Abstract
Background: In retinitis pigmentosa (RP), inherited rod death is followed by cone loss and blindness. Why cones die is still a matter of consideration. Here, we investigate the pathogenic role of the sympathetic transmission in the rd10 mouse model of RP. Methods: Retinal levels of beta adrenergic receptor (BAR) 2 and norepinephrine (NE) were measured. After administration of the BAR1/2 blocker propranolol or the hypoxia-inducible factor (HIF)-1 activator dimethyloxalylglycine (DMOG), retinal levels of HIF-1α, BAR2 or proteins involved in BAR2 desensitization were also measured. In DMOG treated mice, expression and localization of BAR2, inflammatory markers and cone arrestin were determined. Finally, rd10 mice were subjected to electroretinogram (ERG) analysis to assess rod and cone function. Results: In the rd10 retina, BAR2 overexpression and NE accumulation were found, with BAR2 immunoreactivity localized to Müller cells. BAR2 overexpression was likely due to desensitization defects. Upregulated levels of BAR2 were drastically reduced by propranolol that also restored desensitization defects. Due to the low level of HIF-1 consequent to the hyperoxic environment in the rd10 retina, we hypothesized a link between HIF-1 and BAR2. HIF-1α stabilization with DMOG resulted in i. increased HIF-1α accumulation, ii. decreased BAR2 levels, iii. restored desensitization processes, iv. reduced expression of inflammatory markers and v. increased cone survival without improved retinal function. Conclusions: Our results support a pathogenic role of the sympathetic system in RP that might help to understand why rd10 mice show a positive response to BAR blockers.
Highlights
Retinitis pigmentosa (RP) refers to a family of genetically determined retinal diseases characterized by progressive and irreversible loss of vision due to rod inherited death followed by cone degeneration [1]
Mouse models of retinitis pigmentosa (RP) are characterized by hypoxia-inducible factor (HIF)-1 levels that are about 50% lower than those measured in wild type (WT) mice [5,6]
BAR2 transcripts not differ from those measured in WT mice (Figure 1A)
Summary
Retinitis pigmentosa (RP) refers to a family of genetically determined retinal diseases characterized by progressive and irreversible loss of vision due to rod inherited death followed by cone degeneration [1]. Why cones die following rods in RP is still a matter of consideration. In a rat model of RP, the oxygen tension in the outer retina is about 50% higher than in wild type (WT) rats [3]. This hyperoxic state is accompanied by reduced levels of the transcription factor hypoxia-inducible factor (HIF)-1, which responds to oxygen levels in the retinal environment [4]. In retinitis pigmentosa (RP), inherited rod death is followed by cone loss and blindness. After administration of the BAR1/2 blocker propranolol or the hypoxia-inducible factor (HIF)-1 activator dimethyloxalylglycine (DMOG), retinal levels of HIF-1α, BAR2 or proteins involved in BAR2 desensitization were measured. Due to the low level of HIF-1 consequent to the hyperoxic environment in the rd retina, we hypothesized a link between HIF-1 and BAR2
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