ATF3 protects against renal ischemia-reperfusion injury
ATF3 protects against renal ischemia-reperfusion injury
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DOI：
10.1681/asn.2005111155
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发表时间：
2008-02-01
影响因子：
13.6
通讯作者：
Nitta, Kosaku
中科院分区：
文献类型：
--
作者：
Yoshida, Takumi;Sugiura, Hidekazu;Nitta, Kosaku
氧化应激诱导的细胞死亡在缺血性急性肾衰竭的进展中起主要作用。使用微阵列，我们试图确定一个压力诱导的基因，可能是一个治疗的候选人。用过氧化氢（H2 O2）处理人近端小管（HK 2）细胞，并将RNA施加到Affyphin基因芯片上。通过聚类分析，五个基因以平行的时间依赖性方式显著诱导，包括转录激活因子3（ATF 3）、p21（WAF 1/CiP 1）（p21）、CHOP/GADD 153、双特异性蛋白磷酸酶和血红素加氧酶-1。H2 O2在HK 2细胞中快速诱导ATF 3约12倍，在肾缺血-再灌注损伤小鼠模型中约6.5倍。腺病毒介导的ATF 3表达可保护HK 2细胞免受H2 O2诱导的细胞死亡，这与p53 mRNA的减少和p21 mRNA的增加有关。此外，当ATF 3通过腺病毒介导的基因转移在小鼠中过表达时，缺血再灌注损伤减轻。结论：ATF 3对肾缺血再灌注损伤具有保护作用，其机制可能与抑制p53和诱导p21表达有关。
Oxidative stress-induced cell death plays a major role in the progression of ischemic acute renal failure. Using microarrays, we sought to identify a stress-induced gene that may be a therapeutic candidate. Human proximal tubule (HK2) cells were treated with hydrogen peroxide (H2O2) and RNA was applied to an Affymetrix gene chip. Five genes were markedly induced in a parallel time-dependent manner by cluster analysis, including activating transcription factor 3 (ATF3), p21(WAF1/CiP1) (p21), CHOP/GADD153, dual-specificity protein phosphatase, and heme oxygenase-1. H2O2 rapidly induced ATF3 approximately 12-fold in HK2 cells and approximately 6.5-fold in a mouse model of renal ischemia-reperfusion injury. Adenovirus-mediated expression of ATF3 protected HK2 cells against H2O2-induced cell death, and this was associated with a decrease of p53 mRNA and an increase of p21 mRNA. Moreover, when ATF3 was overexpressed in mice via adenovirus-mediated gene transfer, ischemia-reperfusion injury was reduced. In conclusion, ATF3 plays a protective role in renal ischemia-reperfusion injury and the mechanism of the protection may involve suppression of p53 and induction of p21.