TNF-α inhibition reduces renal injury in DOCA-salt hypertensive rats
TNF-α inhibition reduces renal injury in DOCA-salt hypertensive rats
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DOI：
10.1152/ajpregu.00466.2007
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发表时间：
2008-01-01
影响因子：
2.8
通讯作者：
Pollock, David M.
中科院分区：
文献类型：
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作者：
Elmarakby, Ahmed A.;Quigley, Jeffrey E.;Pollock, David M.
研究表明炎症细胞因子 TNF-α 在终末期肾病的预后中发挥作用。我们之前表明，TNF-α 抑制可减缓血管紧张素 II 盐敏感性高血压的高血压进展和肾损伤。因此，我们假设 TNF-α 在盐皮质激素诱导的高血压模型中导致肾脏炎症。对四组大鼠（n = 5 或 6）进行为期 3 周的以下治疗研究：1）安慰剂，2）安慰剂 + TNF-α 抑制剂依那西普（1.25 mg (.) kg(-1) (.) day(-1) sc），3）醋酸脱氧皮质酮 + 0.9% 氯化钠饮用（DOCA-盐），或 4）DOCA-盐 + 依那西普。与基线相比，DOCA盐大鼠通过遥测测量的平均动脉血压（MAP）增加（177 +/- 4 vs. 107 +/- 3 mmHg；P < 0.05），并且TNF-α抑制对这些大鼠的MAP升高没有影响（177 +/- 8 mmHg）。与安慰剂相比，DOCA 盐大鼠的尿蛋白排泄显着增加（703 +/- 76 vs. 198 +/- 5 mg/天）；依那西普降低蛋白尿（514 +/- 64 mg/天；与单独使用 DOCA 盐相比，P < 0.05）。每组的尿白蛋白排泄遵循相似的模式。与安慰剂相比，DOCA 盐大鼠的尿单核细胞趋化蛋白 (MCP)-1 和内皮素 (ET)-1 排泄量也有所增加（MCP-1：939 +/- 104 对比 43 +/- 7 ng/天，ET-1：3.30 +/- 0.29 对比 1.07 +/- 0.03 fmol/天；均 P < 0.05); TNF-α 抑制显着降低 MCP-1 和 ET-1 排泄（分别为 409 +/- 138 ng/天和 2.42 +/- 0.22 fmol/天；与单独使用 DOCA 盐相比，两者 P < 0.05）。 DOCA-盐高血压大鼠的肾皮质 NF-κ B 活性也增加，而依那西普治疗显着降低了这种效应。这些数据支持以下假设：TNF-α 导致 DOCA 盐大鼠肾脏炎症增加。
Studies suggest that the inflammatory cytokine TNF-alpha plays a role in the prognosis of end-stage renal diseases. We previously showed that TNF-alpha inhibition slowed the progression of hypertension and renal damage in angiotensin II salt-sensitive hypertension. Thus, we hypothesize that TNF-alpha contributes to renal inflammation in a model of mineralocorticoid-induced hypertension. Four groups of rats (n = 5 or 6) were studied for 3 wk with the following treatments: 1) placebo, 2) placebo + TNF-alpha inhibitor etanercept (1.25 mg (.) kg(-1) (.) day(-1) sc), 3) deoxycorticosterone acetate + 0.9% NaCl to drink (DOCA-salt), or 4) DOCA-salt + etanercept. Mean arterial blood pressure (MAP) measured by telemetry increased in DOCA-salt rats compared with baseline (177 +/- 4 vs. 107 +/- 3 mmHg; P < 0.05), and TNF-alpha inhibition had no effect in the elevation of MAP in these rats (177 +/- 8 mmHg). Urinary protein excretion significantly increased in DOCA-salt rats compared with placebo (703 +/- 76 vs. 198 +/- 5 mg/day); etanercept lowered the proteinuria (514 +/- 64 mg/day; P < 0.05 vs. DOCA-salt alone). Urinary albumin excretion followed a similar pattern in each group. Urinary monocyte chemoattractant protein (MCP)-1 and endothelin (ET)-1 excretion were also increased in DOCA-salt rats compared with placebo (MCP-1: 939 +/- 104 vs. 43 +/- 7 ng/day, ET-1: 3.30 +/- 0.29 vs. 1.07 +/- 0.03 fmol/day; both P < 0.05); TNF-alpha inhibition significantly decreased both MCP-1 and ET-1 excretion (409 +/- 138 ng/day and 2.42 +/- 0.22 fmol/day, respectively; both P < 0.05 vs. DOCA-salt alone). Renal cortical NF-kappa B activity also increased in DOCA-salt hypertensive rats, and etanercept treatment significantly reduced this effect. These data support the hypothesis that TNF-alpha contributes to the increase in renal inflammation in DOCA-salt rats.