Results of a study in mice by researchers at the University of California, San Diego strongly suggest that the protein kinase JNK1 plays a key role in the development of retinopathy in premature infants.
Their findings, reported online the week of May 4-9 in advance of print in the Proceedings of the National Academy of Sciences (PNAS), may lead to an effective way to treat the leading cause of childhood blindness in industrialized countries using JNK1 inhibitors.
Retinopathy, damage to the thin layer of cells at the back of the eyeball where light is converted into neural signals sent to the brain, is often caused by the growth of abnormal blood vessels and can lead to loss of vision. Retinopathy of prematurity (ROP) affects infants exposed to high oxygen concentrations as a part of the essential treatment they receive to allow their lungs and other organs to develop after premature birth.
"Paradoxically, it isn't high oxygen levels that damage the retina," explained first author Monica Guma, MD, PhD, of the departments of pharmacology and pathology at the UC San Diego School of Medicine. "Rather, the premature retina is first exposed to a high-oxygen environment and becomes accustomed to it. When the infant is more mature and is returned to a 'normal' oxygen environment, the retina reacts to this hypoxia - or decrease in oxygen availability - as a stress."
The JNK group of protein kinases - discovered in the lab of principal investigator Michael Karin in 1993 - responds to the stress of hypoxia by inducing the over-production of vascular endothelial growth factor (VEGF), which promotes the growth of blood cells. In ROP, as well as in diabetic retinopathy or age-related macular degeneration, this results in vision loss due to aberrant angiogenesis, or unregulated growth of new capillaries from pre-existing blood vessels.
Using a mouse model of ROP, the UC San Diego researchers showed that mice lacking JNK1 exhibited lower levels of VEGF in the retina, so angiogenesis and normal retinal function were barely disrupted.
"We found that injection of a highly specific and cell-permeable JNK peptide inhibitor, D-JNKi, into the mouse retina decreased VEGF expression, thus reducing the abnormal growth of blood vessels that can lead to loss of vision," said UC San Diego investigator Jordi Rius, PhD.