Jennings Brett L, Moore Joseph A, Pingili Ajeeth K, Estes Anne M, Fang Xiao R, Kanu Alie, Gonzalez Frank J, Malik Kafait U
Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee;
Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; and.
Am J Physiol Renal Physiol. 2015 May 1;308(9):F981-92. doi: 10.1152/ajprenal.00597.2014. Epub 2015 Feb 18.
Recently, we demonstrated in female mice that protection against ANG II-induced hypertension and associated cardiovascular changes depend on cytochrome P-450 (CYP)1B1. The present study was conducted to determine if Cyp1b1 gene disruption ameliorates renal dysfunction and organ damage associated with ANG II-induced hypertension in female mice. ANG II (700 ng·kg(-1)·min(-1)) infused by miniosmotic pumps for 2 wk in female Cyp1b1(+/+) mice did not alter water consumption, urine output, Na(+) excretion, osmolality, or protein excretion. However, in Cyp1b1(-/-) mice, ANG II infusion significantly increased (P < 0.05) water intake (5.50 ± 0.42 ml/24 h with vehicle vs. 8.80 ± 0.60 ml/24 h with ANG II), urine output (1.44 ± 0.37 ml/24 h with vehicle vs. 4.30 ± 0.37 ml/24 h with ANG II), and urinary Na(+) excretion (0.031 ± 0.016 mmol/24 h with vehicle vs. 0.099 ± 0.010 mmol/24 h with ANG II), decreased osmolality (2,630 ± 79 mosM/kg with vehicle vs. 1,280 ± 205 mosM/kg with ANG II), and caused proteinuria (2.60 ± 0.30 mg/24 h with vehicle vs. 6.96 ± 0.55 mg/24 h with ANG II). Infusion of ANG II caused renal fibrosis, as indicated by an accumulation of renal interstitial α-smooth muscle actin, collagen, and transforming growth factor-β in Cyp1b1(-/-) but not Cyp1b1(+/+) mice. ANG II also increased renal production of ROS and urinary excretion of thiobarburic acid-reactive substances and reduced the activity of antioxidants and urinary excretion of nitrite/nitrate and the 17β-estradiol metabolite 2-methoxyestradiol in Cyp1b1(-/-) but not Cyp1b1(+/+) mice. These data suggest that Cyp1b1 plays a critical role in female mice in protecting against renal dysfunction and end-organ damage associated with ANG II-induced hypertension, in preventing oxidative stress, and in increasing activity of antioxidant systems, most likely via generation of 2-methoxyestradiol from 17β-estradiol.
最近，我们在雌性小鼠中证明，抵御血管紧张素II（ANG II）诱导的高血压及相关心血管变化依赖于细胞色素P-450（CYP）1B1。本研究旨在确定Cyp1b1基因敲除是否能改善雌性小鼠中与ANG II诱导的高血压相关的肾功能障碍和器官损伤。在野生型Cyp1b1(+/+)雌性小鼠中，通过微量渗透泵输注ANG II（700 ng·kg(-1)·min(-1)）2周，未改变水消耗、尿量、钠排泄、渗透压或蛋白质排泄。然而，在Cyp1b1(-/-)小鼠中，输注ANG II显著增加了（P < 0.05）水摄入量（生理盐水组为5.50 ± 0.42 ml/24 h，ANG II组为8.80 ± 0.60 ml/24 h）、尿量（生理盐水组为1.44 ± 0.37 ml/24 h，ANG II组为4.30 ± 0.37 ml/24 h）和尿钠排泄（生理盐水组为0.031 ± 0.016 mmol/24 h，ANG II组为0.099 ± 0.010 mmol/24 h），降低了渗透压（生理盐水组为2,630 ± 79 mosM/kg，ANG II组为1,280 ± 205 mosM/kg），并导致蛋白尿（生理盐水组为2.60 ± 0.30 mg/24 h，ANG II组为6.96 ± 0.55 mg/24 h）。输注ANG II导致肾纤维化，表现为Cyp1b1(-/-)小鼠而非Cyp1b1(+/+)小鼠肾间质α-平滑肌肌动蛋白、胶原蛋白和转化生长因子-β的积累。ANG II还增加了Cyp1b1(-/-)小鼠而非Cyp1b1(+/+)小鼠的肾脏活性氧生成和硫代巴比妥酸反应性物质的尿排泄，降低了抗氧化剂活性以及亚硝酸盐/硝酸盐和17β-雌二醇代谢物2-甲氧基雌二醇的尿排泄。这些数据表明，Cyp1b1在雌性小鼠中对抵御与ANG II诱导的高血压相关的肾功能障碍和终末器官损伤、预防氧化应激以及增加抗氧化系统活性起着关键作用，最有可能是通过将17β-雌二醇转化为2-甲氧基雌二醇来实现的。
