Schietke, RE and Hackenbeck, T and Tran, M and Günther, R and Klanke, B and Warnecke, CL and Knaup, KX and Shukla, D and Rosenberger, C and Koesters, R and Bachmann, S and Betz, P and Schley, G and Schödel, J and Willam, C and Winkler, T and Amann, K and Eckardt, KU and Maxwell, P and Wiesener, MS (2012) Renal tubular HIF-2α expression requires VHL inactivation and causes fibrosis and cysts. PLOS One , 7 (1) , Article e31034. 10.1371/journal.pone.0031034.
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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.
|Title:||Renal tubular HIF-2α expression requires VHL inactivation and causes fibrosis and cysts.|
|Open access status:||An open access publication. A version is also available from UCL Discovery.|
|Additional information:||© 2012 Schietke et al. 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 credited. This work was supported by grants from the Interdisciplinary Centre for Clinical Research (IZKF), the German Research Foundation (SFB 423) and the Ulrich-Gessler Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.|
|Keywords:||Animals, Basic Helix-Loop-Helix Transcription Factors, COS Cells, Cercopithecus aethiops, Fibrosis, Gene Expression, Gene Silencing, HEK293 Cells, HeLa Cells, Humans, Kidney Diseases, Cystic, Kidney Tubules, Mice, Mice, Inbred C57BL, Mice, Transgenic, Opossums, Rats, Von Hippel-Lindau Tumor Suppressor Protein|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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