Tumor necrosis factor-alpha antagonist etanercept decreases blood pressure and protects the kidney in a mouse model of systemic lupus erythematosus.
Tumor necrosis factor-alpha antagonist etanercept decreases blood pressure and protects the kidney in a mouse model of systemic lupus erythematosus.
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DOI：
10.1161/hypertensionaha.110.157685
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发表时间：
2010-10
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影响因子：
--
通讯作者：
Ryan MJ
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作者：
Venegas-Pont M;Manigrasso MB;Grifoni SC;LaMarca BB;Maric C;Racusen LC;Glover PH;Jones AV;Drummond HA;Ryan MJ
慢性炎症与高血压的病理有关；然而，特定细胞因子的作用仍不清楚。我们测试了依那西普（Etan）阻断TNF-α是否能降低系统性红斑狼疮（SLE）雌性小鼠模型的平均动脉压（MAP）。SLE是一种伴有高血压的慢性炎症性疾病。30周龄SLE （NZBWF1）和对照小鼠（NZW/LacJ）接受Etan（每周0.8mg/kg SC）治疗4周或载药。狼疮小鼠的MAP （mmHg）升高（150±5 vs.对照组的113±5，p<0.05），伊坦治疗狼疮小鼠的MAP （mmHg）降低（132±3），而对照组没有升高（117±5）。尿白蛋白（µg/mg肌酐）在SLE小鼠中升高（28742±9032 vs. 1075±883 p<0.05），在伊坦治疗的SLE小鼠中降低（8154±3899），而对照组没有降低（783±226）。狼疮小鼠的肾小球硬化（肾小球百分比）明显（对照组为2.5±1.6比0.0±0.0,p<0.05），而伊坦治疗的狼疮小鼠的肾小球硬化（百分比）有所改善（0.1±0.1）。SLE小鼠肾皮质CD68+细胞染色（%面积）升高（4.75±0.80 vs.对照组0.79±0.12,p<0.05）， Etan治疗SLE小鼠肾皮质CD68+细胞染色（%面积）降低（2.28±0.32），对照组未见差异（1.43±0.25）。与对照组相比，SLE小鼠肾皮质NADPH氧化酶活性（RLU/mg蛋白）较高（10718±1276比7584±229，p<0.05），而依坦治疗的SLE小鼠肾皮质NADPH氧化酶活性（6645±490）较低。与对照组相比，SLE小鼠肾皮质NFκB（磷酸化和非磷酸化）升高，而伊坦治疗的SLE小鼠则降低。这些数据表明，TNF-α通过增加肾脏nf - κ b、氧化应激和炎症，在机制上促进慢性炎症性疾病高血压的发展。
Chronic inflammation has been implicated in the pathology of hypertension; however, the role for specific cytokines remains unclear. We tested whether TNF-α blockade with etanercept (Etan) reduces mean arterial pressure (MAP) in a female mouse model of systemic lupus erythematosus (SLE). SLE is a chronic inflammatory disorder with prevalent hypertension. Thirty week old SLE (NZBWF1) and control mice (NZW/LacJ) received Etan (0.8mg/kg SC weekly) for 4 weeks or vehicle. MAP (mmHg) was increased in SLE mice (150±5 vs. 113±5 in controls, p<0.05) and was lower in Etan treated SLE mice (132±3) but not controls (117±5). Albuminuria (µg/mg creatinine) was elevated in SLE mice (28742±9032 vs. 1075±883 p<0.05) and was lower in Etan treated SLE mice (8154±3899) but not control animals (783±226). Glomerulosclerosis (% of glomeruli) was evident in SLE mice (2.5±1.6 vs. 0.0±0.0 in controls, p<0.05) and was ameliorated in Etan treated SLE mice (0.1±0.1). Renal cortex CD68+ cell staining (% area) was elevated in SLE mice (4.75±0.80 vs. 0.79±0.12 in controls, p<0.05) and was lower in Etan treated SLE mice (2.28±0.32) but not controls (1.43±0.25). Renal cortex NADPH oxidase activity (RLU/mg of protein) was higher in SLE mice compared to controls (10718±1276 vs. 7584±229, p<0.05) and lowered in Etan treated SLE mice (6645±490). Renal cortex NFκB (phosphorylated and non-phosphorylated) was increased in SLE mice compared to controls and lower in Etan treated SLE mice. These data suggest that TNF-α mechanistically contributes to the development of hypertension in a chronic inflammatory disease through increased renal NFκB, oxidative stress and inflammation.