Whaley-Connell Adam, Habibi Javad, Nistala Ravi, Cooper Shawna A, Karuparthi Poorna R, Hayden Melvin R, Rehmer Nathan, DeMarco Vincent G, Andresen Bradley T, Wei Yongzhong, Ferrario Carlos, Sowers James R
University of Missouri-Columbia School of Medicine, Department of Internal Medicine, Division of Nephrology, MA436, DC043.0, One Hospital Dr, Columbia, MO 65212, USA.
Hypertension. 2008 Feb;51(2):474-80. doi: 10.1161/HYPERTENSIONAHA.107.102467. Epub 2008 Jan 2.
Activation of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase by angiotensin II is integral to the formation of oxidative stress in the vasculature and the kidney. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibition is associated with reductions of oxidative stress in the vasculature and kidney and associated decreases in albuminuria. Effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition on oxidative stress in the kidney and filtration barrier integrity are poorly understood. To investigate, we used transgenic TG(mRen2)27 (Ren2) rats, which harbor the mouse renin transgene and renin-angiotensin system activation, and an immortalized murine podocyte cell line. We treated young, male Ren2 and Sprague-Dawley rats with rosuvastatin (20 mg/kg IP) or placebo for 21 days. Compared with controls, we observed increases in systolic blood pressure, albuminuria, renal NADPH oxidase activity, and 3-nitrotryosine staining, with reductions in the rosuvastatin-treated Ren2. Structural changes on light and transmission electron microscopy, consistent with periarteriolar fibrosis and podocyte foot-process effacement, were attenuated with statin treatment. Nephrin expression was diminished in the Ren2 kidney and trended to normalize with statin treatment. Angiotensin II-dependent increases in podocyte NADPH oxidase activity and subunit expression (NOX2, NOX4, Rac, and p22(phox)) and reactive oxygen species generation were decreased after in vitro statin treatment. These data support a role for increased NADPH oxidase activity and subunit expression with resultant reactive oxygen species formation in the kidney and podocyte. Furthermore, statin attenuation of NADPH oxidase activation and reactive oxygen species formation in the kidney/podocyte seems to play roles in the abrogation of oxidative stress-induced filtration barrier injury and consequent albuminuria.
血管紧张素II激活还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶是血管系统和肾脏中氧化应激形成所不可或缺的。3-羟基-3-甲基戊二酰辅酶A还原酶抑制与血管系统和肾脏中氧化应激的降低以及蛋白尿的相关减少有关。3-羟基-3-甲基戊二酰辅酶A还原酶抑制对肾脏氧化应激和滤过屏障完整性的影响尚不清楚。为了进行研究，我们使用了转基因TG(mRen2)27（Ren2）大鼠，其携带小鼠肾素转基因并激活肾素-血管紧张素系统，以及一种永生化的小鼠足细胞系。我们用瑞舒伐他汀（20mg/kg腹腔注射）或安慰剂处理年轻雄性Ren2大鼠和Sprague-Dawley大鼠21天。与对照组相比，我们观察到收缩压、蛋白尿、肾脏NADPH氧化酶活性和3-硝基酪氨酸染色增加，而瑞舒伐他汀处理的Ren2大鼠则有所降低。光镜和透射电镜下的结构变化与动脉周围纤维化和足细胞足突消失一致，他汀类药物治疗可使其减轻。肾2肾中nephrin表达减少，他汀类药物治疗后有恢复正常的趋势。体外他汀类药物治疗后，血管紧张素II依赖性的足细胞NADPH氧化酶活性和亚基表达（NOX2、NOX4、Rac和p22(phox)）以及活性氧生成减少。这些数据支持NADPH氧化酶活性和亚基表达增加以及由此导致的肾脏和足细胞中活性氧形成的作用。此外，他汀类药物对肾脏/足细胞中NADPH氧化酶激活和活性氧形成的减弱似乎在消除氧化应激诱导的滤过屏障损伤和随之而来的蛋白尿中起作用。
