Meldrum K K, Misseri R, Metcalfe P, Dinarello C A, Hile K L, Meldrum D R
Department of Urology, Indiana University, Indianapolis, IN 46202, USA.
Am J Physiol Regul Integr Comp Physiol. 2007 Apr;292(4):R1456-64. doi: 10.1152/ajpregu.00620.2005. Epub 2006 Dec 14.
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.
上尿路梗阻会导致肾小管间质纤维化和肾功能的逐步下降。尽管几种炎症介质已被认为与肾梗阻的病理生理学有关，但肿瘤坏死因子-α（TNF-α）对梗阻诱导的纤维化和肾功能障碍的作用尚未得到充分评估。为了研究这一点，将雄性Sprague-Dawley大鼠进行左侧单侧输尿管梗阻或假手术。大鼠每84小时接受一次载体或聚乙二醇化形式的可溶性肿瘤坏死因子受体1型（PEG-sTNFR1）。术后1、3或7天收获肾脏，并对组织样本进行TNF-α表达分析（酶联免疫吸附测定）、巨噬细胞浸润分析（ED-1染色）、转化生长因子-β（1）表达分析（酶联免疫吸附测定、逆转录-聚合酶链反应）、I型和IV型胶原活性分析（蛋白质免疫印迹法、免疫组织化学）、α-平滑肌肌动蛋白积聚分析（免疫组织化学、蛋白质免疫印迹分析）以及血管紧张素原表达分析（蛋白质免疫印迹法）。在另一组实验中，测定了在存在载体或PEG-sTNFR1的情况下单侧输尿管梗阻大鼠的肾小球滤过率（菊粉清除率）。肾梗阻导致组织TNF-α和转化生长因子-β（1）水平升高、I型和IV型胶原活性增加、间质体积增大、α-平滑肌肌动蛋白积聚、血管紧张素原表达增加以及肾功能障碍，而用PEG-sTNFR1治疗可显著降低这些肾纤维化标志物中的每一项。这些结果表明，TNF-α介导梗阻诱导的肾纤维化，并确定中和TNF-α是改善梗阻诱导的肾损伤的一种潜在治疗选择。
