Short communication: Renal tubular vacuolation in animals treated with polyethylene-glycol-conjugated proteins
Short communication: Renal tubular vacuolation in animals treated with polyethylene-glycol-conjugated proteins
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DOI：
10.1093/toxsci/42.2.152
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发表时间：
1998-04-01
影响因子：
3.8
通讯作者：
Shopp, G
中科院分区：
文献类型：
--
作者：
Bendele, A;Seely, J;Shopp, G
在二聚体PEG连接蛋白、肿瘤坏死因子结合蛋白（TNF-bp）的毒理学评价期间，以40、20或10 mg/kg剂量每隔一天静脉给药3个月，在雄性和雌性Sprague-Dawley大鼠（200-300 g）中观察到肾皮质小管上皮细胞空泡化。以20或40 mg/kg剂量给药3个月的大鼠肾小管病变在2个月恢复期后仅部分可逆。尽管存在明显空泡化，但BUN、肌酐、尿分析参数、尿NAG、尿B-2-微球蛋白或钠排泄分数无变化。大于或等于20 mg/kg TNF-bp的单次静脉给药引起相似但较轻的变化。然而，等同剂量的单独PEG或非PEG连接的TNF-bp未引起空泡化的光学显微镜证据。用另一种分子量相似的PEG连接蛋白质治疗大鼠，也产生了类似的变化。TNF-bp的免疫染色显示，在静脉给药后1小时内，肾小管上皮细胞的顶端细胞质中呈阳性。长期给药大鼠肾脏的免疫染色表明，只要继续给药，一些空泡中就存在蛋白质;然而，可逆性研究动物的肾脏存在空泡，但没有TNF-bp的免疫染色。这些结果，沿着一项研究，该研究显示具有较低分子量的PEG连接蛋白的更严重病变和具有PEG连接蛋白>70 kDa的最小病变（如果有的话），表明TNF-bp通过肾小球过滤，并且具有附着的PEG的蛋白被近端小管重吸收。由于PEG的吸湿性，溶酶体的液体膨胀可能导致脂质化。这些研究表明，PEG连接蛋白具有在高剂量下诱导肾小管空泡化的能力。然而，这种变化与临床病理学或功能标志物的改变无关。(C)1998年毒理学学会。
During toxicologic evaluation of a dimeric PEG-linked protein, tumor necrosis factor binding protein (TNF-bp), vacuolation of renal cortical tubular epithelium was seen in male and female Sprague-Dawley rats (200-300 g) given iv doses of 40, 20, or 10 mg/kg every other day for 3 months. Tubular lesions in rats treated with 20 or 40 mg/kg for 3 months were only partially reversible after a 2-month recovery period. Despite the presence of marked vacuolation, there were no changes in BUN, creatinine, urinalysis parameters, urinary NAG, urinary B-2-microglobulin, or fractional sodium excretion. Single iv doses greater than or equal to 20 mg/kg TNF-bp caused similar but milder changes. However, equivalent doses of PEG alone or the non-PEG-linked TNF-bp did not cause light microscopic evidence of vacuolation. Treatment of rats with another PEG-linked protein of similar molecular weight resulted in similar changes. Immunostaining for TNF-bp revealed positivity in the apical cytoplasm of renal tubular epithelium within 1 h of iv dosing. Immunostaining of kidneys from chronically dosed rats indicated that protein was present in some vacuoles as long as dosing continued; however, kidneys from animals on a reversibility study had vacuoles but no immunostaining for TNF-bp. These results, along with a study that showed more severe lesions with PEG-linked proteins of lower molecular weight and minimal if any lesions with PEG-linked proteins >70 kDa, suggest that TNF-bp is filtered through the glomerulus and that the protein with attached PEG is reabsorbed by the proximal tubules. Vacuolation may be a result of fluid distension of lysosomes due to the hygroscopic nature of PEG. These studies demonstrated that PEG-linked proteins have the capacity to induce renal tubular vacuolation at high doses. However, the change was not associated with alteration of clinical pathology or functional markers. (C) 1998 Society of Toxicology.