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Nature. 2017 Dec 14;552(7684):248-252. doi: 10.1038/nature25013. Epub 2017 Dec 6.

Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy.

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Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany.
German Centre for Cardiovascular Research (DZHK) partner site Rhein-Main, Germany.
5th Medical Department, University Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
Institute for Biophysical Chemistry and Centre for Biomolecular Magnetic Resonance, Goethe University, Frankfurt am Main, Germany.
Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Germany.
Institute of Neurology (Edinger-Institute), Goethe University, Frankfurt am Main, Germany.
Henan Eye Institute & Henan Eye Hospital, Henan, China.
Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, California, USA.
Department of Internal Medicine III, University of Kiel, Arnold-Heller-Strasse 3, 24105 Kiel, Germany.


Diabetic retinopathy is an important cause of blindness in adults, and is characterized by progressive loss of vascular cells and slow dissolution of inter-vascular junctions, which result in vascular leakage and retinal oedema. Later stages of the disease are characterized by inflammatory cell infiltration, tissue destruction and neovascularization. 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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