PMID- 20032114
OWN - NLM
STAT- MEDLINE
DCOM- 20100319
LR  - 20211020
IS  - 1522-1466 (Electronic)
IS  - 0363-6127 (Print)
IS  - 1522-1466 (Linking)
VI  - 298
IP  - 3
DP  - 2010 Mar
TI  - Progressive histone alterations and proinflammatory gene activation: consequences 
      of heme protein/iron-mediated proximal tubule injury.
PG  - F827-37
LID - 10.1152/ajprenal.00683.2009 [doi]
AB  - Rhabdomyolysis (Fe)-induced acute renal failure (ARF) causes renal inflammation, 
      and, with repetitive insults, progressive renal failure can result. To gain 
      insights into these phenomena, we assessed the impact of a single episode of 
      glycerol-induced rhabdomyolysis on proinflammatory/profibrotic [TNF-alpha, 
      monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta1 
      (TGF-beta1)] gene expression and the time course of these changes. CD-1 mice were 
      studied 1-7 days after glycerol injection. Normal mice served as controls. RNA 
      polymerase II (Pol II) binding to the TNF-alpha, MCP-1, and TGF-beta1 genes, 
      "gene-activating" histone modifications [histone 3 lysine 4 (H3K4) trimethylation 
      (H3K4m3) and histone 2 variant H2A.Z], and cognate mRNA levels were assessed. 
      Results were contrasted to changes in anti-inflammatory heme oxygenase-1 (HO-1). 
      Glycerol produced severe ARF (blood urea nitrogen approximately 150-180 mg/dl) 
      followed by marked improvement by day 7 (blood urea nitrogen approximately 40 
      mg/dl). Early increases in TNF-alpha, MCP-1, and TGF-beta1 mRNAs, Pol II gene 
      binding, and H3K4m3/H2A.Z levels were observed. These progressed with time, 
      despite resolution of azotemia. Comparable early HO-1 changes were observed. 
      However, HO-1 mRNA normalized by day 7, and progressive Pol II binding/histone 
      alterations did not occur. Fe-mediated injury to cultured proximal tubule (HK-2) 
      cells recapitulated these in vivo results. Hence, this in vitro model was used 
      for mechanistic assessments. On the basis of these studies, it was determined 
      that 1) the H3K4m3/H2A.Z increases are early events (i.e., they precede mRNA 
      increases), 2) subsequent mRNA elevations reflect transcription, not mRNA 
      stabilization (actinomycin D assessments), and 3) increased transcription, per 
      se, helps sustain elevated H2A.Z levels. We conclude that 1) Fe/glycerol-induced 
      tubular injury causes sustained proinflammatory gene activation, 2) decreasing 
      HO-1 expression, as reflected by mRNA levels, may facilitate this proinflammatory 
      state, and 3) gene-activating histone modifications are early injury events and 
      progressively increase at selected proinflammatory genes. Thus they may help 
      sustain a proinflammatory state, despite resolving ARF.
FAU - Zager, Richard A
AU  - Zager RA
AD  - Fred Hutchinson Cancer Research Center and Department of Medicine, University of 
      Washington, Seattle, Washington 98109, USA. dzager@fhcrc.org
FAU - Johnson, Ali C M
AU  - Johnson AC
LA  - eng
GR  - R37 DK038432/DK/NIDDK NIH HHS/United States
GR  - R37 DK-38432/DK/NIDDK NIH HHS/United States
GR  - R21-DK-083315-01/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20091223
PL  - United States
TA  - Am J Physiol Renal Physiol
JT  - American journal of physiology. Renal physiology
JID - 100901990
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Hemeproteins)
RN  - 0 (Histones)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Membrane Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - E1UOL152H7 (Iron)
RN  - EC 1.14.14.18 (HMOX1 protein, human)
RN  - EC 1.14.14.18 (Heme Oxygenase-1)
RN  - EC 1.14.14.18 (Hmox1 protein, mouse)
RN  - EC 2.7.7.- (RNA Polymerase II)
RN  - PDC6A3C0OX (Glycerol)
SB  - IM
MH  - Acute Kidney Injury/*genetics/metabolism/pathology
MH  - Animals
MH  - Blood Urea Nitrogen
MH  - Cell Survival
MH  - Cells, Cultured
MH  - Chemokine CCL2/genetics
MH  - Disease Models, Animal
MH  - Disease Progression
MH  - Fibrosis
MH  - Gene Expression Regulation
MH  - Glycerol
MH  - Heme Oxygenase-1/metabolism
MH  - Hemeproteins/*metabolism
MH  - Histones/*metabolism
MH  - Humans
MH  - Inflammation Mediators/*metabolism
MH  - Iron/*metabolism
MH  - Kidney Tubules, Proximal/*metabolism/pathology
MH  - Male
MH  - Membrane Proteins/metabolism
MH  - Mice
MH  - RNA Polymerase II/metabolism
MH  - RNA, Messenger/biosynthesis
MH  - Rhabdomyolysis/chemically induced/complications/*genetics/metabolism/pathology
MH  - Time Factors
MH  - Transcriptional Activation
MH  - Transforming Growth Factor beta1/genetics
MH  - Tumor Necrosis Factor-alpha/genetics
PMC - PMC2838607
EDAT- 2009/12/25 06:00
MHDA- 2010/03/20 06:00
PMCR- 2011/03/01
CRDT- 2009/12/25 06:00
PHST- 2009/12/25 06:00 [entrez]
PHST- 2009/12/25 06:00 [pubmed]
PHST- 2010/03/20 06:00 [medline]
PHST- 2011/03/01 00:00 [pmc-release]
AID - 00683.2009 [pii]
AID - F-00683-2009 [pii]
AID - 10.1152/ajprenal.00683.2009 [doi]
PST - ppublish
SO  - Am J Physiol Renal Physiol. 2010 Mar;298(3):F827-37. doi: 
      10.1152/ajprenal.00683.2009. Epub 2009 Dec 23.