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

Oliver Jung, Felix Jansen, Anja Mieth, Eduardo Barbosa-Sicard, Rainer U. Pliquett, Andrea Babelova, Christophe Morisseau, Sung H. Hwang, Cindy Tsai, Bruce D. Hammock, Liliana Schaefer, Gerd Geisslinger, Kerstin Amann, Ralf P. Brandes

Research output: Contribution to journalArticle

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Abstract

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-Nxmice 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-Nxmodel and showed a tendency to aggravate the disease. These effects might be consequence of a shift of arachidonic acid metabolism into the lipoxygenase pathway.

Original languageEnglish (US)
Article numbere11979
JournalPLoS One
Volume5
Issue number8
DOIs
StatePublished - 2010

Fingerprint

epoxide hydrolase
Epoxide Hydrolases
Albuminuria
kidney diseases
Kidney
mice
Ramipril
placebos
Placebos
renal failure
lipoxygenase
arachidonic acid
Arachidonic Acid
Chronic Kidney Failure
Fenbendazole
kidneys
Lipoxygenases
Hydroxyeicosatetraenoic Acids
fenbendazole
antihypertensive agents

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Jung, O., Jansen, F., Mieth, A., Barbosa-Sicard, E., Pliquett, R. U., Babelova, A., ... Brandes, R. P. (2010). Inhibition of the soluble epoxide hydrolase promotes albuminuria in mice with progressive renal disease. PLoS One, 5(8), [e11979]. https://doi.org/10.1371/journal.pone.0011979

Inhibition of the soluble epoxide hydrolase promotes albuminuria in mice with progressive renal disease. / Jung, Oliver; Jansen, Felix; Mieth, Anja; Barbosa-Sicard, Eduardo; Pliquett, Rainer U.; Babelova, Andrea; Morisseau, Christophe; Hwang, Sung H.; Tsai, Cindy; Hammock, Bruce D.; Schaefer, Liliana; Geisslinger, Gerd; Amann, Kerstin; Brandes, Ralf P.

In: PLoS One, Vol. 5, No. 8, e11979, 2010.

Research output: Contribution to journalArticle

Jung, O, Jansen, F, Mieth, A, Barbosa-Sicard, E, Pliquett, RU, Babelova, A, Morisseau, C, Hwang, SH, Tsai, C, Hammock, BD, Schaefer, L, Geisslinger, G, Amann, K & Brandes, RP 2010, 'Inhibition of the soluble epoxide hydrolase promotes albuminuria in mice with progressive renal disease', PLoS One, vol. 5, no. 8, e11979. https://doi.org/10.1371/journal.pone.0011979
Jung, Oliver ; Jansen, Felix ; Mieth, Anja ; Barbosa-Sicard, Eduardo ; Pliquett, Rainer U. ; Babelova, Andrea ; Morisseau, Christophe ; Hwang, Sung H. ; Tsai, Cindy ; Hammock, Bruce D. ; Schaefer, Liliana ; Geisslinger, Gerd ; Amann, Kerstin ; Brandes, Ralf P. / Inhibition of the soluble epoxide hydrolase promotes albuminuria in mice with progressive renal disease. In: PLoS One. 2010 ; Vol. 5, No. 8.
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abstract = "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-Nxmice 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-Nxmodel 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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AU - Morisseau, Christophe

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