Synthetic triterpenoids attenuate cytotoxic retinal injury: cross-talk between Nrf2 and PI3K/AKT signaling through inhibition of the lipid phosphatase PTEN.
OBJECTIVE
Evidence implicating oxidative stress in the pathogenesis of age-related macular degeneration suggests that antioxidant therapy could play a role in preventing its progression. The aim of this study was to determine whether derivatives of the triterpenoid (TP) 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO; CDDO-imidazolide [-Im], CDDO-ethylamide [-EA], and CDDO-trifluoroethylamide [-TFEA]) confer cytoprotection from oxidative- and photooxidative-induced cellular damage and to explore the molecular mechanisms of this cytoprotection.


METHODS
Retinal pigment epithelial and retinal photoreceptor cell lines were treated with TP derivatives. Induction of Nrf2 signaling was measured by reporter assay. Cytoprotection was quantified by MTT assay. To determine whether TPs confer in vivo cytoprotection, BALB/c mice were pretreated with CDDO-TFEA, and retinal degeneration was induced by light exposure. To explore the association of TPs with PTEN, a biotinylated derivative of CDDO (CDDO-Bt) was used.


RESULTS
Treatment with CDDO-Im-, -TFEA-, or -EA-induced Nrf2 signaling and TP pretreatment protected retinal cell lines from oxidant-induced cell death. The antioxidant and cytoprotective potential of these compounds was then examined in vivo. Treatment of BALB/c mice with CDDO-TFEA induced the Nrf2-regulated transcripts glcl and trx1 in retinal tissue and was protective from photooxidative retinal damage. Treatment with CDDO-Im leads to phosphorylation of AKT. CDDO-Bt directly binds cysteine 124 within PTEN's active site and inhibits PTEN's lipid phosphatase activity in vitro. Thus the stimulation of AKT activity is mediated by TP inhibition of PTEN activity.


CONCLUSIONS
These studies highlight the potential of TPs in retinal cytoprotection and implicate PTEN inhibition as a target in cytoprotection.
Pitha-Rowe
Ian
I
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire, USA.
Liby
Karen
K
Royce
Darlene
D
Sporn
Michael
M
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D019610:Cytoprotection; D053492:Elafin / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D008027:Light / Q000009:adverse effects; D051379:Mice; D008807:Mice, Inbred BALB C; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D018384:Oxidative Stress; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011833:Radiation Injuries, Experimental / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012160:Retina / Q000528:radiation effects; D012162:Retinal Degeneration / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction
C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D053492:Elafin; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C506806:PI3 protein, human; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D009828:Oleanolic Acid; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase