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Inhibition of soluble epoxide hydrolase (sEH) may slow progression of diabetic retinopathy

Researchers led by investigators at the Institute for Vascular Signaling, Goethe University, Frankfurt, Germany, have identified an enzyme, “soluble epoxide hydrolase” (sEH), to be involved in the loss of pericyte cells and vascular permeability, characteristic of the pathology of diabetic retinopathy. The expression levels of the enzyme were found to be increased in animal models of diabetic retinopathy and in vitreous samples taken from patients with diabetes. Treatment of diabetic animal models with an inhibitor of the sEH enzyme appeared to prevent both pericyte loss and vascular permeability suggesting a potential therapeutic role for sEH inhibitors to delay the development and progression of DR.


The Frankfurt-based research team looked at both wild-type and diabetic models of DR, and in the vitreous of human patients and found a clear correlation between the enzyme activity and the absence or presence of DR. The sEH enzyme, encoded by the Ephx2 gene, was also studied in normal animals and showed a similar activity-disease relationship when such animals were fed a high-fat high-carbohydrate diet for 20 weeks leading to hyperglycaemia. In examining the biochemistry of the enzymatic activity the researchers were able to detect the diol, 19,20-dihydroxydocosapentaenoic acid, a breakdown product derived from docosahexaenoic acid following metabolism of endogenously derived fatty acid epoxides and other lipid epoxides by sEH. Mechanistic studies indicated that that the diol breakdown product interacted with the cell membrane in vivo causing an alteration in the localization of cholesterol binding proteins leading to interference with pericyte-endothelial cell interactions, and with the endothelial cell-cell junctions. Increased vascular permeability is a major contributor to the progression of DR and the application of specific sEH inhibitors appeared to be capable of preventing disease progression in animal models.


Pericyte loss is thought to be among the first of the vascular changes brought about by diabetes leading to downstream secondary changes and progression of more the full blown pathology. Consequently, interference in the disease at this stage of development may present an opportunity to halt an early stage of the disorder, potentially delaying disease progression and extending years of valuable vision. To double-check the significance of the sEH involvement, the researchers used a gene therapy approach to cause an over-expression of sEH in normal non-diabetic mice. Within 14 days of injecting an AAV carrying the sEH gene, over expression of the transcript led to “a notable increase in vascular abnormalities, including decreased numbers of vascular-associated pericytes, increased numbers of extravascular pericytes and acellular capillaries, and vascular leakage”. This phenotype could then be abrogated by the treatment of the same animals with the sEH inhibitor. As a result, the sEH target appears to be a verifiable target with significant potential value.