IGF-I maintains calpastatin expression and attenuates apoptosis in several models of photoreceptor cell death.
Retinitis pigmentosa is a heterogeneous group of inherited retinal dystrophies in which the loss of photoreceptor cells via apoptosis leads to blindness. In this study we have experimentally mimicked this condition by treating 661W cells and wild-type mouse retinal explants with a Ca(2+) ionophore. Ca(2+) overload induced apoptosis, which was correlated with calpain-2 activation, loss of calpastatin, its endogenous inhibitor, as well as the loss of its transcriptional activator, phospho-cAMP response element binding (CREB). All are similar changes to those observed in the rd1 mouse model of retinitis pigmentosa. Insulin like-growth factor-I (IGF-I) attenuated this Ca(2+)-induced apoptosis, as well as decreased the activation of calpain-2 and maintained calpastatin levels through the activation of the Akt-CREB pathway. Similarly, IGF-I decreased photoreceptor apoptosis in rd1 mouse retinal explants in parallel with reduced activation of calpain-2 and increased levels of calpastatin and activation of phospho-CREB. In conclusion, IGF-I seems to protect neural cells following a physiopathological or an experimental increase in intracellular Ca(2+), an observation that may have therapeutic consequences in neurodegenerative diseases such as retinitis pigmentosa.
Arroba
Ana I
AI
Department of Biochemistry, Bioscience Research Institute, University College Cork, Cork, Ireland.
Wallace
Deborah
D
Mackey
Ashley
A
de la Rosa
Enrique J
EJ
Cotter
Thomas G
TG
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism / Q000633:toxicity; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019610:Cytoprotection; D005455:Fluorescent Antibody Technique; D005456:Fluorescent Dyes; D020287:In Situ Nick-End Labeling; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation; D010786:Photoreceptor Cells / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002135:Calcium-Binding Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D005456:Fluorescent Dyes; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; C033668:calpastatin; D051057:Proto-Oncogene Proteins c-akt; D002154:Calpain; D002118:Calcium