Renal tubular HIF-2α expression requires VHL inactivation and causes fibrosis and cysts

Schietke RE, Hackenbeck T, Tran M, Guenther R, Klanke B, Warnecke C, Knaup KX, Shukla D, Rosenberger C, Koesters R, Bachmann S, Betz P, Schley G, Schoedel J, Willam C, Winkler T, Amann KU, Eckardt KU, Maxwell P, Wiesener MS (2012)

Publication Status: Published

Publication Type: Journal article, Original article

Publication year: 2012

Journal

Publisher: PUBLIC LIBRARY SCIENCE

Book Volume: 7

Article Number: e31034

Journal Issue: 1

DOI: 10.1371/journal.pone.0031034

Abstract

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. © 2012 Schietke et al.

Authors with CRIS profile

Involved external institutions

Charité - Universitätsmedizin Berlin Germany (DE) University College London (UCL) United Kingdom (GB) University of Paris 6 - Pierre et Marie Curie / Université Paris VI Pierre et Marie Curie (UPMC) France (FR)

How to cite

APA:

Schietke, R.E., Hackenbeck, T., Tran, M., Guenther, R., Klanke, B., Warnecke, C.,... Wiesener, M.S. (2012). Renal tubular HIF-2α expression requires VHL inactivation and causes fibrosis and cysts. PLoS ONE, 7(1). https://dx.doi.org/10.1371/journal.pone.0031034

MLA:

Schietke, Ruth E., et al. "Renal tubular HIF-2α expression requires VHL inactivation and causes fibrosis and cysts." PLoS ONE 7.1 (2012).

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