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

Beitrag in einer Fachzeitschrift
(Originalarbeit)


Details zur Publikation

Autor(en): 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
Zeitschrift: PLoS ONE
Verlag: PUBLIC LIBRARY SCIENCE
Jahr der Veröffentlichung: 2012
Band: 7
Heftnummer: 1
ISSN: 1932-6203


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.



FAU-Autoren / FAU-Herausgeber

Amann, Kerstin Ute Prof. Dr.
Nephropathologische Abteilung im Pathologischen Institut
Betz, Peter Prof. Dr.
Lehrstuhl für Rechtsmedizin
Eckardt, Kai-Uwe Prof. Dr. med.
Medizinische Klinik 4 - Nephrologie und Hypertensiologie
Warnecke, Christina PD Dr.
Medizinische Fakultät
Willam, Carsten Prof. Dr.
Medizinische Klinik 4 - Nephrologie und Hypertensiologie
Winkler, Thomas Prof. Dr.
Professur für Genetik


Autor(en) der externen Einrichtung(en)
Charité - Universitätsmedizin Berlin
Université Pierre et Marie Curie (UPMC, Sorbonne 6)
University College London (UCL) (University of London)


Zitierweisen

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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