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 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.
Interdisciplinary Centre for Clinical Research, University Erlangen-Nuremberg, Erlangen, Germany.
Ruth E
RE
Schietke
Thomas
T
Hackenbeck
Maxine
M
Tran
Regina
R
Günther
Bernd
B
Klanke
Christina L
CL
Warnecke
Karl X
KX
Knaup
Deepa
D
Shukla
Christian
C
Rosenberger
Robert
R
Koesters
Sebastian
S
Bachmann
Peter
P
Betz
Gunnar
G
Schley
Johannes
J
Schödel
Carsten
C
Willam
Thomas
T
Winkler
Kerstin
K
Amann
Kai-Uwe
KU
Eckardt
Patrick
P
Maxwell
Michael S
MS
Wiesener
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D005355:Fibrosis / Q000235:genetics; D015870:Gene Expression / Q000502:physiology; D020868:Gene Silencing / Q000502:physiology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009893:Opossums; D051381:Rats; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1