed Phase II clinical trials for DME. Furthermore, it is safe and effective in patients with DME (NCT00306904).

Although RNA-based therapeutics are under investigation for various clinical applications, their use in retinal diseases must consider the physiological barrier, known as the blood-retinal barrier (BRB). The BRB restricts the entry of circulating substances into the retina, with the inner BRB —formed by endothelial cells—limiting the passive diffusion of water-soluble drugs [84]. RNA-based therapies are particularly challenging due to their susceptibility to degradation, high molecular weight, and hydrophilic properties, which hinder their ability to cross the BRB [85]. In addition, RNA-based drugs can activate innate and adaptive immunity responses in the retina, potentially reducing therapeutic efficacy and causing side effects such as vision loss, retinal cell damage, and degeneration [86]. Thus, enhanced delivery technologies and immune evasion strategies are needed to effectively bypass the BRB in the development of RNA-based therapies.

DELIVERY STRATEGIES AND CELL TARGETING METHODS OF RNA-BASED DRUGS INTO THE RETINA

To bypass the BRB, drugs can be administered directly into the retina via intravitreal injection. While this method can deliver high drug concentrations to the retina, it requires repeated treatments and may cause adverse effects [87,88]. Recently, there have been attempts to enhance intraretinal drug delivery using lipid nanoparticles (LNPs) or exosomes. Encapsulating RNA-based drugs in LNPs allows them to bypass the BRB and reach the retina, where they enter cells via membrane fusion or endocytosis. This encapsulation enhances cellular delivery efficiency [89]. However, drug distribution may vary depending on the size of the LNPs, and cationic lipid components can trigger immune responses. Additionally, unintended delivery to non-target cells could result in side effects or unexpected outcomes [90]. Thus, careful selection of LNP composition and properties may be needed for optimal RNA therapy delivery. Exosomes, bio-derived nanoparticles naturally secreted by cells, can more readily cross BRB [91]. Similar to LNPs, exosomes can protect RNA-based drugs and minimize immune rejection in vivo [92 -94]. However, because exosomes are naturally derived, they are difficult to mass-produce, store, and purify to high purity [95]. Therefore, selective delivery to target retinal cells is crucial for the development of RNA-based therapies using LNPs or exosomes. To achieve this, ligand- or aptamer-based targeting strategies can be incorporated into these delivery systems.

Delivery of RNA drugs can be optimized by enhancing target specificity through ligand-based or aptamer-mediated approaches. To facilitate targeted cell binding, ligands capable of binding to specific cell surface receptors can be attached to the surface of LNPs or exosomes [96,97]. For example, transferrin—abundantly expressed on RPE cells—can be used to selectively direct drug delivery to retinal targets [98]. Revusiran, an siRNA targeting human transthyretin mRNA, utilizes a triantennary N-acetylgalactosamine (GalNAc) ligand for hepatic delivery and has been investigated in a Phase 3 clinical trial [99]. Additionally, a GalNAc-conjugated tiny locked nucleic acid-based anti-miR-122 antisense oligonucleotide was specifically delivered to hepatocytes and effectively inhibited miR-122 [100]. These examples suggest that ligand conjugation can significantly enhance the delivery efficiency of RNA-based therapeutics to target cells or organs. Aptamer-mediated delivery can utilize single-stranded RNA aptamers that bind to specific proteins or cellular receptors with high affinity [101]. Aptamers can be directly conjugated to RNA-based drugs or attached to the surface of LNPs or exosomes [102 -104], facilitating specific retinal cell uptake. For example, pegaptanib, an anti-VEGF RNA aptamer, was intravitreally administered to patients with neovascular AMD, resulting in improved visual outcomes [103]. Additionally, GL21.T-222, an aptamer-anti-miR chimera combining GL21 (an aptamer targeting AXL receptor tyrosine kinase) and anti-miR-222, suppressed tyrosine kinase activity and miR-222 expression in glioblastoma cells. Intravenous administration of GL21.T-222 reduced tumor size in vivo, demonstrating effective targeting and therapeutic efficacy [102]. Therefore, employing these targeted delivery strategies can potentially enable RNA-based therapeutics to surpass existing treatment approaches.

