scholarly journals Co-Injection of Sulfotyrosine Facilitates Retinal Uptake of Hyaluronic Acid Nanospheres Following Intravitreal Injection

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1510
Author(s):  
Aiden Eblimit ◽  
Mustafa S. Makia ◽  
Daniel Strayve ◽  
Ryan Crane ◽  
Shannon M. Conley ◽  
...  
Keyword(s):  
Hyaluronic Acid ◽  
Retinal Pigment Epithelium ◽  
Intravitreal Injection ◽  
Targeted Delivery ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Mouse Retina ◽  
Loss Of Function ◽  
Outer Retina ◽  
Fluorescent Reporters

Gene and drug delivery to the retina is a critical therapeutic goal. While the majority of inherited forms of retinal degeneration affect the outer retina, specifically the photoreceptors and retinal pigment epithelium, effective targeted delivery to this region requires invasive subretinal delivery. Our goal in this work was to evaluate two innovative approaches for increasing both the persistence of delivered nanospheres and their penetration into the outer retina while using the much less invasive intravitreal delivery method. We formulated novel hyaluronic acid nanospheres (HA-NS, 250 nm and 500 nm in diameter) conjugated to fluorescent reporters and delivered them intravitreally to the adult Balb/C mouse retina. They exhibited persistence in the vitreous and along the inner limiting membrane (ILM) for up to 30 days (longest timepoint examined) but little retinal penetration. We thus evaluated the ability of the small molecule, sulfotyrosine, to disrupt the ILM, and found that 3.2 µg/µL sulfotyrosine led to significant improvement in delivery to the outer retina following intravitreal injections without causing retinal inflammation, degeneration, or loss of function. Co-delivery of sulfotyrosine and HA-NS led to robust improvements in penetration of HA-NS into the retina and accumulation along the interface between the photoreceptors and the retinal pigment epithelium. These exciting findings suggest that sulfotyrosine and HA-NS may be an effective strategy for outer retinal targeting after intravitreal injection.

Ionized Radiation-Mediated Retinoid Oxidation in the Retina and Retinal Pigment Epithelium of the Murine Eye

2021 ◽  
Author(s):  
Marina A. Yakovleva ◽  
Tatiana B. Feldman ◽  
Kristina N. Lyakhova ◽  
Dina M. Utina ◽  
Inna A. Kolesnikova ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Ionizing Radiation ◽  
Radiation Exposure ◽  
Radiation Effects ◽  
Gamma Ray ◽  
Degradation Products ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Mouse Retina ◽  
Fluorescent Properties

The present study evaluated the effects of proton and gamma-ray ionizing radiation on the mouse eye. The aim of this work was to analyze radiation-mediated retinoid oxidation in the retina and retinal pigment epithelium (RPE). The findings from this analysis can be used to develop a noninvasive method for rapid assessment of the effects of ionizing radiation. Comparative fluorescence and chromatographic analyses of retinoids before and after irradiations were performed. The fluorescent properties of chloroform extracts from irradiated mouse retina and RPE exhibited an increase in fluorescence intensity in the short-wave region of the spectrum (λ < 550 nm). This change is due to increased retinal and RPE retinoid oxidation and degradation products after radiation exposure. Comparative analyses of radiation effects demonstrated that the effect of proton exposure on the retina and RPE was higher than that of gamma-ray exposure. The present study revealed a new approach to assessing the level of radiation exposure in ocular tissues.

scholarly journals Expression of ABCA4 in the retinal pigment epithelium and its implications for Stargardt macular degeneration

2018 ◽  
Vol 115 (47) ◽  
pp. E11120-E11127 ◽  
Author(s):  
Tamara L. Lenis ◽  
Jane Hu ◽  
Sze Yin Ng ◽  
Zhichun Jiang ◽  
Shanta Sarfare ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Wild Type Mouse ◽  
Mouse Retina ◽  
Sequencing Analysis ◽  
Wild Type ◽  
Rpe Cells ◽  
Photoreceptor Outer Segments ◽  
Quantitative Immunoblotting

Recessive Stargardt disease (STGD1) is an inherited blinding disorder caused by mutations in the Abca4 gene. ABCA4 is a flippase in photoreceptor outer segments (OS) that translocates retinaldehyde conjugated to phosphatidylethanolamine across OS disc membranes. Loss of ABCA4 in Abca4−/− mice and STGD1 patients causes buildup of lipofuscin in the retinal pigment epithelium (RPE) and degeneration of photoreceptors, leading to blindness. No effective treatment currently exists for STGD1. Here we show by several approaches that ABCA4 is additionally expressed in RPE cells. (i) By in situ hybridization analysis and by RNA-sequencing analysis, we show the Abca4 mRNA is expressed in human and mouse RPE cells. (ii) By quantitative immunoblotting, we show that the level of ABCA4 protein in homogenates of wild-type mouse RPE is about 1% of the level in neural retina homogenates. (iii) ABCA4 immunofluorescence is present in RPE cells of wild-type and Mertk−/− but not Abca4−/− mouse retina sections, where it colocalizes with endolysosomal proteins. To elucidate the role of ABCA4 in RPE cells, we generated a line of genetically modified mice that express ABCA4 in RPE cells but not in photoreceptors. Mice from this line on the Abca4−/− background showed partial rescue of photoreceptor degeneration and decreased lipofuscin accumulation compared with nontransgenic Abca4−/− mice. We propose that ABCA4 functions to recycle retinaldehyde released during proteolysis of rhodopsin in RPE endolysosomes following daily phagocytosis of distal photoreceptor OS. ABCA4 deficiency in the RPE may play a role in the pathogenesis of STGD1.

