Neutrophil gelatinase-associated lipocalin is instrumental in the pathogenesis of antibody-mediated nephritis in mice.
Neutrophil gelatinase-associated lipocalin is instrumental in the pathogenesis of antibody-mediated nephritis in mice.
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DOI：
10.1002/art.33485
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发表时间：
2012-05
影响因子：
--
通讯作者：
Putterman, Chaim
中科院分区：
文献类型：
--
作者：
Pawar, Rahul D.;Pitashny, Milena;Gindea, Simona;Tieng, Arlene Tan;Levine, Benjamin;Goilav, Beatrice;Campbell, Sean R.;Xia, Yumin;Qing, Xiaoping;Thomas, David B.;Herlitz, Leal;Berger, Thorsten;Mak, Tak W.;Putterman, Chaim
抗dna抗体介导狼疮性肾炎的机制尚未明确。先前，我们发现用抗dna抗体处理系膜细胞诱导中性粒细胞明胶酶相关脂钙蛋白（NGAL）的高表达，NGAL是一种铁结合蛋白，在肾损伤反应中上调。然而，NGAL是否在发病机制中起作用，作为修复的一部分诱导，或与损伤/修复途径无关，尚不清楚。为了研究NGAL在抗体介导的肾炎中的作用，我们通过被动抗体转移B6或129小鼠诱导肾毒性肾炎。为了确定NGAL上调是否有用，我们比较了NGAL野生型和敲除型小鼠在诱导肾毒性肾炎后肾损害的严重程度。我们发现肾毒性肾炎小鼠的肾脏NGAL表达以及尿液NGAL水平与注射对照组小鼠相比显著增加。NGAL的表达、肾脏组织病理学和尿NGAL排泄密切相关。与野生型小鼠相比，NGAL敲除小鼠蛋白尿减轻，肾脏组织病理学改善。同样，在肾炎诱导后，注射NGAL明显加重肾炎，降低生存率。NGAL通过激活caspase-3诱导细胞凋亡，并在体外和体内注射时上调肾细胞炎症基因的表达。我们得出结论，病原抗体的肾脏结合刺激了NGAL的局部表达，NGAL通过促进炎症和细胞凋亡在肾炎的发病过程中起着至关重要的作用。NGAL阻断可能是治疗由致病抗体介导的肾炎的一种新的治疗方法，包括抗gbm疾病和狼疮性肾炎。
The mechanism by which anti-DNA antibodies mediate lupus nephritis has yet to be conclusively determined. Previously, we found that treatment of mesangial cells with anti-DNA antibodies induced high expression of Neutrophil Gelatinase Associated Lipocalin (NGAL), an iron-binding protein upregulated in response to kidney injury. However, whether NGAL is instrumental in pathogenesis, induced as part of repair, or irrelevant to damage/repair pathways, is not known. To investigate the role of NGAL in antibody-mediated nephritis, we induced nephrotoxic nephritis by passive antibody transfer to B6 or 129 mice. To determine if NGAL upregulation is instrumental, we compared the severity of renal damage in NGAL wild-type and knock-out mice following induction of nephrotoxic nephritis. We found that kidney NGAL expression, as well as urinary NGAL levels, were significantly increased in nephrotoxic nephritis as compared to control injected mice. Tight correlations were observed between NGAL expression, renal histopathology, and urinary NGAL excretion. NGAL knock-out mice had attenuated proteinuria and improved renal histopathology as compared to wild-type mice. Similarly, following nephritis induction, NGAL injection significantly exacerbated nephritis and decreased survival. NGAL induces apoptosis via caspase-3 activation, and upregulates inflammatory gene expression in kidney cells in vitro and when injected in vivo. We conclude that kidney binding of pathogenic antibodies stimulates local expression of NGAL, which plays a crucial role in the pathogenesis of nephritis via promotion of inflammation and apoptosis. NGAL blockade may be a novel therapeutic approach for the treatment of nephritis mediated by pathogenic antibodies, including anti-GBM disease and lupus nephritis.
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DOI：
10.1073/pnas.0510847103
发表时间：
2006-02-07
影响因子：
11.1
作者：
Berger, T;Togawa, A;Mak, TW
通讯作者：
Mak, TW
影响因子：
--
作者：
Brunner, Hermine I.;Mueller, Michelle;Devarajan, Prasad
通讯作者：
Devarajan, Prasad
影响因子：
3
作者：
Mishra, Jaya;Ma, Qing;Devarajan, Prasad
通讯作者：
Devarajan, Prasad
DOI：
10.1097/01.asn.0000088027.54400.c6
发表时间：
2003-10-01
影响因子：
13.6
作者：
Mishra, J;Ma, Q;Devarajan, P
通讯作者：
Devarajan, P
影响因子：
5.5
作者：
Rubinstein, Tamar;Pitashny, Milena;Putterman, Chaim
通讯作者：
Putterman, Chaim