The therapeutic potential of circRNA presents considerable promise in clinical applications. Utilization of the tissue-specific expression profiles of circRNAs may facilitate earlier detection of DR via minimally invasive diagnostic methodologies, thereby enabling prompt intervention and enhanced therapeutic outcomes. Additionally, circRNA shows enhanced stability and prolonged therapeutic effects due to its circular structure. Furthermore, by utilizing LNPs or exosomes, circRNA can overcome the BRB. Since circRNAs can interact with miRNAs and proteins to regulate multiple signaling pathways, multifunctional therapeutic strategies can be considered. This approach may suggest a new treatment paradigm, including personalized therapies tailored to individual patients. Consequently, investigation of circRNA biology and function may reveal novel diagnostic biomarkers or therapeutic targets for the management of DR.

CONCLUSION

As the prevalence of diabetes continues to increase, the number of patients with DR is also increasing yearly, implying that the diagnosis and treatment of DR are becoming increasingly important. Currently, DR diagnosis relies on visual observation with an ophthalmoscope, but early diagnosis remains challenging. Treatment options for DR include medications such as anti-VEGF drugs and laser surgery. However, they can pose serious side effects, such as retinal detachment or vision loss. Therefore, developing new diagnostic and therapeutic methods is urgently required. circRNAs, a class of ncRNAs, play a significant role in various pathogenetic mechanisms of DR and have shown potential as biomarkers for diagnosis and prognosis, as well as novel therapeutic targets for treating DR. Owing to their circular structure and high stability, circRNAs may offer a unique potential as a therapeutic target in treating DR.

ACKNOWLEDGEMENTS

The figures 1 and 2 were created with Biorender.com.

Notes

FUNDING

This research was supported by funding from the Basic Science Research Program of the National Research Foundation of Korea (NRF) by the Ministry of Science, ICT & Future Planning (RS-2021-NR061935 and RS-2020-NR049556). The funder had no role in study design, data collection, analysis, decision to publish, or preparation of the manuscript.

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

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Fig. 1

Cell damage in the retina based on the severity of diabetic retinopathy (DR).

(A) Progression of DR. In the normal retina, the vascular structure remains intact without hemorrhages or exudates. In the non-proliferative diabetic retinopathy stage, pathological features such as hard exudates and hemorrhages can be observed. In the proliferative diabetic retinopathy stage, prolonged exposure to hyperglycemia and ischemic conditions promotes abnormal growth of blood vessels. (B) Retinal cells affected in DR. Under hyperglycemic condition, vascular endothelial cells (ECs), pericyte, and retinal pigment epithelial (RPE) cells can be damaged, resulting in the breakdown of cell-to-cell tight junctions or cell death. Moreover, capillaries lacking pericytes, pericyte ghosts, may be shown. Consequently, retinal blood vessels become structurally compromised, leading to vascular leakage and angiogenesis. BRB, blood-retinal barrier; RGC, retinal ganglion cells.

Fig. 2

Biosynthesis and potential functions of circular RNAs (circRNAs).

CircRNA are biosynthesized in the nucleus through backsplicing, while mRNAs are synthesized by canonical splicing. Based on their components, circRNA can be divided into several types: EcircRNAs consisting solely of exons, EIciRNAs consisting of exons and introns, and ciRNAs comprising of introns alone. After their biogenesis, circRNAs can regulate transcription in the nucleus or be exported to the cytoplasm, where they regulate gene expression or protein function. (A) CircRNAs can bind to miRNAs competitively with the RISC that contains AGO protein. CircRNAs act as miRNA sponges to regulate target gene expression. (B) CircRNAs can regulate protein function by binding to proteins, such as RBP. (C) CircRNAs with enriched IRES and m6A methylation can mediate protein translation. (D) CircRNAs can be transported from the cell via exosomes, influencing biological mechanisms in other cells. CircRNAs in exosomes may serve as a disease-specific biomarker. (E) CircRNAs located within the nucleus can regulate the transcription and splicing of their parental genes. EcircRNAs, exonic circular RNAs; EIciRNAs, exon-intron circRNAs; ciRNAs, circular intronic RNAs; RISC, RNA-induced silencing complex; RBP, RNA binding protein; IRES, internal ribosome entry sites.

