PMID- 18037992
OWN - NLM
STAT- MEDLINE
DCOM- 20080212
LR  - 20230120
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 117
IP  - 12
DP  - 2007 Dec
TI  - Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of 
      epithelial-to-mesenchymal transition.
PG  - 3810-20
AB  - Hypoxia has been proposed as an important microenvironmental factor in the 
      development of tissue fibrosis; however, the underlying mechanisms are not well 
      defined. To examine the role of hypoxia-inducible factor-1 (HIF-1), a key 
      mediator of cellular adaptation to hypoxia, in the development of fibrosis in 
      mice, we inactivated Hif-1alpha in primary renal epithelial cells and in proximal 
      tubules of kidneys subjected to unilateral ureteral obstruction (UUO) using 
      Cre-loxP-mediated gene targeting. We found that Hif-1alpha enhanced 
      epithelial-to-mesenchymal transition (EMT) in vitro and induced epithelial cell 
      migration through upregulation of lysyl oxidase genes. Genetic ablation of 
      epithelial Hif-1alpha inhibited the development of tubulointerstitial fibrosis in 
      UUO kidneys, which was associated with decreased interstitial collagen 
      deposition, decreased inflammatory cell infiltration, and a reduction in the 
      number of fibroblast-specific protein-1-expressing (FSP-1-expressing) 
      interstitial cells. Furthermore, we demonstrate that increased renal HIF-1alpha 
      expression is associated with tubulointerstitial injury in patients with chronic 
      kidney disease. Thus, we provide clinical and genetic evidence that activation of 
      HIF-1 signaling in renal epithelial cells is associated with the development of 
      chronic renal disease and may promote fibrogenesis by increasing expression of 
      extracellular matrix-modifying factors and lysyl oxidase genes and by 
      facilitating EMT.
FAU - Higgins, Debra F
AU  - Higgins DF
AD  - Department of Medicine, Renal Electrolyte and Hypertension Division, University 
      of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
FAU - Kimura, Kuniko
AU  - Kimura K
FAU - Bernhardt, Wanja M
AU  - Bernhardt WM
FAU - Shrimanker, Nikita
AU  - Shrimanker N
FAU - Akai, Yasuhiro
AU  - Akai Y
FAU - Hohenstein, Bernd
AU  - Hohenstein B
FAU - Saito, Yoshihiko
AU  - Saito Y
FAU - Johnson, Randall S
AU  - Johnson RS
FAU - Kretzler, Matthias
AU  - Kretzler M
FAU - Cohen, Clemens D
AU  - Cohen CD
FAU - Eckardt, Kai-Uwe
AU  - Eckardt KU
FAU - Iwano, Masayuki
AU  - Iwano M
FAU - Haase, Volker H
AU  - Haase VH
LA  - eng
GR  - R21 DK072037-02/DK/NIDDK NIH HHS/United States
GR  - R01 DK079912/DK/NIDDK NIH HHS/United States
GR  - P30 DK050306/DK/NIDDK NIH HHS/United States
GR  - R21 DK072037/DK/NIDDK NIH HHS/United States
GR  - P30-DK50306/DK/NIDDK NIH HHS/United States
GR  - DK072037/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (S100 Calcium-Binding Protein A4)
RN  - 0 (S100 Proteins)
RN  - 0 (S100a4 protein, mouse)
RN  - 142662-27-9 (S100A4 protein, human)
RN  - 9007-34-5 (Collagen)
RN  - EC 1.4.3.13 (Protein-Lysine 6-Oxidase)
SB  - IM
MH  - Animals
MH  - Calcium-Binding Proteins/biosynthesis/genetics
MH  - Cell Hypoxia
MH  - *Cell Movement/genetics
MH  - Chronic Disease
MH  - Collagen/biosynthesis/genetics
MH  - Epithelial Cells/*metabolism/pathology
MH  - Extracellular Matrix/genetics/metabolism/pathology
MH  - Fibrosis
MH  - Hypoxia/genetics/*metabolism/pathology
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*biosynthesis/genetics
MH  - Kidney Tubules, Proximal/*metabolism/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Protein-Lysine 6-Oxidase/biosynthesis/genetics
MH  - S100 Calcium-Binding Protein A4
MH  - S100 Proteins
MH  - Signal Transduction/genetics
MH  - Up-Regulation/genetics
MH  - Ureteral Obstruction/genetics/*metabolism/pathology
PMC - PMC2082142
EDAT- 2007/11/27 09:00
MHDA- 2008/02/13 09:00
PMCR- 2007/12/03
CRDT- 2007/11/27 09:00
PHST- 2006/09/27 00:00 [received]
PHST- 2007/09/25 00:00 [accepted]
PHST- 2007/11/27 09:00 [pubmed]
PHST- 2008/02/13 09:00 [medline]
PHST- 2007/11/27 09:00 [entrez]
PHST- 2007/12/03 00:00 [pmc-release]
AID - 30487 [pii]
AID - 10.1172/JCI30487 [doi]
PST - ppublish
SO  - J Clin Invest. 2007 Dec;117(12):3810-20. doi: 10.1172/JCI30487.