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Circular RNAs: Novel target of diabetic retinopathy

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Abstract

In diabetic patients, diabetic retinopathy (DR) is the leading cause of blindness and seriously affects the quality of life. However, current treatment methods of DR are not satisfactory. Advances have been made in understanding abnormal protein interactions and signaling pathways in DR pathology, but little is known about epigenetic regulation. Non-coding RNAs, such as circular RNAs (circRNAs), have been shown to be associated with DR. In this review, we summarized the function of circRNAs and indicated their roles in the pathogenesis of DR, which may provide new therapeutic targets for clinical treatment.

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References

  1. Zhang HD, et al. CircRNA: a novel type of biomarker for cancer. Breast Cancer. 2018;25(1):1–7.

    Article  PubMed  Google Scholar 

  2. Li R, et al. CircRNA: a rising star in gastric cancer. Cell Mol Life Sci. 2020;77(9):1661–80.

    Article  CAS  PubMed  Google Scholar 

  3. Yu J, et al. CircRNA-104718 acts as competing endogenous RNA and promotes hepatocellular carcinoma progression through microRNA-218-5p/TXNDC5 signaling pathway. Clin Sci (Lond). 2019;133(13):1487–503.

    Article  CAS  Google Scholar 

  4. Altesha MA, et al. Circular RNA in cardiovascular disease. J Cell Physiol. 2019;234(5):5588–600.

    Article  CAS  PubMed  Google Scholar 

  5. Garikipati VNS, et al. Circular RNA CircFndc3b modulates cardiac repair after myocardial infarction via FUS/VEGF-A axis. Nat Commun. 2019;10(1):4317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wang Z, et al. Identifying circRNA-associated-ceRNA networks in the hippocampus of Abeta1-42-induced Alzheimer’s disease-like rats using microarray analysis. Aging (Albany NY). 2018;10(4):775–88.

    Article  CAS  Google Scholar 

  7. Zurawska A, Mycko MP, Selmaj KW. Circular RNAs as a novel layer of regulatory mechanism in multiple sclerosis. J Neuroimmunol. 2019;334:576971.

    Article  CAS  PubMed  Google Scholar 

  8. Guo N, et al. Circular RNAs: Novel Promising Biomarkers in Ocular Diseases. Int J Med Sci. 2019;16(4):513–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. He M, et al. Circular RNAs: Potential Star Molecules Involved in Diabetic Retinopathy. Curr Eye Res. 2021;46(3):277–83.

    Article  CAS  PubMed  Google Scholar 

  10. Hu W, et al. Circular RNA circRNA_15698 aggravates the extracellular matrix of diabetic nephropathy mesangial cells via miR-185/TGF-beta1. J Cell Physiol. 2019;234(2):1469–76.

    Article  CAS  PubMed  Google Scholar 

  11. Eshaq RS, et al. Diabetic retinopathy: Breaking the barrier. Pathophysiology. 2017;24(4):229–41.

    Article  PubMed  Google Scholar 

  12. Wong TY, et al. Diabetic Retinopathy Nat Rev Dis Primers. 2016;2:16012.

    Article  PubMed  Google Scholar 

  13. Zheng Y, He M, Congdon N. The worldwide epidemic of diabetic retinopathy. Indian J Ophthalmol. 2012;60(5):428–31.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kusuhara S, et al. Pathophysiology of diabetic retinopathy: the old and the new. Diabetes Metab J. 2018;42(5):364–76.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Flaxel CJ, et al. Diabetic Retinopathy Preferred Practice Pattern(R). Ophthalmology. 2020;127(1):P66–145.

    Article  PubMed  Google Scholar 

  16. Klein BE. Overview of epidemiologic studies of diabetic retinopathy. Ophthalmic Epidemiol. 2007;14(4):179–83.

    Article  PubMed  Google Scholar 

  17. Simo R, Hernandez C. European Consortium for the Early Treatment of Diabetic, Neurodegeneration in the diabetic eye: new insights and therapeutic perspectives. Trends Endocrinol Metab. 2014;25(1): p. 23–33.

  18. Klein R, et al. "The Wisconsin epidemiologic study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years". Arch Ophthalmol. 1984;102(4): p. 520–6.

