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Prolyl-4-Hydroxylases Inhibitor Stabilizes HIF-1a and Increases Mitophagy to Reduce Cell Death After Experimental Retinal Detachment.

Authors: Liu, Haiyang  Zhu, Hong  Li, Tong  Zhang, Pengfei  Wang, Ning  Sun, Xiaodong 
Citation: Liu H, etal., Invest Ophthalmol Vis Sci. 2016 Apr;57(4):1807-15. doi: 10.1167/iovs.15-18066.
Pubmed: (View Article at PubMed) PMID:27082295
DOI: Full-text: DOI:10.1167/iovs.15-18066

PURPOSE: This study investigated the neuroprotective effect against photoreceptor cell death using prolyl-4-hydroxylases inhibitor (PHI), an HIF-1α stabilizer, in experimental retinal detachment (RD).
METHODS: RD was created in Brown Norway rats by subretinal injection of 1% sodium hyaluronate. FG-4592 (a PHI, 25 mg/kg) or a vehicle was administered every 2 days with retro-orbital injection. Photoreceptor death was evaluated by TdT-dUTP terminal nick-end labeling (TUNEL) assay 3 days after RD and by the thickness of the outer nuclear layer 7 days after RD. The mitophagy-related markers Hypoxia Inducible Factor 1α (HIF-1α), BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), autophagy-related gene 5 (Atg5), microtubule-associated protein 1 light chain 3 beta (LC3B), and FUN14 domain containing 1 (FUNDC1) were detected by Western blot and immunofluorescence. Transmission electron microscopy was used to observe ultramicro-morphological changes. Mitochondrial damage was evaluated by the measurement of reactive oxygen species (ROS) by in situ ROS detection with dihydroethidium.
RESULTS: The accumulation of HIF-1α and BNIP3 significantly increased after PHI treatment (P < 0.05), the pattern of Atg5 and LC3 changed, and FUNDC1 and LC3 were colocated. More autophagic vacuoles engulfing mitochondria were observed in transmission electron microscopy sections after PHI treatment when compared with the control. ROS significantly decreased in the PHI-treatment group (P < 0.05). This resulted in reduced TUNEL-positive photoreceptors 3 days after RD and an increased thickness of the outer nuclear layer 7 days after RD (P < 0.05).
CONCLUSIONS: HIF-1α stabilization as a result of PHI treatment, along with the enhancement of mitophagy, could provide protection against photoreceptor injury following RD, which might be mediated by excessive ROS generation.


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CRRD Object Information
CRRD ID: 12738376
Created: 2017-02-02
Species: All species
Last Modified: 2017-02-02
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.