Tumor necrosis factor α blockade increases renal cyp2c23 expression and slows the progression of renal damage in salt-sensitive hypertension
Tumor necrosis factor α blockade increases renal cyp2c23 expression and slows the progression of renal damage in salt-sensitive hypertension
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DOI：
10.1161/01.hyp.0000198545.01860.90
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发表时间：
2006-03-01
期刊：
影响因子：
8.3
通讯作者：
Imig, JD
中科院分区：
文献类型：
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作者：
Elmarakby, AA;Quigley, JE;Imig, JD
我们假设肿瘤坏死因子 (TNF) α 下调 Cyp2c 会导致盐敏感性血管紧张素高血压中的高血压和肾损伤。雄性 Sprague-Dawley 大鼠喂食高盐饮食 (8% NaCl)，并植入微型渗透泵以输送血管紧张素 II，持续 14 天。大鼠被分为3组：高盐组、血管紧张素高盐组、血管紧张素高盐组给予TNF-α阻滞剂依那西普。血管紧张素高盐组的动脉压在第一周从 94 +/- 5 毫米汞柱增加到 148 +/- 7 毫米汞柱，而依那西普在治疗组的第一周减缓了血压升高（90 +/- 2 到 109 +/- 6 毫米汞柱）。 2周后，血管紧张素高盐组的动脉压增至156 +/- 11 mmHg，依那西普治疗组增至141 +/- 6 mmHg。血管紧张素高盐大鼠的蛋白尿和蛋白尿显着升高，而依那西普治疗的大鼠则降低。血管紧张素高盐组尿单核细胞趋化蛋白-1 排泄显着增加（275 +/- 47 与 81 +/- 19 ng/天），而依那西普治疗组则减少（153 +/- 31 ng/天）。血管紧张素高盐大鼠的肾脏单核细胞/巨噬细胞浸润也显着增加，并且依那西普治疗再次减弱了这种情况。血管紧张素高盐大鼠肾脏 Cyp2c23 表达减少，而肾环氧化物水解酶表达增加。依那西普治疗增加了 Cyp2c23 的表达并降低了环氧化物水解酶的表达。这些数据表明，TNF-α 有助于血管紧张素高盐高血压中 Cyp2c23 的下调、血压调节和肾损伤。
We hypothesized that the downregulation of Cyp2c by tumor necrosis factor (TNF) alpha contributes to hypertension and renal injury in salt-sensitive angiotensin hypertension. Male Sprague-Dawley rats were fed a high-salt diet (8% NaCl), and osmotic minipumps were implanted to deliver angiotensin II for 14 days. Rats were divided into 3 groups: high salt, angiotensin high salt, and angiotensin high salt administered the TNF-alpha blocker, etanercept. Arterial pressure increased from 94 +/- 5 to 148 +/- 7 mm Hg during week 1 in the angiotensin high-salt group, whereas etanercept slowed blood pressure elevation during the first week in the treated group (90 +/- 2 to 109 +/- 6 mm Hg). After 2 weeks, arterial pressure increased to 156 +/- 11 mm Hg in the angiotensin high-salt group and 141 +/- 6 mmHg in the etanercept-treated group. Albuminuria and proteinuria were significantly elevated in angiotensin high-salt rats and were reduced in the etanercept-treated rats. Urinary monocyte chemoattractant protein-1 excretion significantly increased in the angiotensin high-salt group (275 +/- 47 versus 81 +/- 19 ng/day) and was decreased in the etanercept-treated group (153 +/- 31 ng/day). Angiotensin high-salt rats also had a significant increase in renal monocyte/macrophage infiltration, and this was again attenuated by etanercept treatment. Renal expression of Cyp2c23 decreased, whereas renal epoxide hydrolase expression increased in angiotensin high-salt rats. Etanercept treatment increased Cyp2c23 expression and lowered epoxide hydrolase expression. These data suggest that TNF-alpha contributes to downregulation of Cyp2c23, blood pressure regulation, and renal injury in angiotensin high-salt hypertension.