Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs.
Cellular responses to oxygen are increasingly recognized as critical in normal development and physiology, and are implicated in pathological processes. Many of these responses are mediated by the transcription factors HIF-1 and HIF-2. Their regulation occurs through oxygen-dependent proteolysis of the alpha subunits HIF-1alpha and HIF-2alpha, respectively. Both are stabilized in cell lines exposed to hypoxia, and recently HIF-1alpha was reported to be widely expressed in vivo. In contrast, regulation and sites of HIF-2alpha expression in vivo are unknown, although a specific role in endothelium was suggested. We therefore analyzed HIF-2alpha expression in control and hypoxic rats. Although HIF-2alpha was not detectable under baseline conditions, marked hypoxic induction occurred in all organs investigated, including brain, heart, lung, kidney, liver, pancreas, and intestine. Time course and amplitude of induction varied between organs. Immunohistochemistry revealed nuclear accumulation in distinct cell populations of each tissue, which were exclusively non-parenchymal in some organs (kidney, pancreas, and brain), predominantly parenchymal in others (liver and intestine) or equally distributed (myocardium). These data indicate that HIF-2 plays an important role in the transcriptional response to hypoxia in vivo, which is not confined to the vasculature and is complementary to rather than redundant with HIF-1.
Wiesener
Michael S
MS
Department of Nephrology and Medical Intensive Care, Charité, Humboldt University Berlin, Germany.
Jürgensen
Jan Steffen
JS
Rosenberger
Christian
C
Scholze
Charlotte K
CK
Hörstrup
Jan H
JH
Warnecke
Christina
C
Mandriota
Stefano
S
Bechmann
Ingo
I
Frei
Ulrich A
UA
Pugh
Christopher W
CW
Ratcliffe
Peter J
PJ
Bachmann
Sebastian
S
Maxwell
Patrick H
PH
Eckardt
Kai-Uwe
KU
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D004386:Duodenum / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000503:physiopathology*; D015151:Immunoblotting; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013687:Telencephalon / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1