TNF-alpha neutralization ameliorates obstruction-induced renal fibrosis and dysfunction.
TNF-alpha neutralization ameliorates obstruction-induced renal fibrosis and dysfunction.
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发表时间：
2007
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通讯作者：
K. Meldrum;R. Misseri;P. Metcalfe;C. Dinarello;K. Hile;D. Meldrum
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作者：
K. Meldrum;R. Misseri;P. Metcalfe;C. Dinarello;K. Hile;D. Meldrum
上尿路梗阻导致肾小管间质纤维化和肾功能进行性下降。尽管几种炎症介质与肾梗阻的病理生理学有关，但 TNF-α 对梗阻引起的纤维化和肾功能障碍的作用尚未得到彻底评估。为了研究这一点，对雄性斯普拉格-道利大鼠进行左侧单侧输尿管梗阻与假手术。大鼠每 84 小时接受载体或聚乙二醇化形式的可溶性 TNF 受体 1 型 (PEG-sTNFR1)。术后1、3或7天收获肾脏，并分析组织样本的TNF-α表达（ELISA）、巨噬细胞浸润（ED-1染色）、转化生长因子-β（1）表达（ELISA、RT-PCR）、胶原蛋白I和IV活性（Western印迹、免疫组织化学）、α-平滑肌肌动蛋白积累（免疫组织化学、Western印迹分析）和血管紧张素原表达（Western blot）印迹）。在另一组中，测定了在载体或 PEG-sTNFR1 存在的情况下遭受单侧输尿管阻塞的大鼠的肾小球滤过率（菊粉清除率）。肾梗阻会导致组织 TNF-α 和转化生长因子-β(1) 水平、胶原蛋白 I 和 IV 活性、间质体积、α-平滑肌肌动蛋白积累、血管紧张素原表达和肾功能障碍增加，而 PEG-sTNFR1 治疗可显着降低肾纤维化的这些标志物。这些结果证明TNF-α介导梗阻性肾纤维化，并确定TNF-α中和作为改善梗阻性肾损伤的潜在治疗选择。
Upper urinary tract obstruction results in tubulointerstitial fibrosis and a progressive decline in renal function. Although several inflammatory mediators have been implicated in the pathophysiology of renal obstruction, the contribution of TNF-alpha to obstruction-induced fibrosis and renal dysfunction has not been thoroughly evaluated. To study this, male Sprague-Dawley rats were subjected to left unilateral ureteral obstruction vs. sham operation. Rats received either vehicle or a pegylated form of soluble TNF receptor type 1 (PEG-sTNFR1) every 84 h. The kidneys were harvested 1, 3, or 7 days postoperatively, and tissue samples were analyzed for TNF-alpha expression (ELISA), macrophage infiltration (ED-1 staining), transforming growth factor-beta(1) expression (ELISA, RT-PCR), collagen I and IV activity (Western Blot, immunohistochemistry), alpha-smooth muscle actin accumulation (immunohistochemistry, Western blot analysis), and angiotensinogen expression (Western blot). In a separate arm, the glomerular filtration rate (inulin clearance) of rats subjected to unilateral ureteral obstruction in the presence of either vehicle or PEG-sTNFR1 was determined. Renal obstruction induced increased tissue TNF-alpha and transforming growth factor-beta(1) levels, collagen I and IV activity, interstitial volume, alpha-smooth muscle actin accumulation, angiotensinogen expression, and renal dysfunction, whereas treatment with PEG-sTNFR1 significantly reduced each of these markers of renal fibrosis. These results demonstrate that TNF-alpha mediates obstruction-induced renal fibrosis and identify TNF-alpha neutralization as a potential therapeutic option for the amelioration of obstruction-induced renal injury.