ATF3-mediated epigenetic regulation protects against acute kidney injury.
A variety of stress stimuli, including ischemia-reperfusion (I/R) injury, induce the transcriptional repressor ATF3 in the kidney. The functional consequences of this upregulation in ATF3 after renal I/R injury are not well understood. Here, we found that ATF3-deficient mice had higher renal I/R-induced mortality, kidney dysfunction, inflammation (number of infiltrating neutrophils, myeloperoxidase activity, and induction of IL-6 and P-selectin), and apoptosis compared with wild-type mice. Furthermore, gene transfer of ATF3 to the kidney rescued the renal I/R-induced injuries in the ATF3-deficient mice. Molecular and biochemical analysis revealed that ATF3 interacted directly with histone deacetylase 1 (HDAC1) and recruited HDAC1 into the ATF/NF-kappaB sites in the IL-6 and IL-12b gene promoters. The ATF3-associated HDAC1 deacetylated histones, which resulted in the condensation of chromatin structure, interference of NF-kappaB binding, and inhibition of inflammatory gene transcription after I/R injury. Taken together, these data demonstrate epigenetic regulation mediated by the stress-inducible gene ATF3 after renal I/R injury and suggest potential targeted approaches for acute kidney injury.
Li
Hsiao-Fen
HF
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
Cheng
Ching-Feng
CF
Liao
Wei-Ju
WJ
Lin
Heng
H
Yang
Ruey-Bing
RB
D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000502:physiology*; D058186:Acute Kidney Injury / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000235:genetics / Q000502:physiology*; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000502:physiology; D018664:Interleukin-12 / Q000235:genetics / Q000502:physiology; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000235:genetics / Q000502:physiology; D009195:Peroxidase / Q000235:genetics / Q000502:physiology; D015427:Reperfusion Injury / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D015850:Interleukin-6; D019007:P-Selectin; D018664:Interleukin-12; D009195:Peroxidase; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1