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

• Published in: PloS one Vol. 7; no. 1; p. e31034
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 2012; Public Library of Science (PLoS)
• Subjects: Anemia; Angiogenesis; Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biology; Cadherins; Cell cycle; Cercopithecus aethiops; COS Cells; Cysts; Deactivation; Epithelial cells; Fibroblasts; Fibrosis; Fibrosis - genetics; Gene Expression - physiology; Gene Silencing - physiology; HEK293 Cells; HeLa Cells; Humans; Hypertension; Hypoxia; Inactivation; Interdisciplinary aspects; Ischemia; Kidney cancer; Kidney Diseases, Cystic - genetics; Kidney Diseases, Cystic - metabolism; Kidney Diseases, Cystic - pathology; Kidney Tubules - metabolism; Kidney Tubules - pathology; Kidney Tubules - physiology; Kidneys; Lesions; Medicine; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasia; Nephrology; Opossums; Oxygen; Physiology; Preservation; Rats; Reperfusion; Rodents; Tumor suppressor genes; Tumorigenesis; Tumors; VHL protein; Von Hippel-Lindau Tumor Suppressor Protein - antagonists & inhibitors; Von Hippel-Lindau Tumor Suppressor Protein - genetics; Von Hippel-Lindau Tumor Suppressor Protein - metabolism; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0031034

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.