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Nawajes A Mandal, Jerome Cole II, Sufiya Khanam, Megan Stiles, Joseph Wilkerson, Richard Proia; Role of Sphingosine 1-phosphate (S1P) in retinal structure and function- lessons learned from mouse models. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1124.
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© ARVO (1962-2015); The Authors (2016-present)
Sphingolipids (SPL) are essential components of every cell membrane. Recently, a signaling role of bioactive sphingolipids such as ceramide and sphingosine 1-phosphate (S1P) has been established. S1P has pleiotropic cellular signaling roles that includes anti-apoptosis, cell proliferation and formation of cellular junctions. Very little information is available regarding its role in the structural and functional aspects of retina, its development, function and disorders. In mammalian cells, S1P is produced from sphingosine (Sph) by two kinases, sphingosine kinase 1 (SPHK1) and 2 (SPHK2). In this study, we have characterized the retinas of Sphk1 and Sphk2 knockout (KO) mice by structural and functional assessments during normal development and when stressed with damaging lights and determined specific roles of sphingosine kinases and S1P in mammalian retina.
We analyzed eyes of both albino and pigmented Sphk1 KO and Sphk2 KO mice by electroretinography (ERG), OCT (optical coherence tomography), OKT (optokinetic tracking), histology and by electron microscopy at different age points up to 15 months. We subjected albino mice to light-induced retinal degeneration at 500 lux for 10 h and analyzed their retina by histology and ERG after 7 days. We determined SPL profile in retina, plasma, and liver. Littermate wild type mice in similar treatments/ conditions served as controls for each respective experiment.
We found that SIP plays an important role in retinal and retinal pigment epithelial (RPE) structural integrity in aging mice. Ultrastructural analysis of Sphk1 KO mouse retinas aged to 15 months or raised with moderate light stress revealed a degenerated outer limiting membranes (OLM). We found that Sphk1 KO mice have reduced retinal function when raised with moderate light stress. Aged mice had morphological degeneration of the RPE, as well as increased lipid storage vacuoles and undigested phagosomes reminiscent of RPE in age-related macular degeneration. Sphk2 KO retinas were found to be similar to their wild-type counterparts in structure, function and sensitivity to damaging light. However, retinal inflammatory response in Sphk2 KO mice was different from the wild type mice.
These findings show that SIP produced by SPHKs plays a vital role in the structural maintenance and inflammatory responses in mammalian retina.
This is a 2020 ARVO Annual Meeting abstract.
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