TY - JOUR
T1 - Prophylactic inhibition of soluble epoxide hydrolase delays onset of nephritis and ameliorates kidney damage in NZB/W F1 mice
AU - Klocke, Jan
AU - Ulu, Arzu
AU - Wu, Kaiyin
AU - Rudolph, Birgit
AU - Dragun, Duska
AU - Gollasch, Maik
AU - Schunck, Wolf Hagen
AU - Hammock, Bruce D.
AU - Riemekasten, Gabriela
AU - Enghard, Philipp
N1 - Funding Information:
We thank Dr Michael Rothe for his expert advice. This work was supported by the Deutsche Forschungsgemeinschaft (DFG, SFB 650), by grants from the University Hospital Charité, by the Open Access Publication Funds of Charité – Universitätsmedizin Berlin and the Stiftung Charité, Berlin. Partial support was provided by the National Institute of Environmental Health Sciences (NIEHS) Ro1 ES002710, NIEHS Superfund Research Program P42 ES004699 and individual grants program of the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG).
Funding Information:
Competing Interests: BDH is a founder of EicOsis Human Health, which is supported by the NIH Blueprint Development Program to introduce sEHI into clinics for neuropathic pain. The other authors declare no competing interests.
Publisher Copyright:
© 2019, The Author(s).
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Epoxy-fatty-acids (EpFAs), cytochrome P450 dependent arachidonic acid derivatives, have been suggested to have anti-inflammatory properties, though their effects on autoimmune diseases like systemic lupus erythematosus (SLE) have yet to be investigated. We assessed the influence of EpFAs and their metabolites in lupus prone NZB/W F1 mice by pharmacological inhibition of soluble epoxide hydrolase (sEH, EPHX2). The sEH inhibitor 1770 was administered to lupus prone NZB/W F1 mice in a prophylactic and a therapeutic setting. Prophylactic inhibition of sEH significantly improved survival and reduced proteinuria. By contrast, sEH inhibitor-treated nephritic mice had no survival benefit; however, histological changes were reduced when compared to controls. In humans, urinary EpFA levels were significantly different in 47 SLE patients when compared to 10 healthy controls. Gene expression of EPHX2 was significantly reduced in the kidneys of both NZB/W F1 mice and lupus nephritis (LN) patients. Correlation of EpFAs with SLE disease activity and reduced renal EPHX gene expression in LN suggest roles for these components in human disease.
AB - Epoxy-fatty-acids (EpFAs), cytochrome P450 dependent arachidonic acid derivatives, have been suggested to have anti-inflammatory properties, though their effects on autoimmune diseases like systemic lupus erythematosus (SLE) have yet to be investigated. We assessed the influence of EpFAs and their metabolites in lupus prone NZB/W F1 mice by pharmacological inhibition of soluble epoxide hydrolase (sEH, EPHX2). The sEH inhibitor 1770 was administered to lupus prone NZB/W F1 mice in a prophylactic and a therapeutic setting. Prophylactic inhibition of sEH significantly improved survival and reduced proteinuria. By contrast, sEH inhibitor-treated nephritic mice had no survival benefit; however, histological changes were reduced when compared to controls. In humans, urinary EpFA levels were significantly different in 47 SLE patients when compared to 10 healthy controls. Gene expression of EPHX2 was significantly reduced in the kidneys of both NZB/W F1 mice and lupus nephritis (LN) patients. Correlation of EpFAs with SLE disease activity and reduced renal EPHX gene expression in LN suggest roles for these components in human disease.
UR - http://www.scopus.com/inward/record.url?scp=85067607854&partnerID=8YFLogxK
U2 - 10.1038/s41598-019-45299-5
DO - 10.1038/s41598-019-45299-5
M3 - Journal articles
C2 - 31222024
AN - SCOPUS:85067607854
SN - 2045-2322
VL - 9
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 8993
ER -
