Analysis of the retinal gene expression profile after hypoxic preconditioning identifies candidate genes for neuroprotection.
BACKGROUND
Retinal degeneration is a main cause of blindness in humans. Neuroprotective therapies may be used to rescue retinal cells and preserve vision. Hypoxic preconditioning stabilizes the transcription factor HIF-1alpha in the retina and strongly protects photoreceptors in an animal model of light-induced retinal degeneration. To address the molecular mechanisms of the protection, we analyzed the transcriptome of the hypoxic retina using microarrays and real-time PCR.


RESULTS
Hypoxic exposure induced a marked alteration in the retinal transcriptome with significantly different expression levels of 431 genes immediately after hypoxic exposure. The normal expression profile was restored within 16 hours of reoxygenation. Among the differentially regulated genes, several candidates for neuroprotection were identified like metallothionein-1 and -2, the HIF-1 target gene adrenomedullin and the gene encoding the antioxidative and cytoprotective enzyme paraoxonase 1 which was previously not known to be a hypoxia responsive gene in the retina. The strongly upregulated cyclin dependent kinase inhibitor p21 was excluded from being essential for neuroprotection.


CONCLUSIONS
Our data suggest that neuroprotection after hypoxic preconditioning is the result of the differential expression of a multitude of genes which may act in concert to protect visual cells against a toxic insult.
Thiersch
Markus
M
Lab of Retinal Cell Biology, Dept Ophthalmology, University of Zurich, Switzerland. markus.thiersch@usz.ch
Raffelsberger
Wolfgang
W
Frigg
Rico
R
Samardzija
Marijana
M
Wenzel
Andreas
A
Poch
Olivier
O
Grimm
Christian
C
D000818:Animals; D019295:Computational Biology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D016678:Genome / Q000235:genetics; D000860:Hypoxia / Q000235:genetics*; D019194:Ischemic Preconditioning; D008027:Light; D051379:Mice; D018696:Neuroprotective Agents; D020411:Oligonucleotide Array Sequence Analysis; D010100:Oxygen / Q000378:metabolism; D012160:Retina / Q000378:metabolism* / Q000473:pathology*; D012162:Retinal Degeneration / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic / Q000235:genetics
D050759:Cyclin-Dependent Kinase Inhibitor p21; D018696:Neuroprotective Agents; D010100:Oxygen