Table 1

Circular RNA (circRNA) research relevant to DR

Condition	circRNA	Target	Expression	Study model	Function	Mechanism of action
Angiogenesis	circ0004805	miR-149-5p	Up	In vitro) high glucose medium cultured HRMEC	Promotes cell proliferation, leading to pathological angiogenesis	Modulates TGFβ2 and pSMAD2 by binding to miR-149-5p
				In vivo) STZ-induced DR rat
	circCOL1A2	miR-29b	Up	In vitro) high glucose medium cultured HRMEC	Induces angiogenesis by promoting endothelial cell dysfunction and proliferation	Control VEGF via targeting miR-29b
				In vivo) STZ-induced DR mouse
	circZNF609	miR-615-5p	Up	In vitro) high glucose medium cultured HUVEC	Facilitates retinal vascular loss and degeneration, leading to pathological angiogenesis	Modulates MEF2A by binding to miR-615-5p
				In vivo) STZ-induced DR mouse
Vascular dysfunction	circDNMT3B	miR-20b-5p	Down	In vitro) high glucose medium cultured HRMEC	Alleviates vascular dysfunction by inhibiting endothelial cell proliferation and migration	Regulates BAMBI by sponging miR-20b
				In vivo) STZ-induced DR rat
	circEHMT1	eIF4A3	Down	In vitro) high glucose medium cultured primary rat retinal microvascular endotheliocyte	Mitigates vascular dysfunction by regulating the expression of tight junction-related proteins and VEGF	Regulates tight junction protein and VEGF by interacting with eIF4A3
				In vivo) STZ-induced DR rat
Inflammation, oxidative stress	circMAP4K2	miR-377	Up	In vitro) high glucose medium cultured HRVEC	Induces vascular leakage and pathological angiogenesis through inflammatory responses	Modulates IL-2 and VEGFA by acting as a sponge for miR-377
				In vivo) STZ-induced DR mouse
	circPWWP2A	miR-579	Up	In vitro) high glucose medium cultured human retinal pericyte	Leads to pericyte-endothelial cell crosstalk from inflammatory responses	Binds to angiopoietin 1, occluding, or SIRT1 via miR-579
				In vivo) STZ-induced DR mouse
	circZNF532	miR-29a-3p	Up	In vitro) high glucose medium cultured human retinal pericyte	Conserves pericytes from inflammatory stimuli	Regulates NG2, LOXL2, or CDK2 by acting as a sponge for miR-29a-3p
				In vivo) STZ-induced DR mouse
	circRSU1	miR-345-3p	Up	In vitro) high glucose medium cultured HRVEC	Accelerate vascular dysfunction by enhancing inflammatory responses	Regulates TAZ and VEGF expression via sponging miR-345-3p
				In vivo) STZ-induced DR rat
	circUBAP2	miR-589-5p	Up	In vitro) high glucose medium cultured HRMEC	Enhances inflammatory responses and oxidative stress	Acts as a sponge for miR-589-5p and upregulates the expression of EGR1
Apoptosis	circMKLN1	miR-26a-5p	Up	In vitro) high glucose medium cultured HRMEC	Increases endothelial cell injury and apoptosis	Regulates ZO-1, and p62 expression by interacting with miR-26a-5p/Rab11a axis
				In vivo) STZ-induced DR rat
	circNNT	miR-320b	Down	In vitro) high glucose medium cultured ARPE-19 cell	Inhibts HG-induced inflammation and apoptosis	Control PCNA, Bcl-2, Bax and IL-6 via miR-320b/TIMP3
	circPSEN1	miR-200b-3p	Up	In vitro) high glucose medium cultured ARPE-19 cell	Promotes DR-induced ferroptosis and suppresses cell survival	Regulates CFL2 expression by binding to miR-200b-3p

ARPE-19, arising retinal pigment epithelia cell; BAMBI, BMP and activin membrane bound inhibitor; Bax, BCL2 associated X; Bcl-2, B-cell leukemia/lymphoma 2; CDK2, cyclin-dependent kinase 2; CFL2, cofilin 2; DR, diabetic retinopathy; EGR1, early growth response protein 1; eIF4A3, eukaryotic initiation factor 4A-III; HG, high glucose; HRMEC, human retinal microvascular endothelial cells; HUVEC, human umbilical vein endothelial cells; IL-2, interleukin-2; IL-6, interleukin-6; LOXL2, lysyl oxidase like 2; MEF2A, myocyte enhancer factor 2A; NG2, neural/glial antigen 2; PCNA, proliferating cell nuclear antigen; pSMAD, phospho suppressor of mothers against decapentaplegic; SIRT1, silent mating type information regulation 2 homolog 1; STZ, streptozotocin; TAZ, transcriptional coactivator with PDZ-binding motif; TGFβ2, transforming growth factor beta 2; TIMP3, TIMP metallopeptidase inhibitor 3; VEGF, vascular endothelial growth factor; ZO-1, zonula occludens-1.

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