Prophylactic inhibition of soluble epoxide hydrolase delays onset of nephritis and ameliorates kidney damage in NZB/W F1 mice

Jan Klocke; Arzu Ulu; Kaiyin Wu; Birgit Rudolph; Duska Dragun; Maik Gollasch; Wolf Hagen Schunck; Bruce D. Hammock; Gabriela Riemekasten; Philipp Enghard

doi:10.1038/s41598-019-45299-5

Prophylactic inhibition of soluble epoxide hydrolase delays onset of nephritis and ameliorates kidney damage in NZB/W F1 mice

Jan Klocke^*, Arzu Ulu, Kaiyin Wu, Birgit Rudolph, Duska Dragun, Maik Gollasch, Wolf Hagen Schunck, Bruce D. Hammock, Gabriela Riemekasten, Philipp Enghard

^*Corresponding author for this work

Department of Rheumatology and Clinical Immunology

9 Citations (Scopus)

Abstract

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.

Original language	English
Article number	8993
Journal	Scientific Reports
Volume	9
Issue number	1
ISSN	2045-2322
DOIs	https://doi.org/10.1038/s41598-019-45299-5
Publication status	Published - 01.12.2019

Funding

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). 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.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

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title = "Prophylactic inhibition of soluble epoxide hydrolase delays onset of nephritis and ameliorates kidney damage in NZB/W F1 mice",

abstract = "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.",

author = "Jan Klocke and Arzu Ulu and Kaiyin Wu and Birgit Rudolph and Duska Dragun and Maik Gollasch and Schunck, \{Wolf Hagen\} and Hammock, \{Bruce D.\} and Gabriela Riemekasten and Philipp Enghard",

note = "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 Charit{\'e}, by the Open Access Publication Funds of Charit{\'e} – Universit{\"a}tsmedizin Berlin and the Stiftung Charit{\'e}, 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: {\textcopyright} 2019, The Author(s). Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

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doi = "10.1038/s41598-019-45299-5",

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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.

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DO - 10.1038/s41598-019-45299-5

M3 - Journal articles

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SN - 2045-2322

VL - 9

JO - Scientific Reports

JF - Scientific Reports

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M1 - 8993

ER -

Prophylactic inhibition of soluble epoxide hydrolase delays onset of nephritis and ameliorates kidney damage in NZB/W F1 mice

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