Metabolic Deregulation of the Blood-Outer Retinal Barrier in Retinitis Pigmentosa

Abstract

SUMMARY Retinitis pigmentosa (RP) initiates with diminished rod photoreceptor function, causing peripheral and nighttime vision loss. However, subsequent loss of cone function and high-resolution daylight and color vision is most debilitating. Visual pigment-rich photoreceptor outer segments (OS) undergo phagocytosis by the retinal pigment epithelium (RPE), and the RPE also acts as a blood-outer retinal barrier transporting nutrients, including glucose, to photoreceptors. We provide evidence that contact between externalized phosphatidylserine (PS) on OS tips and apical RPE receptors activates Akt, linking phagocytosis with glucose transport to photoreceptors for new OS synthesis. As abundant mutant rod OS tips shorten in RP, Akt activation is lost, and onset of glucose metabolism in the RPE and diminished glucose transport combine to cause photoreceptor starvation and accompanying retinal metabolome changes. Subretinal injection of OS tip mimetics displaying PS restores Akt activation, glucose transport, and cone function in end-stage RP after rods are lost.

Eucalyptol Inhibits Amyloid-β-Induced Barrier Dysfunction in Glucose-Exposed Retinal Pigment Epithelial Cells and Diabetic Eyes

“…Loss of RPE cell to cell junction and impairment of blood-retinal barrier are typical events in retinal degenerative diseases, resulting in vascular leakage and retinal edema in DR and RP [ 2 , 7 , 8 ]. Furthermore, the RPE glucose transport to photoreceptors is diminished in RP, and metabolic deregulation of the blood-outer retinal barrier occurs [ 5 ]. Accordingly, the maintenance of the RPE integrity is vital in the visual functions.…”

“…Diabetic retinopathy (DR) is characterized by abnormal permeability of the blood-retinal barrier, pericyte loss, basement thickening and retinal neuronal abnormalities [ 3 , 4 ]. Ultimately, the disruption of blood-retinal barrier and leakage of the blood contents accompany severe vision loss in both RP and DR [ 5 , 6 , 7 ]. The RPE, a monolayer of end part of retina, locates between the neural retina and the choroid, involving the outer blood-retinal barrier, and supports the structural and functional integrity of the retina [ 8 , 9 ].…”

Tight Junctions of the Outer Blood Retina Barrier

“…In addition, RP may be complicated by cystoid macular oedema (CMO), which represents an important and treatable cause of central visual loss in RP [68]. The underlying pathogenesis remains unclear, however, breakdown of the BRB is a proposed mechanism for the development of CMO in RP [68]. The release of toxic products from the degenerating retina or RPE may cause CMO by disrupting the BRB.…”

Metabolic features of mouse and human retinas: rods vs. cones, macula vs. periphery, retina vs. RPE

“…Conversely, impairment of photoreceptor metabolism also influences RPE health 21 . Accumulating evidence supports the concept that photoreceptors and RPE form an inter-dependent metabolic ecosystem 21,22,23,24,25 . Photoreceptors shed lipid-rich outer segment discs and export lactate due to the Warburg effect; the RPE converts the outer segment discs into ketone bodies to fuel photoreceptors and it utilizes lactate to preserve glucose for photoreceptors 23,26 .…”