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F. Paquet-Durand, S. Hauck, T. van Veen, M. Ueffing, P. Ekström; Activity of Protein Kinase G (PKG) Causes Photoreceptor Degeneration in Two Mouse Models for Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3226.
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© ARVO (1962-2015); The Authors (2016-present)
Photoreceptor degeneration in retinitis pigmentosa (RP) is one of the leading causes of hereditary blindness in the developed world. Although causative genetic mutations are often known, the underlying neuronal degeneration mechanisms still remain to be elucidated. Gene mutations affecting the levels cyclic-guanosine-mono-phosphate (cGMP) are often associated with rapid photoreceptor cell death. We asked whether activity of cGMP-dependent protein kinase (PKG) was involved in retinal degeneration mechanisms.
We used custom made antibodies directed against different PKG isoforms to investigate expression in wild-type (wt) and rd1 retina. We then employed organotypic retinal explant cultures derived from wt, rd1, and rd2 animals to test compounds affecting the activities of either phospodeesterase 6 (PDE6) and/or PKG. To confirm the effects observed in vitro, we utilized three different in vivo application techniques (topical application, intravitreal injection, subtenon injection). For evaluation of the treatment outcomes histological staining, immunofluorescence, immunoblot, and TUNEL techniques were used.
We found expression of PKG1 to be restricted mostly to the photoreceptor layer, whereas PKG2 was expressed in the inner nuclear layer and in ganglion cells. More importantly, we showed that activation of PKG hallmarks photoreceptor degeneration in rd1 and rd2 human homologous mouse models. When induced in wt 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 and increased long-term photoreceptor survival. Likewise, inhibition of PKG in vivo, using three different application paradigms, resulted in 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. PKG1 appears to be the more important isoform in this context. Elevations in cGMP and PKG-dependent cell death may be relevant also in other forms of inherited retinal degeneration.
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