Journal
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 21, Issue 6, Pages 1003-1013Publisher
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2009070690
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Funding
- National Taiwan University [97R0066-43]
- Institute of Biomedical Sciences [IBMS-CRC96-P01]
- Academia Sinica [AS-97-FP-L16]
- National Science Council [NSC97-2314-B-320-008, NSC97-2320-B-001-009-MY3, NSC98-2752-B-006-003-PAE, NSC98-2752-B-001-002-PAE, NSC 97-3112-B-001-016]
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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-kappa B 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-kappa B 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.
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