Universität zu Köln

Hu, Jiong ORCID: 0000-0001-8266-0886, Dziumbla, Sarah, Lin, Jihong, Bibli, Sofia-Iris, Zukunft, Sven, de Mos, Julian ORCID: 0000-0003-0103-7078, Awwad, Khader, Froemel, Timo, Jungmann, Andreas, Devraj, Kavi, Cheng, Zhixing, Wang, Liya, Fauser, Sascha, Eberhart, Charles G., Sodhi, Akrit, Hammock, Bruce D., Liebner, Stefan, Mueller, Oliver J., Glaubitz, Clemens ORCID: 0000-0002-3554-6586, Hammes, Hans-Peter, Popp, Ruediger and Fleming, Ingrid ORCID: 0000-0003-1881-3635 (2017). Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy. Nature, 552 (7684). S. 248 - 266. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-4687

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Abstract

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 Muller 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hu, Jiong UNSPECIFIED orcid.org/0000-0001-8266-0886 UNSPECIFIED Dziumbla, Sarah UNSPECIFIED UNSPECIFIED UNSPECIFIED Lin, Jihong UNSPECIFIED UNSPECIFIED UNSPECIFIED Bibli, Sofia-Iris UNSPECIFIED UNSPECIFIED UNSPECIFIED Zukunft, Sven UNSPECIFIED UNSPECIFIED UNSPECIFIED de Mos, Julian UNSPECIFIED orcid.org/0000-0003-0103-7078 UNSPECIFIED Awwad, Khader UNSPECIFIED UNSPECIFIED UNSPECIFIED Froemel, Timo UNSPECIFIED UNSPECIFIED UNSPECIFIED Jungmann, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Devraj, Kavi UNSPECIFIED UNSPECIFIED UNSPECIFIED Cheng, Zhixing UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Liya UNSPECIFIED UNSPECIFIED UNSPECIFIED Fauser, Sascha UNSPECIFIED UNSPECIFIED UNSPECIFIED Eberhart, Charles G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sodhi, Akrit UNSPECIFIED UNSPECIFIED UNSPECIFIED Hammock, Bruce D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Liebner, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Oliver J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Glaubitz, Clemens UNSPECIFIED orcid.org/0000-0002-3554-6586 UNSPECIFIED Hammes, Hans-Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Popp, Ruediger UNSPECIFIED UNSPECIFIED UNSPECIFIED Fleming, Ingrid UNSPECIFIED orcid.org/0000-0003-1881-3635 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-207907
DOI:	10.1038/nature25013
Journal or Publication Title:	Nature
Volume:	552
Number:	7684
Page Range:	S. 248 - 266
Date:	2017
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-4687
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BLOOD-RETINAL BARRIER; VE-CADHERIN; DEPENDENT ENDOCYTOSIS; ENDOTHELIAL-CELLS; ACID; ANGIOGENESIS; ASSOCIATION; CHOLESTEROL; STABILITY; MEMBRANES Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/20790