Increased blood pressure in mice lacking cytochrome P450 2J5
Increased blood pressure in mice lacking cytochrome P450 2J5
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DOI：
10.1096/fj.08-114413
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发表时间：
2008-12-01
期刊：
影响因子：
4.8
通讯作者：
Zeldin, Darryl C.
中科院分区：
文献类型：
--
作者：
Athirakul, Krairerk;Bradbury, J. Alyce;Zeldin, Darryl C.
细胞色素P450（CYP 450）酶参与广泛的生化功能，包括花生四烯酸和类固醇激素的代谢。小鼠CYP 2 J5在肾脏中含量丰富，其产物顺式-环氧二十碳三烯酸（Epoxyeicosatrienoic Acids，EEP）调节钠转运和血管张力。为了确定CYP 2 J5在肾脏中的生理作用，使用常规基因靶向方法产生敲除小鼠。Cyp 2 j5（-/-）小鼠发育正常，未表现出明显的肾脏病理学。虽然肾脏EET生物合成明显不受CYP 2 J5缺乏的影响，但雌性小鼠中这种CYP 2 J5缺乏与血压升高、近端肾小管转运速率增强以及对血管紧张素II和内皮素I的传入小动脉反应增强相关。有趣的是，雌性Cyp 2 j5（-/-）小鼠的血浆17 β-雌二醇水平降低，雌激素替代治疗使血压和血管反应性恢复到正常水平。没有证据表明雌性Cyp 2 j5（-/-）小鼠雌激素代谢增强，或类固醇生成酶的表达或活性改变，但其血浆促黄体激素和促卵泡激素水平不适当地低。总之，我们的研究结果说明了性别特异性的作用，CYP 2 J5在调节血压，近端肾小管运输，并通过雌激素依赖性机制传入小动脉的反应。
The cytochrome P450 (CYP) enzymes participate in a wide range of biochemical functions, including metabolism of arachidonic acid and steroid hormones. Mouse CYP2J5 is abundant in the kidney where its products, the cis-epoxyeicosatrienoic acids (EETs), modulate sodium transport and vascular tone. To define the physiological role of CYP2J5 in the kidney, knockout mice were generated using a conventional gene targeting approach. Cyp2j5 (-/-) mice develop normally and exhibit no overt renal pathology. While renal EET biosynthesis was apparently unaffected by the absence of CYP2J5, deficiency of this CYP in female mice was associated with increased blood pressure, enhanced proximal tubular transport rates, and exaggerated afferent arteriolar responses to angiotensin II and endothelin I. Interestingly, plasma 17 beta-estradiol levels were reduced in female Cyp2j5 (-/-) mice and estrogen replacement restored blood pressure and vascular responsiveness to normal levels. There was no evidence of enhanced estrogen metabolism, or altered expression or activities of steroidogenic enzymes in female Cyp2j5 (-/-) mice, but their plasma levels of luteinizing hormone and follicle stimulating hormone were inappropriately low. Together, our findings illustrate a sex-specific role for CYP2J5 in regulation of blood pressure, proximal tubular transport, and afferent arteriolar responsiveness via an estrogen-dependent mechanism.