Nature. 2017 Dec 14;552(7684):248-252. doi: 10.1038/nature25013. Epub 2017 Dec 6.
Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy.
Hu J1,2, Dziumbla S1,2, Lin J3, Bibli SI1,2, Zukunft S1, de Mos J4, Awwad K1, Frömel T1,2, Jungmann A5,6, Devraj K7, Cheng Z8, Wang L8, Fauser S9, Eberhart CG10, Sodhi A10, Hammock BD11, Liebner S2,7, Müller OJ5,6,12, Glaubitz C4, Hammes HP3, Popp R1,2, Fleming I1,2
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. In this project the authors identified 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 thereby suggesting that targeting sEH is an attractive therapeutic approach to delay the development and progression of diabetic retinopathy.