ATF3-Mediated Epigenetic Regulation Protects against Acute Kidney Injury

Abstract

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-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-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.

Novel Regulatory Action of Ribosomal Inactivation on Epithelial Nod2-Linked Proinflammatory Signals in Two Convergent ATF3-Associated Pathways

“…Although the mechanisms of two pathways for ATF3 downstream regulation in Nod2-activated proinflammatory signal could be different, ATF3 has been found to be an integral signaling molecule that regulates proinflammatory responses triggered by Nod2 activation in the current study as well as TLR activation (by bacterial endotoxins, circulating free fatty acids, reactive oxygen species, high-fat diet, and ischemia reperfusion injury) in previous investigations (14,40,41,74). Therefore, reagents that can modulate ATF3 expression could exert potent anti-inflammatory effects with a broad spectrum, but intervening specific signaling patterns in ATF3 downstream would be required for more delicate therapy in each pathogenic event.…”

“…activation by bacterial infection, ischemia-reperfusion injury, or stress-induced inflammatory responses (13,40,41). These previous studies have indicated that ATF regulates NF-kB expression through epigenetic or transcriptional mechanisms (13,14).…”

MicroRNA-494 Reduces ATF3 Expression and Promotes AKI

“…3,12,13 We found that overexpression of miR-494 elevated IL-6, P-selectin, monocyte chemotactic protein-1 (MCP-1), and polymorphonuclear leukocytes infiltration compared with the control vector after I/R ( Figure 5, A-C and Supplemental Figure 3). Similarly, the renal I/R-induced inflammatory mediators release (IL-6, MCP-1, and P-selectin levels) was decreased with antisense miR-494 overexpression compared with lenti-pSin control after I/R (Supplemental Figure 4, A-C).…”

“…3 The binding between ATF3 and miR-494, which was shown in the in vitro experiment, was further investigated in the kidneys of the mouse I/R model. Using semiquantitative real-time PCR, we found that miR-494 was expressed highly in the liver and brain, moderately in the kidneys, testes, and heart, and lowest in the lung and spleen (Figure 2A).…”

“…Previous study has shown that ATF3-associated histone deacetylases 1 deacetylated histones, which resulted in the condensation of chromatin structure, interference with NF-kB binding, and inhibition of inflammatory gene transcription after I/R injury. 3 Nonetheless, ATF3 gene regulation has not been extensively explored in the kidneys.…”