Endotoxin mediates recruitment of RNA polymerase II to target genes in acute renal failure.
Acute renal failure (ARF) sensitizes the kidney to endotoxin (LPS)-driven production of cytokines and chemokines. This study assessed whether this LPS hyperresponsiveness exists at the genomic level. Three heterogeneous mouse models of ARF were studied: Maleate nephrotoxicity, unilateral ureteral obstruction, and LPS preconditioning. In all cases, LPS was injected approximately 18 h after injury was induced, and over the next 0 to 90 min, RNA polymerase II recruitment to the genome at three LPS-responsive genes (TNF-alpha, monocyte chemoattractant-1 [MCP-1], and heme oxygenase-1 [HO-1]) was assessed by chromatin immunoprecipitation. LPS hyperresponsiveness was noted in each model, measured by exaggerated increases in TNF-alpha and MCP-1 mRNA (approximately two to 10 times higher than LPS-injected controls). Corresponding increases in the recruitment of RNA polymerase II to the TNF-alpha and MCP-1 genes were observed, and increased trimethylation of histone 3 lysine 4 (H3K4m3) at these sites may have played a role in this recruitment. Conversely, recruitment of RNA polymerase II to the HO-1 gene was suppressed ("tolerance"), and no increase in H3K4m3 was observed at HO-1 exons. The ARF-induced changes in mRNA did not correlate with mRNA stability, suggesting the mechanistic importance of RNA polymerase II-mediated transcriptional events. In conclusion, LPS hyperresponsiveness after ARF is likely mediated at the genomic level, possibly by H3K4m3.
Naito
Masayo
M
Department of Medicine, University of Washington, Seattle, Washington, USA.
Bomsztyk
Karol
K
Zager
Richard A
RA
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism*; D000818:Animals; D001806:Blood Urea Nitrogen; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D005091:Exons; D020459:Genes, rRNA; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D007672:Kidney Cortex / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008239:Lysine / Q000378:metabolism; D008298:Maleates / Q000633:toxicity; D051379:Mice; D012319:RNA Polymerase II / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000150:complications
D018932:Chemokine CCL2; D006657:Histones; D008070:Lipopolysaccharides; D008298:Maleates; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C030272:maleic acid; D051547:Heme Oxygenase-1; D012319:RNA Polymerase II; D008239:Lysine