, Volume 62, Issue 3, pp 517–530 | Cite as

lncRNA H19 prevents endothelial–mesenchymal transition in diabetic retinopathy

  • Anu A. Thomas
  • Saumik Biswas
  • Biao Feng
  • Shali Chen
  • John Gonder
  • Subrata ChakrabartiEmail author



The pathophysiology of diabetic retinopathy is linked to hyperglycaemia and its effect on retinal microvascular tissues. The resulting endothelial injury changes the endothelial cell phenotype to acquire mesenchymal properties (i.e. endothelial–mesenchymal transition [EndMT]). Such changes can be regulated by epigenetic mechanisms, including long non-coding RNAs (lncRNAs). lncRNA H19 may influence EndMT through TGF-β. We investigated the role of H19 in regulating EndMT during diabetic retinopathy.


H19 was overexpressed or silenced in human retinal endothelial cells exposed to various glucose levels. The cells were examined for H19, endothelial and mesenchymal markers. We then expanded the study to retinal tissues in a mouse model of diabetic retinopathy and also examined vitreous humour samples from individuals with proliferative diabetic retinopathy.


Expression of H19 was downregulated in high glucose conditions (25 mmol/l). H19 overexpression prevented glucose-induced EndMT. Such changes appear to involve TGF-β through a Smad-independent mechanism. Diabetes caused downregulation of retinal H19. Using H19 knockout mice, we demonstrated similar EndMT in the retina. Examination of vitreous humour from individuals with proliferative diabetic retinopathy also reinforced the downregulation of H19 in diabetes.


We therefore concluded that H19 regulates EndMT in diabetic retinopathy through specific mechanisms.

Data availability

The results from our previous microarray can be found online using the GEO accession number GSE122189.


Diabetic retinopathy Endothelial–mesenchymal transition H19 TGF-β 



Extracellular matrix


Epithelial–mesenchymal transition


Endothelial–mesenchymal transition


Extracellular signal-regulated kinase


Fluorescence in situ hybridisation


Fibroblast-specific protein 1


Gene Expression Omnibus


High d-glucose (25 mmol/l) (experimental treatment)


Human retinal microvascular endothelial cells




Long non-coding RNA


Mitogen-activated protein kinase




Normal d-glucose (5 mmol/l) (experimental treatment)


National Institutes of Health


Proliferative diabetic retinopathy




Smooth muscle 22


α-Smooth muscle actin




TGF-β receptor II


Vascular endothelial cadherin


Vascular endothelial growth factor



We sincerely thank K. Pfeifer and his team from the National Institutes of Health (NIH) Intramural Research Program, Bethesda, MD, USA, for providing us with H19∆exI mice. Parts of this study were presented in abstract form at the 2017 Canadian Society of Endocrinology and Metabolism/Diabetes Canada Professional Conference and Annual Meeting, Edmonton, AB, Canada, 1–4 November 2017.

Contribution statement

AAT, SB, BF, SChe, JG and SCha contributed to the study concept and design, performance of the experiments, data review and analysis, and writing and editing of the manuscript. All authors contributed to the critical revision of the manuscript and gave their final approval of the submitted version. SCha is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.


This work was supported by grants from the Heart and Stroke Foundation of Ontario (HSF-G-16-00012556) and the Canadian Diabetes Association (CDA-OG-3-07-2380-SC) awarded to SC.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2018_4797_MOESM1_ESM.pdf (2.5 mb)
ESM 1 (PDF 2.50 MB)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Anu A. Thomas
    • 1
  • Saumik Biswas
    • 1
  • Biao Feng
    • 1
  • Shali Chen
    • 1
  • John Gonder
    • 2
  • Subrata Chakrabarti
    • 1
    Email author
  1. 1.Department of Pathology and Laboratory MedicineWestern UniversityLondonCanada
  2. 2.Department of OphthalmologyWestern UniversityLondonCanada

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