The role of SIRT1 in mediating renal cells apoptosis and its therapeutic perspective

SIRT1介导肾细胞凋亡的作用及其治疗前景

基本信息

批准号：
17590925
负责人：
KOYA Daisuke
金额：
$ 2.24万
依托单位：
Kanazawa Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590925/
关键词：
kidney diseaes sitr1 apoptosis oxidative stress TGF-beta smad 7 酸化ストレス H2O2

项目摘要

Oxidative stress and/or TGF-beta-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 pro-apoptotic markers [cleavages of caspase-3 and poly (ADP-ribose) polymerase (PARP)] were assessed in murine mesangial cells (MMC_s) exposed to hydrogen peroxide (H_2O_2) or TGF-beta. H_2O_2 or TGF-beta increased mesangial cell apoptosis, predominantly through p53 activation by acetylation, which is a post-transcriptional modification for p53 activation. H_2O … More _2 or TGF-beta-induced apoptosis was significantly attenuated in SIRT1-overexpressing MMCs, but enhanced in SIRT1-knockdown MMCs. We also find that SIRT1 directly interacts with the N-terminus of Smad7. Furthermore, SIRT1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (K64 and K70) on Smad7. In vivo, levels of Smad7 protein expression was reduced by SIRT1-overexpression and increased by SIRT 1-knockdown via modulating smurfl-mediated Smad7 degradation via ubiquitin proteasome action. Our results indicate that SIRT1 can prevent oxidative stress-induced apoptosis through p53 inactivation in mesangial cells and Smad7 is a new target molecule for SIRT1, and functionally SIRT1 attenuates TGFβ-induced vascular cell apoptosis through acceleration of Smad7 degradation. Up-regulation of SIRT1 may provide a new strategy for preventing kidney glomerular diseases. We next examine the target molecules which have the ability to induce SIRT1 by using a protein chip analysis and find that 24 candidates specific to calorie resariction. Less

氧化应激和/或TGF-BetA诱导的肾肾小球细胞凋亡是发展各种肾脏疾病的重要因素。鉴定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无声信息调节剂2（SIRT1）最近被确定为对各种应激源的细胞存活因子，是氧化应激诱导的弥赛亚细胞凋亡的关键调节剂。凋亡细胞死亡（核凝结）的形态特征和生化促凋亡标记的表达[CASPase-3和Poly（ADP-核糖）聚合酶（PARP）的裂解在鼠（MMC_S）中评估在植物（MMC_S）中，这些细胞（MMC_S）暴露于氢（H_2O_2）或TGF-Beta。 H_2O_2或TGF-beta增加了弥赛亚细胞凋亡，主要通过乙酰化通过p53激活，这是p53激活的转录后修饰。 H_2O…在SIRT1过表达的MMC中，更多的_2或TGF-beta诱导的细胞凋亡显着减弱，但在SIRT1-KNOCKDOWN MMC中得到了增强。我们还发现SIRT1直接与SMAD7的N端相互作用。此外，SIRT1逆转了SMAD7上两个赖氨酸残基（K64和K70）的乙酰基转移酶（P300）介导的乙酰化。在体内，通过SIRT1过表达来降低SMAD7蛋白表达的水平，并通过通过泛素蛋白蛋白质体的作用调节SMURFL介导的SMAD7降解，而SIRT 1-KNOCKDOWN通过1敲击增加。我们的结果表明，SIRT1可以通过p53在弥赛亚细胞中的p53失活而防止氧化应激诱导的凋亡，而SMAD7是SIRT1的新靶分子，并且在功能上可以通过加速SMAD7降解来减轻TGFβ诱导的血管诱导的血管细胞凋亡。 SIRT1的上调可能提供了预防肾脏肾小球疾病的新策略。接下来，我们研究具有通过使用蛋白质芯片分析来诱导SIRT1的靶分子，并发现24个针对卡路里竞选的候选者。较少的

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

SIRTl inhibits TGFbeta -induced apoptosis in glomerular mesangial cells via Smad7 deacetylation.

SIRT1通过Smad7脱乙酰化抑制肾小球系膜细胞中TGFβ诱导的细胞凋亡。

DOI：
发表时间：
2007
期刊：
J Biol Chem 282
影响因子：
0
作者：
Kume S;Haneda M;Kanasaki K;Sugimoto T;Araki SI;Isshiki K;Isono M;Uzu T;Guarente L;Kashiwagi A;Koya D
通讯作者：
Koya D

Silent information regulator 2 (SIRT1) attenuates oxidative stress-induced mesangial cell apoptosis via p53 deacetylation

DOI：
10.1016/j.freeradbiomed.2006.02.014
发表时间：
2006-06-15
期刊：
FREE RADICAL BIOLOGY AND MEDICINE
影响因子：
7.4
作者：
Kume, Shinji;Haneda, Masakazu;Koya, Daisuke
通讯作者：
Koya, Daisuke

SIRT1 inhibits TGFbeta-induced apoptosis in glomerular mesangial cells via Smad7 deacetylation.

SIRT1 通过 Smad7 脱乙酰化抑制 TGFbeta 诱导的肾小球系膜细胞凋亡。

DOI：
发表时间：
2007
期刊：
J Biol Chem 282
影响因子：
0
作者：
Kume S;Haneda M;Kanasaki K;Sugimoto T;Araki SI;Isshiki K;Isono M;Uzu T;Guarente L;Kashiwagi A;Koya D
通讯作者：
Koya D

SIRT1 inhibits TGFbeta -induced apoptosis in glomerular mesangial cells via Smad7 deacetylation.

SIRT1 通过 Smad7 脱乙酰化抑制 TGFbeta 诱导的肾小球系膜细胞凋亡。