Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy

A product of the soluble epoxide hydrolase enzyme, 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP), is implicated in the pathogenesis of diabetic retinopathy; levels of 19,20-DHDP increase in the retinas of mice and humans with diabetes, and inhibition of its production can rescue vascular abnormalities in a mouse model of the disease. Rescuing diabetic retinas Untreated diabetes can cause vascular complications including diabetic retinopathy—a progressive loss of retinal vascular cells that causes vessel leakiness, retinal oedema and, ultimately, blindness. Ingrid Fleming and colleagues found that a bioactive lipid derived from docosahexaenoic acid (19,20-DHDP) is implicated in the pathogenesis of this vascular disease. They show that the levels of 19,20-DHDP increase in the retinas of diabetic mice and humans, and that inhibiting the production of this lipid can rescue vascular abnormalities in a mouse model of diabetic retinopathy. The authors suggest that the mechanism that underlies the effect of 19,20-DHDP is an alteration of the dynamics of vascular cell membranes, which affects cell–cell junctions. Diabetic retinopathy is an important cause of blindness in adults 1 , 2 , and is characterized by progressive loss of vascular cells and slow dissolution of inter-vascular junctions, which result in vascular leakage and retinal oedema 3 . Later stages of the disease are characterized by inflammatory cell infiltration, tissue destruction and neovascularization 4 , 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