  19. Xie X, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet. 2016;387(10017):435–43.

    Article  PubMed  Google Scholar 

  20. White NH, et al. Prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus: 10 years after the Diabetes Control and Complications Trial. Arch Ophthalmol. 2008;126(12):1707–15.

    Article  PubMed  Google Scholar 

  21. Wong TY, et al. Relation between fasting glucose and retinopathy for diagnosis of diabetes: three population-based cross-sectional studies. Lancet. 2008;371(9614):736–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kang EY, et al. Association of Statin Therapy With Prevention of Vision-Threatening Diabetic Retinopathy. JAMA Ophthalmol. 2019;137(4):363–71.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Li X, Yang L, Chen LL. The Biogenesis, Functions, and Challenges of Circular RNAs. Mol Cell. 2018;71(3):428–42.

    Article  CAS  PubMed  Google Scholar 

  24. Salzman J, et al. Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS One. 2012;7(2):e30733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Li Z, et al. Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol. 2015;22(3):256–64.

    Article  PubMed  Google Scholar 

  26. Zhang Y, et al. Circular intronic long noncoding RNAs. Mol Cell. 2013;51(6):792–806.

    Article  CAS  PubMed  Google Scholar 

  27. Ebbesen KK, Hansen TB, Kjems J. Insights into circular RNA biology. RNA Biol. 2017;14(8):1035–45.

    Article  PubMed  Google Scholar 

  28. Qu S, et al. Circular RNA: A new star of noncoding RNAs. Cancer Lett. 2015;365(2):141–8.

    Article  CAS  PubMed  Google Scholar 

  29. Suzuki H, Tsukahara T. A view of pre-mRNA splicing from RNase R resistant RNAs. Int J Mol Sci. 2014;15(6):9331–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hansen TB, et al. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495(7441):384–8.

    Article  CAS  PubMed  Google Scholar 

  31. Li F, et al. Circular RNA ITCH has inhibitory effect on ESCC by suppressing the Wnt/beta-catenin pathway. Oncotarget. 2015;6(8):6001–13.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ashwal-Fluss R, et al. circRNA biogenesis competes with pre-mRNA splicing. Mol Cell. 2014;56(1):55–66.

    Article  CAS  PubMed  Google Scholar 

  33. Hansen TB, et al. miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA. EMBO J. 2011;30(21):4414–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ng WL, et al. Inducible RasGEF1B circular RNA is a positive regulator of ICAM-1 in the TLR4/LPS pathway. RNA Biol. 2016;13(9):861–71.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Legnini I, et al. "Circ-ZNF609 Is a Circular RNA that Can Be Translated and Functions in Myogenesis". Mol Cell. 2017;66(1): p. 22–37 e9.

  36. Pamudurti NR, et al. Translation of CircRNAs. Mol Cell, 2017;66(1): p. 9–21 e7.

  37. Hall IF, et al. Circ_Lrp6, a Circular RNA Enriched in Vascular Smooth Muscle Cells, Acts as a Sponge Regulating miRNA-145 Function. Circ Res. 2019;124(4):498–510.

    Article  CAS  PubMed  Google Scholar 

  38. Rong D, et al. An emerging function of circRNA-miRNAs-mRNA axis in human diseases. Oncotarget. 2017;8(42):73271–81.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Zhang X, et al. Circular RNA circNRIP1 acts as a microRNA-149-5p sponge to promote gastric cancer progression via the AKT1/mTOR pathway. Mol Cancer. 2019;18(1):20.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Guo JU, et al. Expanded identification and characterization of mammalian circular RNAs. Genome Biol. 2014;15(7):409.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wilusz JE. A 360 degrees view of circular RNAs: From biogenesis to functions. Wiley Interdiscip Rev RNA. 2018;9(4):e1478.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Conn VM, et al. A circRNA from SEPALLATA3 regulates splicing of its cognate mRNA through R-loop formation. Nat Plants. 2017;3:17053.

    Article  CAS  PubMed  Google Scholar 

  43. Du WW, et al. Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic Acids Res. 2016;44(6):2846–58.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Chen N, et al. A novel FLI1 exonic circular RNA promotes metastasis in breast cancer by coordinately regulating TET1 and DNMT1. Genome Biol. 2018;19(1):218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kovacs B, et al. MicroRNAs in early diabetic retinopathy in streptozotocin-induced diabetic rats. Invest Ophthalmol Vis Sci. 2011;52(7):4402–9.

