Huang Hui, Chang Hsin-Hsin, Xu Yue, Reddy D Sudarshan, Du Juan, Zhou Yiqiang, Dong Zheng, Falck John R, Wang Mong-Heng
Department of Physiology, Medical College of Georgia, Augusta, GA 30912, USA.
Exp Biol Med (Maywood). 2006 Dec;231(11):1744-52. doi: 10.1177/153537020623101112.
In this study we examined the expression of cytochrome P450 (CYP) 2C and CYP2J isoforms in renal proximal tubules and microvessels isolated from rats at different stages of pregnancy. We also selectively inhibited epoxyeicosatrienoic acid (EET) production by the administration of N-methanesulfonyl-6-(2-proparyloxyphenyl)hexanamide (MSPPOH 20 mg/kg/day iv) to rats during Days 14-17 of gestation and to age-matched virgin rats and determined the consequent effects on renal function. Western blot analysis showed that CYP2C11, CYP2C23, and CYP2J2 expression was significantly increased in the renal microvessels of pregnant rats on Day 12 of gestation. In the proximal tubules, CYP2C23 expression was significantly increased throughout pregnancy, while the expression of CYP2C11 was increased in early and late pregnancy and the expression of CYP2J2 was increased in middle and late pregnancy. MSPPOH treatment significantly increased pregnant rats' mean arterial pressure, renal vascular resistance, and sodium balance but significantly decreased renal blood flow, glomerular filtration rate, and urinary sodium excretion, as well as fetal pups' body weight and length. In contrast, MSPPOH treatment had no effect on renal hemodynamics or urinary sodium excretion in age-matched virgin rats. In pregnant rats, MSPPOH treatment also caused selective inhibition of renal cortical EET production and significantly decreased the expression of CYP2C11, CYP2C23, and CYP2J2 in the renal cortex, renal microvessels, and proximal tubules. These results suggest that upregulation of renal vascular and tubular EETs contributes to the control of blood pressure and renal function during pregnancy.
在本研究中，我们检测了妊娠不同阶段大鼠分离的肾近端小管和微血管中细胞色素P450（CYP）2C和CYP2J亚型的表达。我们还在妊娠第14 - 17天对大鼠以及年龄匹配的未孕大鼠静脉注射N - 甲磺酰基 - 6 -（2 - 丙炔氧基苯基）己酰胺（MSPPOH，20 mg/kg/天）以选择性抑制环氧二十碳三烯酸（EET）的生成，并确定其对肾功能的后续影响。蛋白质免疫印迹分析显示，妊娠第12天，妊娠大鼠肾微血管中CYP2C11、CYP2C23和CYP2J2的表达显著增加。在近端小管中，整个妊娠期CYP2C23的表达显著增加，而CYP2C11的表达在妊娠早期和晚期增加，CYP2J2的表达在妊娠中期和晚期增加。MSPPOH处理显著增加了妊娠大鼠的平均动脉压、肾血管阻力和钠平衡，但显著降低了肾血流量、肾小球滤过率和尿钠排泄，以及胎鼠的体重和体长。相比之下，MSPPOH处理对年龄匹配的未孕大鼠的肾血流动力学或尿钠排泄没有影响。在妊娠大鼠中，MSPPOH处理还导致肾皮质EET生成的选择性抑制，并显著降低肾皮质、肾微血管和近端小管中CYP2C11、CYP2C23和CYP2J2的表达。这些结果表明，肾血管和肾小管EETs的上调有助于妊娠期血压和肾功能的调控。
