Abstract
Retinitis pigmentosa (RP) is characterized by progressive loss of vision due to photoreceptor degeneration leading to secondary inflammation. The urokinase‐type plasminogen activator (uPA) system contributes to retinal inflammation, but its role in RP is unknown. In the rd10 mouse model of RP, we addressed this question with the use of the peptide UPARANT designed to interact with the uPA system. UPARANT was systemically administered from post‐natal day (PD) 10 to PD30 when its efficacy in RP rescue was investigated using electroretinographic recordings, Western blot and immunocytochemistry. Temporal profile of protein expression in the uPA system was also investigated. UPARANT reduced both Müller cell gliosis and up‐regulated levels of inflammatory markers and exerted major anti‐apoptotic effects without influencing the autophagy cascade. Rescue from retinal cell degeneration was accompanied by improved retinal function. No scotopic phototransduction was rescued in the UPARANT‐treated animals as determined by the kinetic analysis of rod‐mediated a‐waves and confirmed by rod photoreceptor markers. In contrast, the cone photopic b‐wave was recovered and its rescue was confirmed in the whole mounts using cone arrestin antibody. Investigation of the uPA system regulation over RP progression revealed extremely low levels of uPA and its receptor uPAR both of which were recovered by HIF‐1α stabilization indicating that HIF‐1 regulates the expression of the uPA/uPAR gene in the retina. Ameliorative effects of UPARANT were likely to occur through an inhibitory action on up‐regulated activity of the αvβ3 integrin/Rac1 pathway that was suggested as a novel target for the development of therapeutic approaches against RP.
Highlights
Retinitis pigmentosa (RP) is a heterogeneous group of genetically inherited blinding disorders for which there are no treatments
In the rd[10] mouse model of RP, we addressed this question with the use of the peptide UPARANT designed to interact with the urokinase‐type plasminogen activator (uPA) system
The finding that HIF‐1α stabilization almost recovers retinal levels of uPA and uPAR suggests a strict correlation between the activity of hypoxia‐inducible factor 1 (HIF‐1) and the expression of uPA/ uPAR in the retina in line with the demonstration that uPA/uPAR gene transcription is mediated by HIF‐1 in models of tumour angiogenesis.[36,37]
Summary
Retinitis pigmentosa (RP) is a heterogeneous group of genetically inherited blinding disorders for which there are no treatments. It occurs in 1 out of 4000 people worldwide and is characterized by progressive photoreceptor loss. RP primarily affects the peripheral retina; it results from a genetic defect in rod photoreceptors and invariably evokes secondary cone photoreceptor loss that causes severe visual dysfunction. In addition to mutations in dozens of different genes, a chronic inflammation may be secondary to the primary genetic defect leading to rod death and gliotic events exacerbating inflammation establishing a positive feedback loop that subsequently strengthens retinal degeneration.[1] The prominent role of inflammation in RP has been supported by several findings in humans and in animal models. The complete knowledge of the events linking neuroinflammation to retinal degeneration is far to be reached
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