Received November 4, 2005
Accepted on August 3, 2007

BASIC RESEARCH

ATF3 Protects against Renal Ischemia-Reperfusion Injury

Takumi Yoshida ^*1, Hidekazu Sugiura ^*, Michihiro Mitobe ^*, Ken Tsuchiya ^*, Satsuki Shirota ^*, Sayoko Nishimura ^*, Shunji Shiohira ^*, Hiroshi Ito , Kiyoshi Nobori , Steven R. Gullans ^||, Takashi Akiba ^*, and Kosaku Nitta ^*

*Department of Medicine IV and Department of Blood Purification, Tokyo Women’s Medical University, Tokyo, Japan; Division of Cardiovascular Medicine, Akita University School of Medicine Akita, Japan; Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan; ||Renal Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Cambridge, Massachusetts

¹ To whom correspondence should be addressed. E-mail: tyoshida{at}kc.twmu.ac.jp.

	Abstract

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.