    Article  CAS  PubMed  Google Scholar 

  46. Wang X, et al. microRNA-20b contributes to high glucose-induced podocyte apoptosis by targeting SIRT7. Mol Med Rep. 2017;16(4):5667–74.

    Article  CAS  PubMed  Google Scholar 

  47. Zhu K, et al. Downregulation of circRNA DMNT3B contributes to diabetic retinal vascular dysfunction through targeting miR-20b-5p and BAMBI. EBioMedicine. 2019;49:341–53.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Guillot N, et al. BAMBI regulates angiogenesis and endothelial homeostasis through modulation of alternative TGFbeta signaling. PLoS One. 2012;7(6):e39406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Boeckel JN, et al. Identification and characterization of hypoxia-regulated endothelial circular RNA. Circ Res. 2015;117(10):884–90.

    Article  CAS  PubMed  Google Scholar 

  50. Liu C, et al. Silencing Of Circular RNA-ZNF609 Ameliorates Vascular Endothelial Dysfunction. Theranostics. 2017;7(11):2863–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Qazi Y, Maddula S, Ambati BK. Mediators of ocular angiogenesis. J Genet. 2009;88(4):495–515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hamik A, Wang B, Jain MK. Transcriptional regulators of angiogenesis. Arterioscler Thromb Vasc Biol. 2006;26(9):1936–47.

    Article  CAS  PubMed  Google Scholar 

  53. Shan K, et al. Circular Noncoding RNA HIPK3 Mediates Retinal Vascular Dysfunction in Diabetes Mellitus. Circulation. 2017;136(17):1629–42.

    Article  CAS  PubMed  Google Scholar 

  54. Lee YH, et al. C-myb regulates autophagy for pulp vitality in glucose oxidative stress. J Dent Res. 2016;95(4):430–8.

    Article  CAS  PubMed  Google Scholar 

  55. Liu YC, et al. CircNet: a database of circular RNAs derived from transcriptome sequencing data. Nucleic Acids Res. 2016;44(D1):D209–15.

    Article  CAS  PubMed  Google Scholar 

  56. Munoz-Chapuli R, Quesada AR, Angel MA. Angiogenesis and signal transduction in endothelial cells. Cell Mol Life Sci. 2004;61(17): p. 2224–43.

  57. Robitaille J, et al. Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nat Genet. 2002;32(2):326–30.

    Article  CAS  PubMed  Google Scholar 

  58. Ao J, et al. Retinal pigment epithelium in the pathogenesis of age-related macular degeneration and photobiomodulation as a potential therapy? Clin Exp Ophthalmol. 2018;46(6):670–86.

    Article  PubMed  Google Scholar 

  59. Chen Q, et al. Oxidative stress mediated by lipid metabolism contributes to high glucose-induced senescence in retinal pigment epithelium. Free Radic Biol Med. 2019;130:48–58.

    Article  CAS  PubMed  Google Scholar 

  60. Li Y, et al. circRNA_0084043 contributes to the progression of diabetic retinopathy via sponging miR-140-3p and inducing TGFA gene expression in retinal pigment epithelial cells. Gene. 2020;747:144653.

    Article  CAS  PubMed  Google Scholar 

  61. Collares CV, et al. Identifying common and specific microRNAs expressed in peripheral blood mononuclear cell of type 1, type 2, and gestational diabetes mellitus patients. BMC Res Notes. 2013;6:491.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circ Res. 2005;97(6):512–23.

    Article  CAS  PubMed  Google Scholar 

  63. Liu C, et al. Targeting pericyte-endothelial cell crosstalk by circular RNA-cPWWP2A inhibition aggravates diabetes-induced microvascular dysfunction. Proc Natl Acad Sci USA. 2019;116(15):7455–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Fiedler U, Augustin HG. Angiopoietins: a link between angiogenesis and inflammation. Trends Immunol. 2006;27(12):552–8.

