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Renal Tubular HIF-2α Expression Requires VHL Inactivation and Causes Fibrosis and Cysts
The Hypoxia-inducible transcription Factor (HIF) represents an important adaptive mechanism under hypoxia, whereas sustained activation may also have deleterious effects. HIF activity is determined by the oxygen regulated α-subunits HIF-1α or HIF-2α. Both are regulated by oxygen dependent degradatio...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267769/ https://www.ncbi.nlm.nih.gov/pubmed/22299048 http://dx.doi.org/10.1371/journal.pone.0031034 |
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author | Schietke, Ruth E. Hackenbeck, Thomas Tran, Maxine Günther, Regina Klanke, Bernd Warnecke, Christina L. Knaup, Karl X. Shukla, Deepa Rosenberger, Christian Koesters, Robert Bachmann, Sebastian Betz, Peter Schley, Gunnar Schödel, Johannes Willam, Carsten Winkler, Thomas Amann, Kerstin Eckardt, Kai-Uwe Maxwell, Patrick Wiesener, Michael S. |
author_facet | Schietke, Ruth E. Hackenbeck, Thomas Tran, Maxine Günther, Regina Klanke, Bernd Warnecke, Christina L. Knaup, Karl X. Shukla, Deepa Rosenberger, Christian Koesters, Robert Bachmann, Sebastian Betz, Peter Schley, Gunnar Schödel, Johannes Willam, Carsten Winkler, Thomas Amann, Kerstin Eckardt, Kai-Uwe Maxwell, Patrick Wiesener, Michael S. |
author_sort | Schietke, Ruth E. |
collection | PubMed |
description | The Hypoxia-inducible transcription Factor (HIF) represents an important adaptive mechanism under hypoxia, whereas sustained activation may also have deleterious effects. HIF activity is determined by the oxygen regulated α-subunits HIF-1α or HIF-2α. Both are regulated by oxygen dependent degradation, which is controlled by the tumor suppressor “von Hippel-Lindau” (VHL), the gatekeeper of renal tubular growth control. HIF appears to play a particular role for the kidney, where renal EPO production, organ preservation from ischemia-reperfusion injury and renal tumorigenesis are prominent examples. Whereas HIF-1α is inducible in physiological renal mouse, rat and human tubular epithelia, HIF-2α is never detected in these cells, in any species. In contrast, distinct early lesions of biallelic VHL inactivation in kidneys of the hereditary VHL syndrome show strong HIF-2α expression. Furthermore, knockout of VHL in the mouse tubular apparatus enables HIF-2α expression. Continuous transgenic expression of HIF-2α by the Ksp-Cadherin promotor leads to renal fibrosis and insufficiency, next to multiple renal cysts. In conclusion, VHL appears to specifically repress HIF-2α in renal epithelia. Unphysiological expression of HIF-2α in tubular epithelia has deleterious effects. Our data are compatible with dedifferentiation of renal epithelial cells by sustained HIF-2α expression. However, HIF-2α overexpression alone is insufficient to induce tumors. Thus, our data bear implications for renal tumorigenesis, epithelial differentiation and renal repair mechanisms. |
format | Online Article Text |
id | pubmed-3267769 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-32677692012-02-01 Renal Tubular HIF-2α Expression Requires VHL Inactivation and Causes Fibrosis and Cysts Schietke, Ruth E. Hackenbeck, Thomas Tran, Maxine Günther, Regina Klanke, Bernd Warnecke, Christina L. Knaup, Karl X. Shukla, Deepa Rosenberger, Christian Koesters, Robert Bachmann, Sebastian Betz, Peter Schley, Gunnar Schödel, Johannes Willam, Carsten Winkler, Thomas Amann, Kerstin Eckardt, Kai-Uwe Maxwell, Patrick Wiesener, Michael S. PLoS One Research Article The Hypoxia-inducible transcription Factor (HIF) represents an important adaptive mechanism under hypoxia, whereas sustained activation may also have deleterious effects. HIF activity is determined by the oxygen regulated α-subunits HIF-1α or HIF-2α. Both are regulated by oxygen dependent degradation, which is controlled by the tumor suppressor “von Hippel-Lindau” (VHL), the gatekeeper of renal tubular growth control. HIF appears to play a particular role for the kidney, where renal EPO production, organ preservation from ischemia-reperfusion injury and renal tumorigenesis are prominent examples. Whereas HIF-1α is inducible in physiological renal mouse, rat and human tubular epithelia, HIF-2α is never detected in these cells, in any species. In contrast, distinct early lesions of biallelic VHL inactivation in kidneys of the hereditary VHL syndrome show strong HIF-2α expression. Furthermore, knockout of VHL in the mouse tubular apparatus enables HIF-2α expression. Continuous transgenic expression of HIF-2α by the Ksp-Cadherin promotor leads to renal fibrosis and insufficiency, next to multiple renal cysts. In conclusion, VHL appears to specifically repress HIF-2α in renal epithelia. Unphysiological expression of HIF-2α in tubular epithelia has deleterious effects. Our data are compatible with dedifferentiation of renal epithelial cells by sustained HIF-2α expression. However, HIF-2α overexpression alone is insufficient to induce tumors. Thus, our data bear implications for renal tumorigenesis, epithelial differentiation and renal repair mechanisms. Public Library of Science 2012-01-27 /pmc/articles/PMC3267769/ /pubmed/22299048 http://dx.doi.org/10.1371/journal.pone.0031034 Text en Schietke et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Schietke, Ruth E. Hackenbeck, Thomas Tran, Maxine Günther, Regina Klanke, Bernd Warnecke, Christina L. Knaup, Karl X. Shukla, Deepa Rosenberger, Christian Koesters, Robert Bachmann, Sebastian Betz, Peter Schley, Gunnar Schödel, Johannes Willam, Carsten Winkler, Thomas Amann, Kerstin Eckardt, Kai-Uwe Maxwell, Patrick Wiesener, Michael S. Renal Tubular HIF-2α Expression Requires VHL Inactivation and Causes Fibrosis and Cysts |
title | Renal Tubular HIF-2α Expression Requires VHL Inactivation and Causes Fibrosis and Cysts |
title_full | Renal Tubular HIF-2α Expression Requires VHL Inactivation and Causes Fibrosis and Cysts |
title_fullStr | Renal Tubular HIF-2α Expression Requires VHL Inactivation and Causes Fibrosis and Cysts |
title_full_unstemmed | Renal Tubular HIF-2α Expression Requires VHL Inactivation and Causes Fibrosis and Cysts |
title_short | Renal Tubular HIF-2α Expression Requires VHL Inactivation and Causes Fibrosis and Cysts |
title_sort | renal tubular hif-2α expression requires vhl inactivation and causes fibrosis and cysts |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267769/ https://www.ncbi.nlm.nih.gov/pubmed/22299048 http://dx.doi.org/10.1371/journal.pone.0031034 |
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