title: Normoxic activation of hypoxia-inducible factors in photoreceptors provides transient protection against light-induced retinal degeneration.
abstract: OBJECTIVE
  Hypoxic preconditioning activates hypoxia-inducible transcription factors (HIFs) in the retina and protects photoreceptors from light-induced retinal degeneration. The authors tested whether photoreceptor-specific activation of HIFs in normoxia is sufficient for protection.
  
  
  METHODS
  Rod-specific Vhl knockdown mice were generated using the Cre-lox system with the rod opsin promoter controlling expression of CRE recombinase to stabilize HIF transcription factors in normoxic rods. Cell death was induced by light exposure and quantified by ELISA. Rhodopsin was quantified by spectrophotometry. Gene expression was analyzed by real-time PCR, and levels of proteins were determined by Western blotting. Morphology was investigated by light microscopy and retinal function tested by ERG.
  
  
  RESULTS
  The rod-specific Vhl knockdown stabilized HIF-α proteins and induced expression of HIF target genes in retinas of 10-week-old mice under normoxic conditions. Retinal morphology and function were normal. At 36 hours after exposure to excessive light, Vhl knockdowns showed significantly less photoreceptor cell death than did wild-type controls. Ten days after light exposure, however, photoreceptor degeneration in Vhl knockdowns was similar to that of control animals. Vhl knockdowns expressed Fgf2 at higher basal levels before light exposure. After light exposure, however, expression of Fgf2 was not significantly different from that of wild-type controls.
  
  
  CONCLUSIONS
  Artificial activation of HIF transcription factors in normoxic photoreceptors results in an increased basal expression of Fgf2 that may contribute to a transient protection of rods against light damage. Full photoreceptor protection may require a hypoxia-like response in additional retinal cell types and/or the differential regulation of additional mechanisms.
authors: Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Zurich, Switzerland.
authors: Christina
authors: C
authors: Lange
authors: Severin R
authors: SR
authors: Heynen
authors: Naoyuki
authors: N
authors: Tanimoto
authors: Markus
authors: M
authors: Thiersch
authors: Yun-Zheng
authors: YZ
authors: Le
authors: Isabelle
authors: I
authors: Meneau
authors: Mathias W
authors: MW
authors: Seeliger
authors: Marijana
authors: M
authors: Samardzija
authors: Christian
authors: C
authors: Caprara
authors: Christian
authors: C
authors: Grimm
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology / Q000528:radiation effects; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D005838:Genotype; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D019194:Ischemic Preconditioning; D008027:Light / Q000009:adverse effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D012162:Retinal Degeneration / Q000473:pathology / Q000503:physiopathology*; D017948:Retinal Rod Photoreceptor Cells / Q000473:pathology / Q000502:physiology / Q000528:radiation effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C497397:Arnt protein, mouse; C485502:HIF-2 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D016222:Fibroblast Growth Factor 2; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C494469:VHL protein, mouse