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.
Jung
Oliver
O
Institut für Kardiovaskuläre Physiologie, Fachbereich Medizin der Goethe-Universität, Frankfurt am Main, Germany.
Jansen
Felix
F
Mieth
Anja
A
Barbosa-Sicard
Eduardo
E
Pliquett
Rainer U
RU
Babelova
Andrea
A
Morisseau
Christophe
C
Hwang
Sung H
SH
Tsai
Cindy
C
Hammock
Bruce D
BD
Schaefer
Liliana
L
Geisslinger
Gerd
G
Amann
Kerstin
K
Brandes
Ralf P
RP
D000419:Albuminuria / Q000139:chemically induced* / Q000150:complications / Q000473:pathology; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D004852:Epoxy Compounds / Q000097:blood; D007676:Kidney Failure, Chronic / Q000097:blood / Q000150:complications* / Q000473:pathology* / Q000601:surgery; D008084:Lipoxygenase / Q000097:blood / Q000378:metabolism; D051379:Mice; D009392:Nephrectomy; D011507:Proteinuria / Q000150:complications / Q000473:pathology; D012995:Solubility
D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D003577:Cytochrome P-450 Enzyme System; D008084:Lipoxygenase; D004851:Epoxide Hydrolases