An interleukin-6-neutralizing antibody prevents cyclosporine-induced nephrotoxicity in mice.
An interleukin-6-neutralizing antibody prevents cyclosporine-induced nephrotoxicity in mice.
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白细胞介素 6 中和抗体可预防环孢菌素诱导的小鼠肾毒性。
DOI：
10.1016/j.jss.2007.12.786
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Kittur,DilipS
中科院分区：
文献类型：
--
作者：
LaSpina,Mark;Tripathi,Sudipta;Gatto,LouisA;Bruch,David;Maier,KristopherG;Kittur,DilipS
简介 长期使用环孢素 A (CyA) 可引起肾毒性，主要是由于内皮功能障碍。在我们之前的研究中，在体外确定了潜在的机制，并表明烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 氧化酶和白细胞介素 6 (IL-6) 是导致内皮功能障碍的关键成分。在本研究中，我们在体内模型中测试了 NADPH 氧化酶活性和 IL-6 是肾损伤关键成分的假设。方法来自 Jackson Laboratory（缅因州巴港）的雄性小鼠 C57B/6 小鼠在 6-8 周时在整个试验过程中接受低盐饮食。低盐饮食 1 周后，每天给小鼠注射 50 μL 由 75% cremaphor（Sigma，St. Louis，MO）和乙醇组成的载体，持续 5 周。还预留了一个单独的车辆组。对小鼠称重并每天注射 25 mg/kg/天的环孢素（Novartis Pharma, St. Louis, MO）。罗布麻宁 (Calbiochem, Gibbstown, NJ) 20 mg/kg 单独注射或与 CyA 同时注射。另一组小鼠以 2 μg/天的剂量与 CyA 一起施用 IL-6 抗体（货号 MAB406；R&D Systems，明尼阿波利斯，明尼苏达州）。立即将肾脏整块取出并置于福尔马林中进行石蜡切片。进行三色染色。对载玻片进行盲法处理，并对每个治疗组的皮质区域拍摄 10 张照片，其中以随机方式覆盖了估计的 10% 表面积。通过肾小管坏死确定肾损伤区域，通过每张照片的坏死量来识别和量化。将每张照片分为10块，记录每张照片中含有坏死小管的块数。结果两只对照小鼠（仅低盐）没有受到损伤。四只载体小鼠有微量的肾小管坏死。 CyA 治疗组表现出最高的损伤量（29/70；41%）。含有夹竹桃麻素（一种特定的 NADPH 氧化酶抑制剂）的 CyA 被发现具有 36% (22/60) 的损伤，而仅含有 IL-6 抗体的 CyA 被观察到具有 15% (6/40) 的损伤。比较成像分析，单独使用 CyA 治疗的小鼠和使用 CyA 联合夹竹桃麻素治疗的小鼠之间没有差异。然而，发现用 CyA 和 IL-6 抗体治疗的小鼠中的损伤量显着低于 CyA 和 CyA 加夹竹桃麻素治疗的小鼠。 结论 SCyA 作为钙调神经磷酸酶抑制剂的作用可以延长肾移植的时间，但长期使用会导致同种异体移植肾病等毁灭性后果。此前，我们已经在体外确定了 CyA 诱导内皮功能障碍的潜在机制。目前的研究确定 IL-6 表达增加是 CyA 诱导肾损伤的机制，并且使用 IL-6 中和抗体可能有助于减少 CyA 诱导的肾损伤。
INTRODUCTIONChronic use of cyclosporine A (CyA) induces nephrotoxicity primarily due to endothelial dysfunction. In our previous studies, potential mechanisms were identified in vitro and implicated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and interleukin-6 (IL-6) as key components in causing endothelial dysfunction. In this study, we tested the hypothesis that NADPH oxidase activity and IL-6 are key components in renal damage in an in vivo model.METHODSMale mice C57B/6 mice from Jackson Laboratory (Bar Harbor, ME) at 6–8 wks were subjected to a low-salt diet throughout the trial. After 1 week on a low-salt diet, the mice were injected daily with treatments in 50 μL vehicle composed of 75% cremaphor (Sigma, St. Louis, MO) and ethanol for 5 wks. A vehicle-alone group was also set aside. Mice were weighed and 25 mg/kg/day cyclosporine (Novartis Pharma, St. Louis, MO) was injected daily. Apocynin (Calbiochem, Gibbstown, NJ) 20 mg/kg were injected either alone or concomitantly with CyA. Another group of mice were administered IL-6 antibody (Cat no. MAB406; R&D Systems, Minneapolis, MN) at 2 μg/day along with CyA. The kidneys were removed en bloc immediately and submitted in formalin for paraffin sections. Trichrome stains were performed. Slides were blinded and 10 photographs of cortical areas per treatment group were taken, which covered an estimate of 10% surface area in random fashion. Areas of renal damage, which were determined by tubular necrosis, were identified and quantified by amount of necrosis per photograph. Each photograph was divided into 10 blocks, and the number of blocks that contained necrotic tubules per photo was recorded.RESULTSThe two control mice (low salt only) had no damage. The four vehicle mice had trace amounts of tubular necrosis. CyA treatment group demonstrated the highest amount of damage (29/70; 41%). CyA with apocynin, a specific NADPH oxidase inhibitor, was found to have 36% (22/60) damage, whereas the CyA with IL-6 antibody only was observed to have 15% (6/40) damage. Comparing imaging analysis, there was no difference between mice treated with CyA alone and with CyA with apocynin. However, the amount of damage in mice treated with CyA and IL-6 antibody was found to be significantly lower than both CyA and CyA with apocynin.CONCLUSIONSCyA action as a calcineurin inhibitor has allowed prolongation of kidney transplants, but its chronic use has led to devastating consequences such as allograft nephropathy. Previously, we have identified potential mechanisms of CyA-induced endothelial dysfunction in vitro. The current study identifies increased IL-6 expression as a mechanism by which CyA induces renal damage and that the use of an IL-6-neutralizing antibody may be useful in reducing CyA-induced renal damage.
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泌尿外科检查：肾移植和肾血管性高血压接受西罗莫司的肾移植受者早期停用环孢素 A 可预防慢性病理性同种异体移植病变的进展
DOI：
--
发表时间：
2005
期刊：
影响因子：
--
作者：
D. Goldfarb
通讯作者：
D. Goldfarb
钙调神经磷酸酶抑制剂对肾移植受者内皮功能的影响
影响因子：
2.1
作者：
H. Oflaz;A. Turkmen;R. Kazancioglu;S. Kayacan;B. Bunyak;H. Gençhallaç;B. Erol;F. Mercanoğlu;S. Umman;M. Sever
通讯作者：
M. Sever
内皮功能障碍的信号转导途径。
影响因子：
2
作者：
C. Wilasrusmee;G. Shah;S. Kittur;A. Halverson;D. Bruch;D. Kittur
通讯作者：
D. Kittur
使用环孢素维持肾移植受者的内皮功能障碍。
影响因子：
19.6
作者：
S. Morris;J. McMurray;R. Rodger;Rosemary Farmer;A. Jardine
通讯作者：
A. Jardine
内皮素-1在环孢菌素A引起的微血管功能障碍中的作用。
影响因子：
5.2
作者：
C. Wilasrusmee;Monica da Silva;J. Siddiqui;D. Bruch;S. Kittur;S. Wilasrusmee;D. Kittur
通讯作者：
D. Kittur