PKG activity causes photoreceptor cell death in two retinitis pigmentosa models.
Photoreceptor degeneration in retinitis pigmentosa is one of the leading causes of hereditary blindness in the developed world. Although causative genetic mutations have been elucidated in many cases, the underlying neuronal degeneration mechanisms are still unknown. Here, we show that activation of cGMP-dependent protein kinase (PKG) hallmarks photoreceptor degeneration in rd1 and rd2 human homologous mouse models. When induced in wild-type retinae, PKG activity was both necessary and sufficient to trigger cGMP-mediated photoreceptor cell death. Target-specific, pharmacological inhibition of PKG activity in both rd1 and rd2 retinae strongly reduced photoreceptor cell death in organotypic retinal explants. Likewise, inhibition of PKG in vivo, using three different application paradigms, resulted in robust photoreceptor protection in the rd1 retina. These findings suggest a pivotal role for PKG activity in cGMP-mediated photoreceptor degeneration mechanisms and highlight the importance of PKG as a novel target for the pharmacological intervention in RP.
Paquet-Durand
François
F
University of Tübingen, Centre for Ophthalmology, Institute for Ophthalmic Research, Division of Experimental Ophthalmology, Röntgenweg 11, Tübingen, Germany. francois.paquet-durand@klinikum.uni-tuebingen.de
Hauck
Stefanie M
SM
van Veen
Theo
T
Ueffing
Marius
M
Ekström
Per
P
D000818:Animals; D015153:Blotting, Western; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005455:Fluorescent Antibody Technique; D020287:In Situ Nick-End Labeling; D007267:Injections; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D012162:Retinal Degeneration / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000201:enzymology / Q000473:pathology*; D012174:Retinitis Pigmentosa / Q000201:enzymology / Q000473:pathology*; D046509:Tissue Culture Techniques; D014822:Vitreous Body
D004791:Enzyme Inhibitors; D017869:Cyclic GMP-Dependent Protein Kinases