    Article  CAS  PubMed  Google Scholar 

  66. Murakami T, Felinski EA, Antonetti DA. Occludin phosphorylation and ubiquitination regulate tight junction trafficking and vascular endothelial growth factor-induced permeability. J Biol Chem. 2009;284(31):21036–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Potente M, et al. SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev. 2007;21(20):2644–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Zhang SJ, et al. Identification and Characterization of Circular RNAs as a New Class of Putative Biomarkers in Diabetes Retinopathy. Invest Ophthalmol Vis Sci. 2017;58(14):6500–9.

    Article  CAS  PubMed  Google Scholar 

  69. Zou J, et al. Circular RNA COL1A2 promotes angiogenesis via regulating miR-29b/VEGF axis in diabetic retinopathy. Life Sci. 2020;256:117888.

    Article  CAS  PubMed  Google Scholar 

  70. Dantas da Costa e Silva ME, et al. Plasma levels of miR-29b and miR-200b in type 2 diabetic retinopathy. J Cell Mol Med. 2019;23(2): p. 1280–1287.

  71. Bahr HI, et al. Duloxetine protects against experimental diabetic retinopathy in mice through retinal GFAP downregulation and modulation of neurotrophic factors. Exp Eye Res. 2019;186:107742.

    Article  CAS  PubMed  Google Scholar 

  72. Fu Y, et al. Dynamic Expression of HDAC3 in db/db Mouse RGCs and Its Relationship with Apoptosis and Autophagy. J Diabetes Res. 2020;2020:6086780.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Jiang Q, et al. Circular RNA-ZNF532 regulates diabetes-induced retinal pericyte degeneration and vascular dysfunction. J Clin Invest. 2020;130(7):3833–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bischoff FC, et al. Identification and functional characterization of hypoxia-induced endoplasmic reticulum stress regulating lncRNA (HypERlnc) in pericytes. Circ Res. 2017;121(4):368–75.

    Article  CAS  PubMed  Google Scholar 

  75. Pagano M, et al. Regulation of the cell cycle by the cdk2 protein kinase in cultured human fibroblasts. J Cell Biol. 1993;121(1):101–11.

    Article  CAS  PubMed  Google Scholar 

  76. Sun H, Kang X. hsa_circ_0041795 contributes to human retinal pigment epithelial cells (ARPE 19) injury induced by high glucose via sponging miR-646 and activating VEGFC. Gene. 2020;747:144654.

    Article  CAS  PubMed  Google Scholar 

  77. Xue M, et al. hsa_circ_0081143 promotes cisplatin resistance in gastric cancer by targeting miR-646/CDK6 pathway. Cancer Cell Int. 2019;19:25.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Pan H, et al. Enhanced expression of circ_0000267 in hepatocellular carcinoma indicates poor prognosis and facilitates cell progression by sponging miR-646. J Cell Biochem. 2019.

  79. Liu G, et al. Inhibition of hsa_circ_0002570 suppresses high-glucose-induced angiogenesis and inflammation in retinal microvascular endothelial cells through miR-1243/angiomotin axis. Cell Stress Chaperon. 2020.

  80. Hiramoto H, et al. miR-509-5p and miR-1243 increase the sensitivity to gemcitabine by inhibiting epithelial-mesenchymal transition in pancreatic cancer. Sci Rep. 2017;7(1):4002.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Taghavi Y, et al. Monocyte chemoattractant protein-1 (MCP-1/CCL2) in diabetic retinopathy: latest evidence and clinical considerations. J Cell Commun Signal. 2019;13(4):451–62.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Stępień, E, et al. The circulating non-coding RNA landscape for biomarker research: lessons and prospects from cardiovascular diseases. Acta Pharmacol Sin. 2018;39(7): p. 1085–1099.

  83. Wu Z, et al. Discovery and validation of hsa_circ_0001953 as a potential biomarker for proliferative diabetic retinopathy in human blood. Acta Ophthalmol. 2020.

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Huan-ran Zhou wrote the paper; Hong-yu Kuang supervised the paper.

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Correspondence to Hong-yu Kuang.

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Zhou, Hr., Kuang, Hy. Circular RNAs: Novel target of diabetic retinopathy. Rev Endocr Metab Disord 22, 205–216 (2021). https://doi.org/10.1007/s11154-021-09646-0

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