Inhibition of the soluble epoxide hydrolase promotes albuminuria in mice with progressive renal disease

  • Epoxyeicotrienoic acids (EETs) are cytochrome P450-dependent anti-hypertensive and anti-inflammatory derivatives of arachidonic acid, which are highly abundant in the kidney and considered reno-protective. EETs are degraded by the enzyme soluble epoxide hydrolase (sEH) and sEH inhibitors are considered treatment for chronic renal failure (CRF). We determined whether sEH inhibition attenuates the progression of CRF in the 5/6-nephrectomy model (5/6-Nx) in mice. 5/6-Nx mice were treated with a placebo, an ACE-inhibitor (Ramipril, 40 mg/kg), the sEH-inhibitor cAUCB or the CYP-inhibitor fenbendazole for 8 weeks. 5/6-Nx induced hypertension, albuminuria, glomerulosclerosis and tubulo-interstitial damage and these effects were attenuated by Ramipril. In contrast, cAUCB failed to lower the blood pressure and albuminuria was more severe as compared to placebo. Plasma EET-levels were doubled in 5/6 Nx-mice as compared to sham mice receiving placebo. Renal sEH expression was attenuated in 5/6-Nx mice but cAUCB in these animals still further increased the EET-level. cAUCB also increased 5-HETE and 15-HETE, which derive from peroxidation or lipoxygenases. Similar to cAUCB, CYP450 inhibition increased HETEs and promoted albuminuria. Thus, sEH-inhibition failed to elicit protective effects in the 5/6-Nx model and showed a tendency to aggravate the disease. These effects might be consequence of a shift of arachidonic acid metabolism into the lipoxygenase pathway.

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Author:Oliver Jung, Felix Jansen, Anja Mieth, Eduardo Barbosa SicardGND, Rainer U. Pliquett, Andrea Babelova, Christophe MorisseauORCiD, Sung H. Hwang, Cindy Tsai, Bruce D. Hammock, Liliana SchäferORCiD, Gerd GeisslingerORCiDGND, Kerstin Amann, Ralf BrandesORCiDGND
URN:urn:nbn:de:hebis:30-80676
DOI:https://doi.org/10.1371/journal.pone.0011979
Parent Title (English):PLoS One
Document Type:Article
Language:English
Date of Publication (online):2010/08/04
Date of first Publication:2010/08/04
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2010/09/24
Volume:5
Issue:(8): e11979
Note:
This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
Source:PLoS ONE 5(8): e11979. doi:10.1371/journal.pone.0011979
HeBIS-PPN:228920795
Institutes:Medizin / Medizin
Fachübergreifende Einrichtungen / Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoDeutsches Urheberrecht