1. Prophylactic inhibition of soluble epoxide hydrolase delays onset of nephritis and ameliorates kidney damage in NZB/W F1 mice
- Author
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Klocke, Jan, Ulu, Arzu, Wu, Kaiyin, Rudolph, Birgit, Dragun, Duska, Gollasch, Maik, Schunck, Wolf-Hagen, Hammock, Bruce D, Riemekasten, Gabriela, and Enghard, Philipp
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Immunology ,Autoimmune Disease ,Kidney Disease ,Lupus ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Adult ,Aged ,Animals ,Biomarkers ,Biopsy ,Case-Control Studies ,Disease Models ,Animal ,Disease Progression ,Enzyme Activation ,Enzyme Inhibitors ,Epoxide Hydrolases ,Female ,Humans ,Immunohistochemistry ,Lipids ,Lupus Nephritis ,Male ,Mice ,Mice ,Inbred NZB ,Middle Aged ,Premedication ,Prognosis ,Young Adult - 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.
- Published
- 2019