PKG activity causes photoreceptor cell death in two retinitis pigmentosa models
PKG activity causes photoreceptor cell death in two retinitis pigmentosa models
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DOI：
10.1111/j.1471-4159.2008.05822.x
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发表时间：
2009-02-01
影响因子：
4.7
通讯作者：
Ekstrom, Per
中科院分区：
文献类型：
--
作者：
Paquet-Durand, Francois;Hauck, Stefanie M.;Ekstrom, Per
视网膜色素变性中的光感受器变性是发达国家遗传性失明的主要原因之一。虽然致病基因突变已在许多情况下阐明，潜在的神经元变性机制仍然是未知的。在这里，我们表明，cGMP依赖性蛋白激酶（PKG）的激活标志着在rd1和rd2人类同源小鼠模型的感光细胞变性。当在野生型视网膜中诱导时，PKG活性是触发cGMP介导的感光细胞死亡所必需的并且是足够的。在rd1和rd2视网膜中PKG活性的靶向特异性药理学抑制强烈降低了器官型视网膜外植体中的感光细胞死亡。同样，使用三种不同的应用范例，在体内抑制PKG，导致鲁棒的光感受器保护在rd1视网膜。这些发现表明PKG活性在cGMP介导的光感受器变性机制中具有关键作用，并突出了PKG作为RP药理学干预的新靶点的重要性。
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.