MicroRNA-200b Regulates Vascular Endothelial Growth Factor-mediated Alterations in Diabetic Retinopathy

Overview

Journal Diabetes

Specialty Endocrinology

Date 2011 Mar 2

PMID 21357793

Citations 150

Authors

Kara McArthur

Biao Feng

Yuexiu Wu

Shali Chen

Subrata Chakrabarti

Affiliations

Soon will be listed here.

Abstract

Objective: Diabetic retinopathy (DR) is a leading cause of blindness. Increased vascular endothelial growth factor (VEGF), promoting angiogenesis and increased permeability, is a key mechanistic abnormality in DR. We investigated microRNA (miRNA) alterations in DR with specific focus on miR-200b, and its downstream target, VEGF.

Research Design And Methods: miRNA expression profiling microarray was used to examine the retinas of streptozotocin-induced diabetic rats. Expressions of specific miRNAs were verified with PCR in the rat retina and in glucose-exposed endothelial cells. A target search, based on sequence complementarities, identified specific targets. We analyzed mRNA levels and protein expression in endothelial cells from large vessels and retinal capillaries and in the rat retina, with or without injection of miR-200b mimic or antagomir. Localization of miR-200b and its functional analysis in the rat and human retinas were performed.

Results: Alteration of several miRNAs, including downregulation of miR-200b, were observed in the retina in diabetes. Such downregulation was validated in the retina of diabetic rats and in endothelial cells incubated in glucose. In parallel, VEGF (target of miR-200b) mRNA and protein were elevated. In the retina, miR-200b was localized in neuronal, glial, and vascular elements. Transfection of endothelial cells and intravitreal injection of miR-200b mimic prevented diabetes-induced increased VEGF mRNA and protein. Also prevented were glucose-induced increased permeability and angiogenesis. Furthermore, transfection of miR-200b antagonists (antagomir) led to increased VEGF production. Similar alterations were seen in the human retina.

Conclusions: These studies show a novel mechanism involving miR-200b in DR. Identification of such mechanisms may lead to the development of novel miRNA-based therapy.

Citing Articles

miR-200-mediated inactivation of cancer-associated fibroblasts via targeting of NRP2-VEGFR signaling attenuates lung cancer invasion and metastasis.

Cheon I, Lee S, Oh S, Ahn Y Mol Ther Nucleic Acids. 2024; 35(2):102194.

PMID: 38766528 PMC: 11101731. DOI: 10.1016/j.omtn.2024.102194.

Diabetic Retinopathy and Cardiovascular Disease: A Literature Review.

Yu W, Yang B, Xu S, Gao Y, Huang Y, Wang Z Diabetes Metab Syndr Obes. 2024; 16:4247-4261.

PMID: 38164419 PMC: 10758178. DOI: 10.2147/DMSO.S438111.

MicroRNA-93 promotes the pathogenesis of glaucoma by inhibiting matrix metalloproteinases as well as up-regulating extracellular matrix and Rho/ROCK signaling pathways.

Xu M, Wang Y, Zhou J, Zhang X, Yu Y, Li K Heliyon. 2023; 9(11):e22012.

PMID: 38045197 PMC: 10689882. DOI: 10.1016/j.heliyon.2023.e22012.

Advances and Perspectives in Relation to the Molecular Basis of Diabetic Retinopathy-A Review.

Blaszkiewicz M, Walulik A, Florek K, Gorecki I, Slawatyniec O, Gomulka K Biomedicines. 2023; 11(11).

PMID: 38001952 PMC: 10669459. DOI: 10.3390/biomedicines11112951.

Non-coding RNA-mediated endothelial-to-mesenchymal transition in human diabetic cardiomyopathy, potential regulation by DNA methylation.

Wang E, Chen S, Wang H, Chen T, Chakrabarti S Cardiovasc Diabetol. 2023; 22(1):303.

PMID: 37924123 PMC: 10625293. DOI: 10.1186/s12933-023-02039-4.

