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HIF-mediated metabolic switching in bladder outlet obstruction mitigates the relaxing effect of mitochondrial inhibition.

Ekman, Mari LU ; Uvelius, Bengt LU ; Albinsson, Sebastian LU and Swärd, Karl LU (2014) In Laboratory Investigation 94(5). p.557-568
Abstract
Prior work demonstrated increased levels of hypoxia-inducible factor-1α (HIF-1α) in the bladder following outlet obstruction, associated with bladder growth and fibrosis. Here we hypothesized that HIF induction in outlet obstruction also switches energetic support of contraction from mitochondrial respiration to glycolysis. To address this hypothesis, we created infravesical outlet obstruction in female Sprague-Dawley rats and examined HIF induction and transcriptional activation. HIF-1α increased after 6 weeks of outlet obstruction as assessed by western blotting and yet transcription factor-binding site analysis indicated HIF activation already at 10 days of obstruction. Accumulation HIF-2α and of Arnt2 proteins were found at 10 days,... (More)
Prior work demonstrated increased levels of hypoxia-inducible factor-1α (HIF-1α) in the bladder following outlet obstruction, associated with bladder growth and fibrosis. Here we hypothesized that HIF induction in outlet obstruction also switches energetic support of contraction from mitochondrial respiration to glycolysis. To address this hypothesis, we created infravesical outlet obstruction in female Sprague-Dawley rats and examined HIF induction and transcriptional activation. HIF-1α increased after 6 weeks of outlet obstruction as assessed by western blotting and yet transcription factor-binding site analysis indicated HIF activation already at 10 days of obstruction. Accumulation HIF-2α and of Arnt2 proteins were found at 10 days, providing an explanation for the lack of correlation between HIF-1α protein and transcriptional activation. HIF signature targets, including Slc2a1, Tpi1, Eno1 and Ldha increased in obstructed compared with sham-operated bladders. The autophagy markers Bnip3 and LC3B-II were also increased at 6 week of obstruction, but electron microscopy did not support mitophagy. Mitochondria were, however, remodeled with increased expression of Cox4 compared with other markers. In keeping with a switch toward glycolytic support of contraction, we found that relaxation by the mitochondrial inhibitor cyanide was reduced in obstructed bladders. This was mimicked by organ culture with the HIF-inducer dimethyloxalylglycine, which also upregulated expression of Ldha. On the basis of these findings, we conclude that HIF activation in outlet obstruction involves mechanisms beyond the accumulation of HIF-1α protein and that it results in a switch of the energetic support of contraction to anaerobic glycolysis. This metabolic adaptation encompasses increased expression of glucose transporters and glycolytic enzymes combined with mitochondrial remodeling. Together, these changes uphold contractility when mitochondrial respiration is limited.Laboratory Investigation advance online publication, 3 March 2014; doi:10.1038/labinvest.2014.48. (Less)
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organization
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type
Contribution to journal
publication status
published
subject
in
Laboratory Investigation
volume
94
issue
5
pages
557 - 568
publisher
Nature Publishing Group
external identifiers
  • pmid:24589856
  • wos:000335286300008
  • scopus:84899527570
ISSN
1530-0307
DOI
10.1038/labinvest.2014.48
language
English
LU publication?
yes
id
33cff735-4f7f-4ec2-bc5a-28bf2fce6c1f (old id 4383982)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24589856?dopt=Abstract
date added to LUP
2014-04-01 23:11:41
date last changed
2017-09-17 03:35:33
@article{33cff735-4f7f-4ec2-bc5a-28bf2fce6c1f,
  abstract     = {Prior work demonstrated increased levels of hypoxia-inducible factor-1α (HIF-1α) in the bladder following outlet obstruction, associated with bladder growth and fibrosis. Here we hypothesized that HIF induction in outlet obstruction also switches energetic support of contraction from mitochondrial respiration to glycolysis. To address this hypothesis, we created infravesical outlet obstruction in female Sprague-Dawley rats and examined HIF induction and transcriptional activation. HIF-1α increased after 6 weeks of outlet obstruction as assessed by western blotting and yet transcription factor-binding site analysis indicated HIF activation already at 10 days of obstruction. Accumulation HIF-2α and of Arnt2 proteins were found at 10 days, providing an explanation for the lack of correlation between HIF-1α protein and transcriptional activation. HIF signature targets, including Slc2a1, Tpi1, Eno1 and Ldha increased in obstructed compared with sham-operated bladders. The autophagy markers Bnip3 and LC3B-II were also increased at 6 week of obstruction, but electron microscopy did not support mitophagy. Mitochondria were, however, remodeled with increased expression of Cox4 compared with other markers. In keeping with a switch toward glycolytic support of contraction, we found that relaxation by the mitochondrial inhibitor cyanide was reduced in obstructed bladders. This was mimicked by organ culture with the HIF-inducer dimethyloxalylglycine, which also upregulated expression of Ldha. On the basis of these findings, we conclude that HIF activation in outlet obstruction involves mechanisms beyond the accumulation of HIF-1α protein and that it results in a switch of the energetic support of contraction to anaerobic glycolysis. This metabolic adaptation encompasses increased expression of glucose transporters and glycolytic enzymes combined with mitochondrial remodeling. Together, these changes uphold contractility when mitochondrial respiration is limited.Laboratory Investigation advance online publication, 3 March 2014; doi:10.1038/labinvest.2014.48.},
  author       = {Ekman, Mari and Uvelius, Bengt and Albinsson, Sebastian and Swärd, Karl},
  issn         = {1530-0307},
  language     = {eng},
  number       = {5},
  pages        = {557--568},
  publisher    = {Nature Publishing Group},
  series       = {Laboratory Investigation},
  title        = {HIF-mediated metabolic switching in bladder outlet obstruction mitigates the relaxing effect of mitochondrial inhibition.},
  url          = {http://dx.doi.org/10.1038/labinvest.2014.48},
  volume       = {94},
  year         = {2014},
}