Letter

Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy

Received:
Accepted:
Published online:

Abstract

Diabetic retinopathy is an important cause of blindness in adults1,2, and is characterized by progressive loss of vascular cells and slow dissolution of inter-vascular junctions, which result in vascular leakage and retinal oedema3. Later stages of the disease are characterized by inflammatory cell infiltration, tissue destruction and neovascularization4,5. Here we identify soluble epoxide hydrolase (sEH) as a key enzyme that initiates pericyte loss and breakdown of endothelial barrier function by generating the diol 19,20-dihydroxydocosapentaenoic acid, derived from docosahexaenoic acid. The expression of sEH and the accumulation of 19,20-dihydroxydocosapentaenoic acid were increased in diabetic mouse retinas and in the retinas and vitreous humour of patients with diabetes. Mechanistically, the diol targeted the cell membrane to alter the localization of cholesterol-binding proteins, and prevented the association of presenilin 1 with N-cadherin and VE-cadherin, thereby compromising pericyte–endothelial cell interactions and inter-endothelial cell junctions. Treating diabetic mice with a specific sEH inhibitor prevented the pericyte loss and vascular permeability that are characteristic of non-proliferative diabetic retinopathy. Conversely, overexpression of sEH in the retinal Müller glial cells of non-diabetic mice resulted in similar vessel abnormalities to those seen in diabetic mice with retinopathy. Thus, increased expression of sEH is a key determinant in the pathogenesis of diabetic retinopathy, and inhibition of sEH can prevent progression of the disease.

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Acknowledgements

The authors thank K. Engel-Herbig, K. Bruch, N. Dietrich and I. Winter for expert technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft (SFB-TR 23/A6 and B7, SFB 1118/C03, GRK 1874/1and Exzellenzcluster 147 ‘Cardio-Pulmonary Systems’) with partial support from NIEHS R01 ES002710. J.dM. was supported by the Deutsche Forschungsgemeinschaft Graduate School CLIC, and J.H. was the recipient of a research award from the Global Ophthalmology Awards Program from Bayer.

Author information

Author notes

    • Sarah Dziumbla
    •  & Jihong Lin

    These authors contributed equally to this work.

Affiliations

  1. Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany

    • Jiong Hu
    • , Sarah Dziumbla
    • , Sofia-Iris Bibli
    • , Sven Zukunft
    • , Khader Awwad
    • , Timo Frömel
    • , Rüdiger Popp
    •  & Ingrid Fleming
  2. German Centre for Cardiovascular Research (DZHK) partner site Rhein-Main, Germany

    • Jiong Hu
    • , Sarah Dziumbla
    • , Sofia-Iris Bibli
    • , Timo Frömel
    • , Stefan Liebner
    • , Rüdiger Popp
    •  & Ingrid Fleming
  3. 5th Medical Department, University Medicine Mannheim, University of Heidelberg, Mannheim, Germany

    • Jihong Lin
    •  & Hans-Peter Hammes
  4. Institute for Biophysical Chemistry and Centre for Biomolecular Magnetic Resonance, Goethe University, Frankfurt am Main, Germany

    • Julian de Mos
    •  & Clemens Glaubitz
  5. Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany

    • Andreas Jungmann
    •  & Oliver J. Müller
  6. German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Germany

    • Andreas Jungmann
    •  & Oliver J. Müller
  7. Institute of Neurology (Edinger-Institute), Goethe University, Frankfurt am Main, Germany

    • Kavi Devraj
    •  & Stefan Liebner
  8. Henan Eye Institute & Henan Eye Hospital, Henan, China

    • Zhixing Cheng
    •  & Liya Wang
  9. Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany

    • Sascha Fauser
  10. Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

    • Charles G. Eberhart
    •  & Akrit Sodhi
  11. Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, California, USA

    • Bruce D. Hammock
  12. Department of Internal Medicine III, University of Kiel, Arnold-Heller-Strasse 3, 24105 Kiel, Germany

    • Oliver J. Müller

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Contributions

J.H. and I.F. designed the experiments and analysed the data. J.H., S.D., S.-I.B., K.D., S.L. and R.P. performed experiments, S.Z. and K.A. generated the epoxide and diol profiles. J.L. and H.-P.H. generated and characterized the retinal digest preparations. Z.C., L.W., C.G.E., A.S. and S.F. characterized and provided human samples. J.d.M. and C.G. performed the NMR studies using isolated membranes, and T.F., A.J. and O.J.M. generated the adenoviruses and adeno-associated viruses. B.D.H. provided advice, feedback and the sEH inhibitor. J.H. and I.F. wrote the manuscript.

Competing interests

J.H., T.F., R.P. and I.F. are authors of patent applications for the use of sEH inhibitors in the treatment of non-proliferative diabetic retinopathy (German Patent Application no. 10 2016 109 709.8, International PCT Patent Application no. PCT/EP2017/062618). S.F. is an employee of F. Hoffmann-La Roche Ltd, Basel, Switzerland. B.D.H. is author of the University of California patents on sEH inhibitors licensed to EicOsis. None of the other authors has any disclosures to declare.

Corresponding author

Correspondence to Ingrid Fleming.

Reviewer Information Nature thanks T. Hla, M. Weingarth and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

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    Supplementary Figure 1

    This file contains source data (gels) for Figures 1- 3, and Extended Data Figures 2- 4.

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    Life Sciences Reporting Summary

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