Endotoxin mediates recruitment of RNA polymerase II to target genes in acute renal failure.

Publication Type:

Journal Article

Source:

Journal of the American Society of Nephrology : JASN, Volume 19, Issue 7, p.1321-30 (2008)

Keywords:

2008, Acute Kidney Injury, Animals, Blood Urea Nitrogen, Chemokine CCL2, Clinical Research Division, Exons, Genes, rRNA, Heme Oxygenase-1, Histones, Kidney Cortex, Kidney Tubules, Proximal, Lipopolysaccharides, Lysine, Maleates, MICE, RNA Polymerase II, RNA, Messenger, Transcription, Genetic, Tumor Necrosis Factor-alpha, Ureteral Obstruction

Abstract:

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.