Regulation of the renin expression in the retinal pigment epithelium by systemic stimuli

2010 ◽  
Vol 299 (2) ◽  
pp. F396-F403 ◽  
Author(s):  
Vladimir M. Milenkovic ◽  
Marisa Brockmann ◽  
Christian Meyer ◽  
Michael Desch ◽  
Frank Schweda ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Enzyme Inhibitor ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Renin Angiotensin System ◽  
Mouse Retina ◽  
Ang Ii ◽  
Rpe Cells ◽  
Renin Synthesis ◽  
Short Time

The retina expresses a local renin-angiotensin system (RAS). This study aimed to investigate the influence of systemic modulation of renin synthesis on the expression of renin in the retinal pigment epithelium (RPE), which forms part of the blood/retina barrier. Freshly isolated RPE cells showed expression of renin 1A, which is the secreted isoform of renin. Systemic administration of the angiotensin-converting enzyme inhibitor enalapril in mice increased the renin expression in both the kidney and the retina. Systemic infusion of ANG II led to a decrease in the renin expression in the kidney and in the retina and RPE. The ANG II-dependent down-regulation of renin expression in the RPE was prevented by systemic application of the AT1 receptor blocker losartan. However, water deprivation lead to an increase of the renin expression in the kidney but unexpectedly to a decrease of the renin expression in the retina. In sections of the mouse retina, the ANG II receptor AT1 was found in the RPE and localized at the blood side of the epithelium. Short-time cultured RPE cells showed increases in intracellular free Ca2+ in response to stimulation by ANG II that were sensitive to losartan. In summary, we conclude that the renin expression in cells of the blood/retina barrier is influenced by the systemic RAS. ANG II circulating in the plasma is likely a mediator of this influence.

scholarly journals The Retinal Pigment Epithelium Is a Notch Signaling Niche in the Mouse Retina

Cell Reports ◽  
2017 ◽  
Vol 19 (2) ◽  
pp. 351-363 ◽  
Author(s):  
Taejeong Ha ◽  
Kyeong Hwan Moon ◽  
Le Dai ◽  
Jun Hatakeyama ◽  
Keejung Yoon ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Notch Signaling ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Mouse Retina

scholarly journals Expression of molecular equivalent of hypothalamic–pituitary–adrenal axis in adult retinal pigment epithelium

2007 ◽  
Vol 193 (1) ◽  
pp. 157-169 ◽  
Author(s):  
Michal A Zmijewski ◽  
Rajesh K Sharma ◽  
Andrzej T Slominski
Keyword(s):  
Retinal Pigment Epithelium ◽  
Hpa Axis ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Ocular Tissue ◽  
Luciferase Reporter ◽  
Mouse Retina ◽  
Rt Pcr ◽  
Hypothalamic Pituitary Adrenal ◽  
Responsive Element

We have investigated expression of molecular elements of the hypothalamic–pituitary–adrenal (HPA) axis in the human retinal pigment epithelium (RPE) cells. The presence of corticotropin-releasing factor (CRF); urocortins I, II and III; CRF receptor type 1 (CRFR1); POMC and prohormone convertases 1 and 2 (PC1 and PC2) mRNAs were shown by RT-PCR; the protein products were detected by ELISA, western blot or immunocytochemical methods in an ARPE-19 cell line derived from an adult human donor. CRFR2 was below the level of detectability. The CRFR1 was functional as evidenced by CRF stimulation of cAMP and inositol triphosphate production as well as by ligand induction of transcriptional activity of inducible cis-elements cAMP responsive element (CRE), activator protein 1 responsive element (AP-1) and POMC promoter) in ARPE-19 using luciferase reporter assay. Immunoreactivities representative of CRF, pre-urocortin, CRFR1 receptor and ACTH were also detected in mouse retina by in situ immunocytochemistry. Finally, using RT-PCR, we detected expression of genes encoding four key enzymes participating in steroids synthesis (CYP11A1, CYP11B1, CYP17 and CYP21A2) and showed transformation of progesterone into cortisol-immunoreactivity in cultured ARPE-19 cells. Therefore, we suggest that ocular tissue expresses CRF-driven signalling system that follows organisational structure of the HPA axis.

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