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-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.
Highlights
Epoxyeicosatrienoic acids (EETs) are anti-inflammatory derivatives of arachidonic acid (AA) which are generated by cytochrome P450 (CYP) epoxygenases [1]
EET levels are dependent on the activity and expression of the CYP epoxygenases, which generate them and the enzyme soluble epoxide hydrolase which converts the EETs to their corresponding dihydroxyeicosatrienoic acids (DHETs) [3]
To further elucidate the lack of beneficial effects of soluble epoxide hydrolase (sEH) inhibition on the progression of chronic renal failure, we investigated the pro-inflammatory lipoxygenase system. 5/6-Nx had no significant effect on the renal expression of 5-Lox and 12Lox, whereas a trend towards increased expression of 15-Lox was observed. (Fig. 6C) this did not reach statistical significance, 15-HETE plasma levels were the only lipoxygenase products which were significantly higher in the plasma of mice after 5/6-Nx receiving placebo treatment (Fig. 7)
Summary
Epoxyeicosatrienoic acids (EETs) are anti-inflammatory derivatives of arachidonic acid (AA) which are generated by cytochrome P450 (CYP) epoxygenases [1]. EETs are antihypertensive, anti-inflammatory, anti-proliferative and pro-fibrinolytic. They act as an endothelium-derived hyperpolarizing factor (EDHF) in some vascular beds [1]. The CYP450 expression in the kidney is high and EETs promote renal sodium excretion [1,2]. EET levels are dependent on the activity and expression of the CYP epoxygenases, which generate them and the enzyme soluble epoxide hydrolase (sEH) which converts the EETs to their corresponding dihydroxyeicosatrienoic acids (DHETs) [3]. Genetic deletion of the sEH as well as pharmacological inhibition increase plasma EET levels and potentiate their effects [5], and sEH inhibition elicits antihypertensive and anti-inflammatory effects [2,5,6]. We have previously shown that sEH inhibition reduces angiotensin IIinduced hypertension [7], neo-intima formation in hyperlipidemic mice [8] and vascular remodelling in the monocrotaline-model in rats [9]
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