Silent information regulator 2 (SIRT1) attenuates oxidative stress-induced mesangial cell apoptosis via p53 deacetylation
Silent information regulator 2 (SIRT1) attenuates oxidative stress-induced mesangial cell apoptosis via p53 deacetylation
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DOI：
10.1016/j.freeradbiomed.2006.02.014
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发表时间：
2006-06-15
影响因子：
7.4
通讯作者：
Koya, Daisuke
中科院分区：
文献类型：
--
作者：
Kume, Shinji;Haneda, Masakazu;Koya, Daisuke
氧化应激诱导的肾小球细胞凋亡是各种肾脏疾病发生发展的重要因素。识别调节这一过程的分子可能会导致预防肾脏疾病的新策略的发展。在这项研究中，我们评估了哺乳动物沉默信息调节因子2（SIRT 1），这是最近被确定为细胞生存因子对抗各种压力，是否是氧化应激诱导的系膜细胞凋亡的关键调节。在暴露于过氧化氢（H2 O2）的小鼠系膜细胞（MMCs）中评估凋亡细胞死亡（核凝聚）的形态学特征和生化促凋亡标志物[caspase-3和聚（ADP-核糖）聚合酶（PARP）的裂解]的表达。H2 O2增加系膜细胞凋亡，主要是通过乙酰化激活p53，这是一个转录后修饰p53激活。H2 O2诱导的细胞凋亡在SIRT 1过表达的MMCs中显著减弱，但在SIRT 1敲低的MMCs中增强。虽然SIRT 1不影响H2 O2介导的丝裂原活化蛋白（MAP）激酶的磷酸化，但它与p53相互作用并抑制H2 O2介导的P53乙酰化，但不影响MMC中的磷酸化。我们的研究结果表明，SIRT 1可以防止氧化应激诱导的系膜细胞凋亡，通过p53去乙酰化。SIRT 1的上调可能为预防肾小球疾病提供新的策略。(c)2006年爱思唯尔公司All rights reserved.
Oxidative stress-induced apoptosis of renal glomerular cells is an important factor for the development of various kidney diseases. Identification of molecules that modulate this process could lead to the development of new strategies for preventing kidney diseases. In this study, we evaluated whether mammalian silent information regulator 2 (SIRT1), which has been recently identified as a cell survival factor countering various stressors, is a key regulator of oxidative stress-induced mesangial cell apoptosis. Morphological features of apoptotic cell death (nuclear condensation) and the expression of biochemical proapoptotic markers [cleavages of caspase-3 and poly (ADP-ribose) polymerase (PARP)] were assessed in murine mesangial cells (MMCs) exposed to hydrogen peroxide (H2O2). H2O2 increased mesangial cell apoptosis, predominantly through p53 activation by acetylation, which is a posttranscriptional modification for p53 activation. H2O2-induced apoptosis was significantly attenuated in SIRT1-overexpressing MMCs, but enhanced in SIRT1-knockdown MMCs. Although SIRT1 did not affect H2O2-mediated phosphorylation of mitogen-activated protein (MAP) kinase, it interacted with p53 and inhibited H2O2-mediated p53 acetylation but not phosphorylation in MMCs. Our results indicate that SIRT1 can prevent oxidative stress-induced apoptosis through p53 deacetylation in mesangial cells. Upregulation of SIRT1 may provide a new strategy for preventing kidney glomerular diseases. (c) 2006 Elsevier Inc. All rights reserved.