PMID- 12885785
OWN - NLM
STAT- MEDLINE
DCOM- 20031202
LR  - 20220311
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 278
IP  - 41
DP  - 2003 Oct 10
TI  - The role of HIF-1 alpha in transcriptional regulation of the proximal tubular 
      epithelial cell response to hypoxia.
PG  - 40296-304
AB  - Epithelial cells of the kidney represent a primary target for hypoxic injury in 
      ischemic acute renal failure (ARF); however, the underlying transcriptional 
      mechanism(s) remain undefined. In this study, human proximal tubular epithelial 
      cells (HK-2) exposed to hypoxia in vitro demonstrated a non-lethal but 
      dysfunctional phenotype, closely reflective of the epithelial pathobiology of 
      ARF. HK-2 cells exposed to hypoxia demonstrated increased paracellular 
      permeability, decreased proliferation, loss of tight junctional integrity, and 
      significant actin disassembly in the absence of cell death. Microarray analysis 
      of transcriptomic changes underlying this response identified a distinct cohort 
      of 48 genes with a closely shared hypoxia-dependent expression profile. Within 
      this hypoxia-sensitive cluster were genes identified previously as 
      hypoxia-inducible factor-1 (HIF-1)-dependent (e.g. vascular endothelial growth 
      factor and adrenomedullin) as well as genes not previously known to be 
      hypoxia-responsive (e.g. stanniocalcin 2). In hypoxia, HIF-1 bound to 
      evolutionarily conserved hypoxia-response elements (HRE) in the promoters of 
      these genes as well as to the HRE consensus motif. A further subset of these 
      genes, not associated with transcriptional regulation by HIF-1, was also present, 
      suggesting alternative HIF-1-independent pathways. Overexpression of HIF-1 alpha 
      in normoxia induced the expression of a significant number of the 
      hypoxia-dependent genes; however, it did not induce the pathophysiologic 
      epithelial response. In summary, hypoxia-elicited alterations in renal proximal 
      tubular epithelial cells in vitro closely resemble the epithelial pathophysiology 
      of ARF. Our data indicate that although this event may rely heavily on 
      HIF-1-dependent gene transcription, it is likely that separate hypoxia-dependent 
      transcriptional regulators also play a role.
FAU - Leonard, Martin O
AU  - Leonard MO
AD  - Conway Institute of Biomolecular and Biomedical Research and the Dublin Molecular 
      Medicine Centre, University College Dublin, Belfield, Dublin 4, Ireland.
FAU - Cottell, David C
AU  - Cottell DC
FAU - Godson, Catherine
AU  - Godson C
FAU - Brady, Hugh R
AU  - Brady HR
FAU - Taylor, Cormac T
AU  - Taylor CT
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20030728
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (DNA, Complementary)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Acute Kidney Injury/genetics/physiopathology
MH  - Base Sequence
MH  - Binding Sites/genetics
MH  - Cell Division
MH  - Cell Hypoxia/*genetics/*physiology
MH  - Cell Line
MH  - DNA, Complementary/genetics/metabolism
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation
MH  - Genes, Regulator
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Kidney Tubules, Proximal/cytology/*physiology
MH  - Oligonucleotide Array Sequence Analysis
MH  - Phenotype
MH  - Promoter Regions, Genetic
MH  - Transcription Factors/genetics/*physiology
EDAT- 2003/07/30 05:00
MHDA- 2003/12/03 05:00
CRDT- 2003/07/30 05:00
PHST- 2003/07/30 05:00 [pubmed]
PHST- 2003/12/03 05:00 [medline]
PHST- 2003/07/30 05:00 [entrez]
AID - S0021-9258(20)83086-5 [pii]
AID - 10.1074/jbc.M302560200 [doi]
PST - ppublish
SO  - J Biol Chem. 2003 Oct 10;278(41):40296-304. doi: 10.1074/jbc.M302560200. Epub 
      2003 Jul 28.