title: Heterogeneity of epigenetic changes at ischemia/reperfusion- and endotoxin-induced acute kidney injury genes.
abstract: Aberrant gene expression is a molecular hallmark of acute kidney injury (AKI). As epigenetic processes control gene expression in a cell- and environment-defined manner, understanding the epigenetic pathways that regulate genes altered by AKI may open vital new insights into the complexities of disease pathogenesis and identify possible therapeutic targets. Here we used matrix chromatin immunoprecipitation and integrative analysis to study 20 key permissive and repressive epigenetic histone marks at transcriptionally induced Tnf, Ngal, Kim-1, and Icam-1 genes in mouse models of AKI; unilateral renal ischemia/reperfusion, lipopolysaccharide (LPS), and their synergistically injurious combination. Results revealed unexpected heterogeneity of transcriptional and epigenetic responses. Tnf and Ngal were transcriptionally upregulated in response to both treatments individually, and to combination treatment. Kim-1 was induced by ischemia/reperfusion and Icam-1 by LPS only. Epigenetic alterations at these genes exhibited distinct time-dependent changes that shared some similarities, such as reduction in repressive histone modifications, and also had major ischemia/reperfusion versus endotoxin differences. Thus, diversity of changes at AKI genes in response to different insults indicates involvement of several epigenetic pathways. This could be exploited pharmacologically through rational-drug design to alter the course and improve clinical outcomes of this syndrome.
authors.affiliation: UW Medicine at Lake Union, University of Washington, Seattle, Washington, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mar
authors.affiliation: UW Medicine at Lake Union, University of Washington, Seattle, Washington, USA.|Computational Medicine Core, Center for Lung Biology, University of Washington, Seattle, Washington, USA.
authors.forename: Sina A
authors.initials: SA
authors.lastname: Gharib
authors.affiliation: The Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Zager
authors.affiliation: The Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Johnson
authors.affiliation: UW Medicine at Lake Union, University of Washington, Seattle, Washington, USA.
authors.forename: Oleg
authors.initials: O
authors.lastname: Denisenko
authors.affiliation: UW Medicine at Lake Union, University of Washington, Seattle, Washington, USA.
authors.forename: Karol
authors.initials: K
authors.lastname: Bomsztyk
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D000072596:Hepatitis A Virus Cellular Receptor 1; D059014:High-Throughput Nucleotide Sequencing; D006657:Histones / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D006657:Histones; C090509:Icam1 protein, mouse; D000071068:Lipocalin-2; D054834:Lipocalins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D015513:Oncogene Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C071332:Lcn2 protein, mouse; D018799:Intercellular Adhesion Molecule-1; D012319:RNA Polymerase II