Inhibition of the soluble epoxide hydrolase promotes albuminuria in mice with progressive renal disease.
Inhibition of the soluble epoxide hydrolase promotes albuminuria in mice with progressive renal disease.
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DOI：
10.1371/journal.pone.0011979
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发表时间：
2010-08-04
期刊：
影响因子：
3.7
通讯作者：
Brandes RP
中科院分区：
文献类型：
--
作者：
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
环氧二十碳三烯酸（Epoxyeicotrienoic Acids，ESTs）是花生四烯酸的细胞色素P450依赖性抗高血压和抗炎衍生物，在肾脏中含量很高，被认为具有肾脏保护作用。雌二醇被可溶性环氧化物水解酶（sEH）降解，sEH抑制剂被认为是慢性肾衰竭（CRF）的治疗药物。我们在小鼠的5/6-肾切除模型（5/6-Nx）中确定sEH抑制是否减弱CRF的进展。5/6-Nx小鼠用安慰剂、ACE抑制剂（雷米普利，40 mg/kg）、sEH抑制剂cAUCB或CYP抑制剂芬苯达唑治疗8周。5/6-Nx引起的高血压、蛋白尿、肾小球硬化和肾小管-间质损害，这些作用可被雷米普利减弱。相比之下，cAUCB未能降低血压，与安慰剂相比，白蛋白尿更严重。与接受安慰剂的假手术小鼠相比，5/6只Nx小鼠的血浆EET水平加倍。在5/6-Nx小鼠中肾脏sEH表达减弱，但这些动物中的cAUCB仍进一步增加EET水平。cAUCB还增加了5-HETE和15-HETE，其来源于过氧化或脂氧合酶。与cAUCB相似，CYP 450抑制增加HETE并促进白蛋白尿。因此，在5/6-Nx模型中，sEH抑制未能引起保护作用，并显示出加重疾病的趋势。这些影响可能是花生四烯酸代谢转移到脂氧合酶途径的结果。
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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DOI：
10.1097/01.asn.0000082999.46030.fe
发表时间：
2003-09-01
影响因子：
13.6
作者：
Haas, CS;Amann, K;Hartner, A
通讯作者：
Hartner, A
影响因子：
2.7
作者：
Chamberlain, R. M.;Shirley, D. G.
通讯作者：
Shirley, D. G.
影响因子：
10.3
作者：
Kim, SK;Russell, JS
通讯作者：
Russell, JS
影响因子：
13.6
作者：
Kim, YS;Xu, ZG;Natarajan, R
通讯作者：
Natarajan, R
影响因子：
5.8
作者：
Liu, Jun-Yan;Yang, Jun;Inceoglu, Bora;Qiu, Hong;Ulu, Arzu;Hwang, Sung-Hee;Chiamvimonvat, Nipavan;Hammock, Bruce D.
通讯作者：
Hammock, Bruce D.