Active HIF-1 in the normal human retina.
A unique feature of the retina is the presence of photoreceptors, which require an enormous amount of oxygen for the conversion of light to an electrical signal. Hypoxia-inducible factor-1 alpha (HIF-1alpha) is a transcription factor that is the master regulator of cellular adaptation to low oxygen tension. Only in hypoxic conditions is HIF-1alpha protein stabilized and translocated to the nucleus, where it induces transcription of target genes involved in oxygen delivery and energy metabolism. We hypothesized that HIF-1alpha is constitutively stabilized and active in the normal human retina. We investigated the cellular distribution of HIF-1alpha and the expression of its downstream targets, vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT-1), and carbonic anhydrase IX (CAIX), by immunohistochemistry and immunoblotting in the retina of normal rats and human donor eyes. Both human and rat retinas displayed prominent staining of HIF-1alpha in nuclei of most cell types in inner and outer nuclear layers and the ganglion cell layer, a cellular distribution pattern which was confirmed in human retina by immunoblotting of nuclear extracts. A negative correlation was found between HIF-1alpha protein levels and postmortem times. In human retina, staining of VEGF, GLUT-1, and CAIX was found. Our observations indicate that active HIF-1 signaling occurs constitutively in the normal human and rat retina, suggesting that HIF-1 has a physiological role in the retina.
Hughes
John M
JM
Department of Ophthalmology, Academic Medical Center, University of Amsterdam, The Netherlands.
Groot
Arjan J
AJ
van der Groep
Petra
P
Sersansie
René
R
Vooijs
Marc
M
van Diest
Paul J
PJ
Van Noorden
Cornelis J F
CJ
Schlingemann
Reinier O
RO
Klaassen
Ingeborg
I
D000328:Adult; D000368:Aged; D000818:Animals; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D051381:Rats; D017208:Rats, Wistar; D012160:Retina / Q000378:metabolism* / Q000648:ultrastructure
C497442:HIF1A protein, human; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit