Superoxide dismutase mimetic drug tempol aggravates anti-GBM antibody-induced glomerulonephritis in mice
Superoxide dismutase mimetic drug tempol aggravates anti-GBM antibody-induced glomerulonephritis in mice
复制标题
DOI：
10.1152/ajprenal.00583.2009
复制
发表时间：
2010-08-01
影响因子：
4.2
通讯作者：
Zhou, Xin J.
中科院分区：
文献类型：
--
作者：
Lu, Hua;Zhen, Junhui;Zhou, Xin J.
陆H，甄J，吴T，彭A，叶T，王T，于X，Vaziri ND，Mohan C，周XJ.超氧化物歧化酶模拟药物tempol抑制抗GBM抗体诱导的小鼠肾小球肾炎。美国肾脏生理学杂志299：F445-F452，2010年。首次发表于2010年5月26日; doi：10.1152/ajprenal.00583.2009。氧化应激在抗肾小球基底膜抗体诱导的肾小球肾炎（anti-GBMGN）的发病机制中起重要作用。超氧化物歧化酶（SOD）是抵抗氧化应激的第一道防线，通过将超氧化物转化为过氧化氢（H2 O2）。我们研究了SOD模拟药物tempol对小鼠抗GBM-GN的作用。用兔抗小鼠GBM血清攻击129/svJ小鼠以诱导GN，随后分成tempol（200 mg.kg（-1）.day（-1），口服）和载体处理组。进行常规组织学、SOD和过氧化氢酶活性、丙二醛（MDA）、H2 O2以及中性粒细胞、淋巴细胞、巨噬细胞、p65-NF-κ B和骨桥蛋白的免疫组织化学染色。抗GBM-GN小鼠肾脏SOD和过氧化氢酶活性显著降低，H2 O2和MDA水平显著升高。出乎意料的是，tempol给药加重了抗GBM-GN，如通过蛋白尿的强化、伴随白细胞流入的严重新月体GN的存在和治疗组中的加速死亡所证明的。Tempol处理可提高尿中SOD活性和H2 O2水平，上调肾脏中p65-NF-κ B和骨桥蛋白，但对肾脏过氧化氢酶活性无影响。因此，Tempol通过增加H2 O2的产生来抑制抗GBM-GN，H2 O2是一种有效的NF-κ B激活剂，因此可以加剧炎症和肾损伤。tempo处理组肾脏中p65-NF-κ B、骨桥蛋白和白细胞流入增加支持了这一假设。
Lu H, Zhen J, Wu T, Peng A, Ye T, Wang T, Yu X, Vaziri ND, Mohan C, Zhou XJ. Superoxide dismutase mimetic drug tempol aggravates anti-GBM antibody-induced glomerulonephritis in mice. Am J Physiol Renal Physiol 299: F445-F452, 2010. First published May 26, 2010; doi:10.1152/ajprenal.00583.2009.-Oxidative stress plays an important role in the pathogenesis of anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBMGN). Superoxide dismutase (SOD) is the first line of defense against oxidative stress by converting superoxide to hydrogen peroxide (H2O2). We investigated the effect of the SOD mimetic drug tempol on anti-GBM-GN in mice. 129/svJ mice were challenged with rabbit anti-mouse-GBM sera to induce GN and subsequently divided into tempol (200 mg.kg(-1).day(-1), orally) and vehicle-treated groups. Routine histology, SOD and catalase activities, malondialdehyde (MDA), H2O2, and immunohistochemical staining for neutrophils, lymphocytes, macrophages, p65-NF-kappa B, and osteopontin were performed. Mice with anti-GBM-GN had significantly reduced renal SOD and catalase activities and increased H2O2 and MDA levels. Unexpectedly, tempol administration exacerbated anti-GBM-GN as evidenced by intensification of proteinuria, the presence of severe crescentic GN with leukocyte influx, and accelerated mortality in the treated group. Tempol treatment raised SOD activity and H2O2 level in urine, upregulated p65-NF-kappa B and osteopontin in the kidney, but had no effect on renal catalase activity. Thus tempol aggravates anti-GBM-GN by increasing production of H2O2 which is a potent NF-kappa B activator and as such can intensify inflammation and renal injury. This supposition is supported by increases seen in p65-NF-kappa B, osteopontin, and leukocyte influx in the kidneys of the tempol-treated group.