References

Latronico M, Catalucci D, Condorelli G . MicroRNA and cardiac pathologies. Physiol Genomics. 2008; 34(3):239-42. DOI: 10.1152/physiolgenomics.90254.2008. View

Chen S, Feng B, George B, Chakrabarti R, Chen M, Chakrabarti S . Transcriptional coactivator p300 regulates glucose-induced gene expression in endothelial cells. Am J Physiol Endocrinol Metab. 2009; 298(1):E127-37. DOI: 10.1152/ajpendo.00432.2009. View

Van Rooij E, Sutherland L, Liu N, Williams A, McAnally J, Gerard R . A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci U S A. 2006; 103(48):18255-60. PMC: 1838739. DOI: 10.1073/pnas.0608791103. View

Kato M, Zhang J, Wang M, Lanting L, Yuan H, Rossi J . MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors. Proc Natl Acad Sci U S A. 2007; 104(9):3432-7. PMC: 1805579. DOI: 10.1073/pnas.0611192104. View

Wang B, Koh P, Winbanks C, Coughlan M, McClelland A, Watson A . miR-200a Prevents renal fibrogenesis through repression of TGF-β2 expression. Diabetes. 2010; 60(1):280-7. PMC: 3012183. DOI: 10.2337/db10-0892. View

Tang X, Tang G, Ozcan S . Role of microRNAs in diabetes. Biochim Biophys Acta. 2008; 1779(11):697-701. PMC: 2643014. DOI: 10.1016/j.bbagrm.2008.06.010. View

Cukiernik M, Hileeto D, Evans T, Mukherjee S, Downey D, Chakrabarti S . Vascular endothelial growth factor in diabetes induced early retinal abnormalities. Diabetes Res Clin Pract. 2004; 65(3):197-208. DOI: 10.1016/j.diabres.2004.02.002. View

Feng B, Chen S, George B, Feng Q, Chakrabarti S . miR133a regulates cardiomyocyte hypertrophy in diabetes. Diabetes Metab Res Rev. 2009; 26(1):40-9. DOI: 10.1002/dmrr.1054. View

Khan Z, Farhangkhoee H, Chakrabarti S . Towards newer molecular targets for chronic diabetic complications. Curr Vasc Pharmacol. 2006; 4(1):45-57. DOI: 10.2174/157016106775203081. View

10.

Liu J, Valencia-Sanchez M, Hannon G, Parker R . MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies. Nat Cell Biol. 2005; 7(7):719-23. PMC: 1855297. DOI: 10.1038/ncb1274. View

11.

Zhang X, Bao S, Lai D, Rapkins R, Gillies M . Intravitreal triamcinolone acetonide inhibits breakdown of the blood-retinal barrier through differential regulation of VEGF-A and its receptors in early diabetic rat retinas. Diabetes. 2008; 57(4):1026-33. PMC: 2836241. DOI: 10.2337/db07-0982. View

12.

Chiu J, Khan Z, Farhangkhoee H, Chakrabarti S . Curcumin prevents diabetes-associated abnormalities in the kidneys by inhibiting p300 and nuclear factor-kappaB. Nutrition. 2009; 25(9):964-72. DOI: 10.1016/j.nut.2008.12.007. View

13.

Aiello L . Vascular endothelial growth factor and the eye: biochemical mechanisms of action and implications for novel therapies. Ophthalmic Res. 1997; 29(5):354-62. DOI: 10.1159/000268033. View

14.

Hu X, Macdonald D, Huettner P, Feng Z, El Naqa I, Schwarz J . A miR-200 microRNA cluster as prognostic marker in advanced ovarian cancer. Gynecol Oncol. 2009; 114(3):457-64. DOI: 10.1016/j.ygyno.2009.05.022. View

15.

Adam L, Zhong M, Choi W, Qi W, Nicoloso M, Arora A . miR-200 expression regulates epithelial-to-mesenchymal transition in bladder cancer cells and reverses resistance to epidermal growth factor receptor therapy. Clin Cancer Res. 2009; 15(16):5060-72. PMC: 5938624. DOI: 10.1158/1078-0432.CCR-08-2245. View

16.

King G, Loeken M . Hyperglycemia-induced oxidative stress in diabetic complications. Histochem Cell Biol. 2004; 122(4):333-8. DOI: 10.1007/s00418-004-0678-9. View

17.

Li Y, VandenBoom 2nd T, Kong D, Wang Z, Ali S, Philip P . Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res. 2009; 69(16):6704-12. PMC: 2727571. DOI: 10.1158/0008-5472.CAN-09-1298. View

18.

Brownlee M . Biochemistry and molecular cell biology of diabetic complications. Nature. 2001; 414(6865):813-20. DOI: 10.1038/414813a. View

19.

Dejana E . Endothelial adherens junctions: implications in the control of vascular permeability and angiogenesis. J Clin Invest. 1997; 100(11 Suppl):S7-10. View

20.

He L, Hannon G . MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004; 5(7):522-31. DOI: 10.1038/nrg1379. View