Poly(ADP-ribose) polymerase-1 regulates the progression of autoimmune nephritis in males by inducing necrotic cell death and modulating inflammation.
Poly(ADP-ribose) polymerase-1 regulates the progression of autoimmune nephritis in males by inducing necrotic cell death and modulating inflammation.
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DOI：
10.4049/jimmunol.0803565
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发表时间：
2009-06-01
期刊：
影响因子：
--
通讯作者：
Caricchio R
中科院分区：
文献类型：
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作者：
Jog NR;Dinnall JA;Gallucci S;Madaio MP;Caricchio R
坏死性病变和坏死细胞死亡是严重自身免疫性肾炎的特征，并有助于局部炎症和疾病的进展。聚（ADP-核糖）聚合酶-1（PARP-1）是一种DNA修复酶，参与诱导坏死，是急性和慢性炎症的关键参与者。因此，我们假设PARP-1通过介导肾脏坏死的诱导来控制肾炎的严重程度。我们使用狼疮和抗肾小球基底膜肾炎模型来确定PARP-1对肾脏炎症反应的影响。我们在这项研究中表明，PARP-1确实在肾小球肾炎过程中被激活。我们还表明，PARP-1或其药理学抑制的缺乏导致轻度肾炎，血尿素氮水平较低，坏死病变减少，存活率较高。PARP-1的相关性显示出强烈的雄性特异性，用17β-雌二醇治疗雄性小鼠可延长其在肾炎过程中的存活时间。PARP-1还调节TNF-α表达和粘附分子的上调，进一步支持PARP-1在肾脏内炎症过程中的作用。我们的研究结果表明，PARP-1的激活和随之而来的坏死细胞死亡在男性肾炎的发病机制中起着重要作用，并建议PARP-1可以成为肾小球肾炎的一个新的治疗靶点。免疫学杂志，2009，182：7297-7306。
Necrotic lesions and necrotic cell death characterize severe autoimmune nephritides, and contribute to local inflammation and to progression of the disease. Poly(ADP-ribose) polymerase-1 (PARP-1), a DNA repair enzyme, is involved in the induction of necrosis and is a key player in the acute and chronic inflammation. Therefore, we hypothesized that PARP-1 controls the severity of nephritis by mediating the induction of necrosis in the kidney. We used lupus and anti-glomerular basement membrane models of nephritis to determine the effects of PARP-1 on the inflammatory response in the kidney. We show in this study that PARP-1 is indeed activated during the course of glomerulonephritis. We also show that the absence of PARP-1 or its pharmacological inhibition results in milder nephritis, with lower blood urea nitrogen levels, reduced necrotic lesions, and higher survival rates. The relevance of PARP-1 showed a strong male sex specificity, and treatment of male mice with 17β-estradiol prolonged their survival during the course of nephritis. PARP-1 also regulated TNF-α expression and up-regulation of adhesion molecules, further supporting a role of PARP-1 in the inflammatory process within the kidney. Our results demonstrate that PARP-1 activation and consequent necrotic cell death play an important role in the pathogenesis of male nephritis, and suggest that PARP-1 can be a novel therapeutic target in glomerulonephritis. The Journal of Immunology, 2009, 182: 7297–7306.