ATF3 protects against renal ischemia-reperfusion injury.
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.
Yoshida
Takumi
T
Department of Internal Medicine IV, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-city, Tokyo, Japan 162-8666. tyoshida@kc.twmu.ac.jp
Sugiura
Hidekazu
H
Mitobe
Michihiro
M
Tsuchiya
Ken
K
Shirota
Satsuki
S
Nishimura
Sayoko
S
Shiohira
Shunji
S
Ito
Hiroshi
H
Nobori
Kiyoshi
K
Gullans
Steven R
SR
Akiba
Takashi
T
Nitta
Kosaku
K
D051700:Activating Transcription Factor 3 / Q000235:genetics* / Q000378:metabolism; D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003404:Creatinine / Q000097:blood; D018014:Gene Transfer Techniques; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D016877:Oxidants; D003404:Creatinine; D006861:Hydrogen Peroxide