Inhibition of oxygen-induced retinopathy in RTP801-deficient mice.

Abstract

PURPOSE:

Ischemic proliferative retinopathy, which occurs as a complication of diabetes mellitus, prematurity, or retinal vein occlusion, is a major cause of blindness worldwide. In addition to retinal neovascularization, it involves retinal degeneration, of which apoptosis is the main cause. A prior report has described the cloning of a novel HIF-1-responsive gene, RTP801, which displays strong hypoxia-dependent upregulation in ischemic cells of neuronal origin, both in vitro and in vivo. Moreover, inducible overexpression of RTP801 promotes the apoptotic death of differentiated neuron-like PC12 cells and increases their sensitivity to ischemic injury and oxidative stress. The purpose of the study was to examine the potential role of RTP801 in the pathogenesis of retinopathy, using RTP801-deficient mice.

METHODS:

Wild-type and RTP801-knockout mice were used in a model of retinopathy of prematurity (ROP). Their retinas were collected at postnatal day (P)14 and P17. They were examined by fluorescein angiography and by analysis of VEGF expression, neovascularization, and apoptosis.

RESULTS:

The expression of RTP801 was induced in the wild-type retina after hypoxia treatment. The retinal expression of VEGF after transfer to normoxic conditions was similarly upregulated in both wild-type and knockout mice. Nevertheless, the retinas of the RTP801-knockout mice in an ROP model showed a significant reduction in retinal neovascularization (P < 0.0001) and in the number of apoptotic cells in the inner nuclear layer (P < 0.0001).

CONCLUSIONS:

In the absence of RTP801 expression, development of retinopathy in the mouse model of ROP was significantly attenuated, thus implying an important role of RTP801 in the pathogenesis of ROP.

• Authors: Anat Brafman, Igor Mett, Millicent Shafir, Helen Gottlieb, Golda Damari, Sabrina Gozlan-Kelner, Vicktoria Vishnevskia-Dai, Rami Skaliter, Paz Einat, Alexander Faerman, Elena Feinstein, Tzipora Shoshani
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 45 Issue 10 Pg. 3796-805 (Oct 2004) ISSN: 0146-0404 [Print] United States
• PMID: 15452091 (Publication Type: Journal Article)

Chemical References

• Adaptor Proteins, Signal Transducing
• DNA-Binding Proteins
• Ddit4l protein, mouse
• Transcription Factors
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse
• Oxygen

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• Apoptosis (physiology)
• DNA-Binding Proteins (deficiency, physiology)
• Disease Models, Animal
• Fluorescein Angiography
• Humans
• Hyperoxia (complications)
• In Situ Hybridization
• Infant, Newborn
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Oxygen (toxicity)
• Retinal Neovascularization (etiology, metabolism, pathology, prevention & control)
• Retinopathy of Prematurity (etiology, metabolism, pathology, prevention & control)
• Transcription Factors (deficiency, physiology)
• Up-Regulation
• Vascular Endothelial Growth Factor A (metabolism)